Understanding DMG: current treatment options and prospective solutions using nanoparticles.

Introduction

Diffuse Midline Glioma (DMG) is an aggressive, malignant, and currently incurable high-grade glioma primarily affecting children and adolescents. DMG is a broad diagnostic category for high-grade gliomas located in midline structures such as the thalamus, brainstem (pons), and spinal cord, representing 10–20% of all pediatric central nervous system (CNS) tumors. Diffuse Intrinsic Pontine Glioma (DIPG) is the term referred specifically to the subset of DMG located in the pons, typically estimated to account for 10–15% of pediatric CNS tumors. Prognosis remains poor with a median survival of approximately 8–11 months and a less than 2% survival in five years following initial diagnosis [ 1 – 6 ].

The rapid and infiltrative growth of DMG causes the sudden onset of a characteristic constellation of neurological symptoms associated with movement, speech, and swallowing, largely driven by brainstem involvement and compression of the corticospinal tracts. These include: cranial nerve palsies, long-tract signs (e.g., hyperreflexia, Babinski sign, motor deficits), and cerebellar dysfunction (e.g., ataxia, dysmetria) [ 7 ]. However, the precise location of the tumor dictates the patient’s symptoms (e.g., motor deficits result from lesions in the thalamus or spinal cord). Documented cases of extra-neural DMG metastasis exist but are exceedingly rare, with reported rates of ~ 0.4–2% in intracranial gliomas overall and only isolated case reports described in DMG [ 8 – 10 ]. Widespread intracranial spread has been reported, encompassing the brainstem (medulla/midbrain), cerebellum, thalamus, and leptomeninges [ 11 , 12 ].

The molecular pathology of DMG (Fig. 1 ) is predominantly distinguished by a specific oncohistone mutation. According to the 2021 WHO CNS classification, this entity is defined as ‘Diffuse Midline Glioma, H3 K27-altered,’ encompassing both H3K27M mutations and cases with EZHIP overexpression that similarly disrupt histone methylation. The H3K27M mutation, a lysine-to-methionine substitution, occurs in the histone 3 genes H3F3A and HIST1H3B , which encode the H3.3 and H3.1 variants, respectively [ 13 , 14 ]. This mutation inhibits the polycomb repressive complex 2 (PRC2), leading to a global loss of H3K27 trimethylation (H3K27me3) and subsequent transcriptional dysregulation. The resulting epigenetic changes promote unchecked cellular proliferation and tumor growth [ 15 ]. Beyond the defining or driver H3 K27M gene mutations crucial for tumor initiation, DMGs are further characterized by a complex mutational landscape that drives their development and aggressive progression (passenger gene mutations). Mutations in the tumor suppressor gene TP53 are of high prevalence, occurring in approximately 60–80% of cases, and frequently co-occur with H3.3 K27M alterations. This association is key to increased genomic instability, therapeutic resistance to radiation, and a significantly worse prognosis [ 1 , 16 – 18 ]. Another frequent cooperating mutation occurs in the ACVR1 gene in approximately 20–30% of cases, typically found alongside H3.1 K27M mutations, which leads to the overactivation of the bone morphogenetic protein signaling pathway that blocks cell differentiation [ 19 – 21 ]. Amplifications and gain-of-function mutations in the receptor tyrosine kinase gene PDGFRA are also found in 14–21% of cases, promoting cell proliferation and survival by activating downstream signaling pathways like PI3K/AKT/mTOR and Ras/Raf/MEK/ERK [ 22 – 24 ]. Additionally, truncating mutations in the phosphatase-encoding gene PPM1D are found in a subset of DMGs, suppressing the p53-dependent DNA damage response and enhancing tumorigenesis [ 25 ]. Aberrations in cell cycle regulators, such as amplifications of CCND family members and CDK4/6 , lead to bypassing of normal cell cycle control and drive unchecked proliferation [ 26 ]. Finally, mutations in the chromatin remodeling gene ATRX are also observed in some DMGs and contribute to genomic instability, though they are less frequent in H3 K27M tumors than in other pediatric gliomas [ 13 ]. Beyond the established drivers, emerging evidence suggests that mutations in PARP1 may contribute to DMG pathogenesis. Although their precise impact on DNA repair mechanisms is still exploratory, they underline the complex molecular landscape of this malignancy [ 27 ]. Furthermore, in a subset of DMGs (~ 4%) lacking the H3 K27M mutation, aberrant overexpression of enhancer of zeste homolog 2 inhibitory protein (EZHIP) from the CXorf67 gene has been observed. This overexpression mimics the effect of the oncohistone by inhibiting the PRC2 pathway (driver mutation), which in turn leads to global genome remodeling and a similar loss of H3K27 trimethylation [ 28 ].

Fig. 1 The Evolving Molecular Landscape of DMG Progression. Driver mutations fuel tumor development, while passenger mutations act as hitchhikers accumulating during tumor evolution. The figure highlights key temporal changes from diagnosis to recurrence, including Driver and Passenger mutations, and clonal evolution

Given the genomic landscape and poor prognosis of DMG, a better understanding of the tumor microenvironment (TME) is crucial for developing effective therapeutic strategies. Research indicates that DMG fosters a unique microenvironment that differs significantly from other high-grade gliomas (Fig. 2 ). They show an increase in immunosuppressive cells like regulatory T (T reg ) cells and neutrophils, but a decrease in anti-tumor cells such as CD8 + T cells and natural killer (NK) cells. Characterized as an immunologically ‘cold’ microenvironment, this response often shows limited T cell presence, while findings on neutrophil infiltration remain variable across studies. This imbalance is critical, as a higher neutrophil count in the TME is specifically linked to poor prognosis for the patient [ 29 , 30 ]. Immunohistochemical studies to further characterize the immune landscape reveal significantly reduced infiltration of CD163 + and CD68 + macrophages in DMG compared to both high- and low-grade gliomas, with some studies instead identifying a predominance of resident microglia-derived myeloid populations [ 31 ]. Similar, flow cytometry data confirmed a lower abundance of CD3 + lymphocytes and an increased presence of CD11b+ myeloid cells in DMG compared to adult glioblastoma (GBM) [ 30 ]. The expression of cytokines and immune checkpoint inhibitors in DMG also deviates from other gliomas.

Fig. 2 Schematic displaying the unique TME of DMG. Schematic displaying the unique TME of DMG with decreased infiltration of common tumor immune mediators such as neutrophils, CD8 + T cells, and natural killer cells in comparison to other High Grade Gliomas

Studies have shown that PD-L1 levels are similar or even decreased, and there is no significant increase in the expression of immune checkpoints such as PD-1, PD-L2, or CTLA-4 [ 30 – 32 ]. The observed scarcity of these immune mediators suggests a uniquely immune-suppressive environment in DMG. While the DMG TME remains under investigation, Fig. 2 illustrates that the decreased infiltration of T cells, macrophages, and key cytokines, along with low immune checkpoint expression (≤ 1%) relative to other HGGs like GBM (~ 60%), offers a plausible explanation for the aggressive nature of DMG and the limited efficacy of checkpoint inhibitor therapies [ 30 – 32 ]. This suggests a promising new treatment pathway that focuses on strategies to increase the recruitment of these specific cell types to the tumor site.

The inability of historical clinical trials to improve patient outcomes necessitates a rigorous evaluation of past therapeutic strategies to guide future innovation. To address the ongoing challenges in DMG treatment, this review will perform a three-part analysis. First, we will examine the evolution of DMG treatment strategies, tracing the trajectory from foundational therapeutic approaches to current emerging targeted and immunotherapeutic interventions under investigation. Next, we will analyze the application of nanoparticles (NPs) in brain cancers to understand their potential and limitations. Finally, we will explore how the emergent field of nano-scaled materials offers avenues for improving DMG therapy, guided imaging, and diagnosis.

Managing diagnostic approach and standard-of-care for DMG

Diagnosis of DMG in non-brainstem locations can benefit from surgical biopsy when required, while diagnosis of pontine DMG is frequently established by correlating the patient’s clinical history and characteristic radiologic findings with biopsy serving a more nuanced role. The Magnetic Resonance Imaging (MRI) typically demonstrates ( Fig. 3 ) a diffusedly infiltrative lesion involving > 50% of the pons, with associated expansion, a hypointense signal on T1-weighted images, a hyperintense signal on T2-weighted images and encasement of the basilar artery [ 33 , 34 ]. While contrast uptake or rim enhancing portions of the mass may be present, a notable lack of enhancement after gadolinium contrast administration, is what differentiates DMG from other CNS tumors [ 35 ].

Fig. 3 MRI-based radiomics for prognosis of a pediatric H3 K27-altered DMG (Courtesy Neurosurgery, Children’s Hospital Los Angeles) ( A ) T1-weighted pre-contrast axial MRI: infiltrative, expansile tumor in pons, slightly hypointense with mass effect on fourth ventricle (*) ( B ) T2-weighted axial MRI: slightly hyperintense signal throughout the tumor ( C ) T1 post-contrast axial MRI: minimal to no enhancement. The hyperintense and hypointense in MRI scans describe the relative brightness of the tumor tissue compared to the surrounding or normal brain tissue

While surgical biopsy for classically appearing DMG was historically controversial, stereotactic biopsy has become increasingly accepted in modern clinical practice, with reported overall complication rates of approximately 5–10% in experienced centers [ 36 – 39 ]. This paradigm shift is driven by three main factors: (i) the use of molecular genomics to identify actionable target mutations, (ii) the requirement of tissue for clinical trial enrollment, and (iii) enhanced safety profiles in modern neurosurgical stereotaxis, which has significantly reduced the morbidity and mortality rates reported in previous decades [ 40 – 42 ]. Despite these advances, the procedure remains risky for pediatric patients. To address this, liquid biopsy of blood and cerebrospinal fluid (CSF) has emerged as a safer, minimally invasive method for monitoring tumor evolution via circulating tumor DNA (ctDNA) [ 43 – 46 ].

Although pontine DMG is not surgically resectable, the role of resection or debulking for non-brainstem DMG remains to be established. Such procedures require careful evaluation of involved structures and a balance of risks versus benefits, particularly considering the limited outcomes data for H3K27M-mutated tumors.

Treatment efficacy is severely limited because most therapeutics, particularly chemotherapy, cannot effectively reach the tumor site [ 36 ]. This is primarily due to the blood-brain barrier (BBB), which is especially restrictive in the pons where 80% of H3 K27-altered DMGs originate [ 47 ] and where drug efflux transporters are also present, further reducing drug concentration [ 48 ]. The unique DMG microenvironment and potential anisotropic effects following chemotherapy which decreases the agents’ diffusional capacity also contribute to making conventional cancer treatments ineffective [ 49 ].

Radiotherapy has been the mainstay of treatment for DMG since the 1970s. Current standard of care includes fractionated focal radiation—typically 54–60 Gy over six weeks—using techniques such as intensity-modulated radiation therapy (IMRT). While this approach can provide symptomatic and quality of life improvements with temporary reduction in tumor size, disease progression usually occurs within six months, with an estimated survival advantage quoted as approximately three months [ 50 , 51 ]. Both hypo-fractionation and hyper-fractionation of radiation therapy for DMG have failed to improve survival rates. Doses below 50 Gy are linked to worse outcomes, while doses above 66 Gy offer no additional survival benefit [ 52 , 53 ]. Re-irradiation of progressive tumors shows promise, although increased risk of cumulative radiation necrosis must be considered when weighing the value of this treatment option [ 54 – 56 ]. Supportive treatment often includes corticosteroids to manage peri-tumoral edema (brain swelling). While 70–80% of patients see some neurological improvement from corticosteroids, over 50% experience significant side effects from the medication [ 57 ].

Therapeutic strategies in dmg clinical trials

Chemotherapy

Traditional chemotherapies, including cisplatin [ 58 ], carboplatin [ 59 ], temozolomide [ 60 ], motexafin gadolinium [ 2 ], tamoxifen [ 61 ], and methotrexate [ 62 ], have failed to improve survival outcomes in DMG, whether used alone, in combination, or alongside radiotherapy. Clinical trials consistently report a median overall survival (OS) of 9–11 months (Table 1 ), showing no significant advantage over radiation therapy alone, which yields median OS rates of 12.0, 10.2, and 7.9 months for conventional, hyperfractionated, and hypofractionated regimens, respectively [ 63 ]. This lack of success is likely due to a combination of inadequate drug delivery and factors within the TME [ 2 , 50 , 60 , 64 - 72 ].

Table 1 Summary of survival metrics comparing radiation and chemoradiation trials for DMG Treatment regimen Median overall survival Radiation therapy (RT) 7.9 - 12.0 months RT + Cisplatin 8.5 months RT + carboplatin 9 months RT + Temozolomide 9.6 months RT + Motexafin gadolinium 8.4 months RT + Tamoxifen 6.31 months RT + Methotrexate 12.5 months

Targeted drug therapies for DMG patients have shown promise. Recent advances include dordaviprone (formerly ONC201, brand name Modeyso), which received accelerated FDA approval in August 2025 for treating progressive H3 K27M-mutant DMG based on surrogate endpoints in a relapsed setting. However, this approval is conditional, and long-term survival benefit remains under investigation in the Phase 3 clinical trial ( NCT05580562 ), which is currently evaluating which is currently evaluating dordaviprone efficacy in newly diagnosed patients. The oral imipridone medication works by antagonizing the dopamine receptor D2 (DRD2) and acting as an agonist for the mitochondrial protease ClpP. The mechanism of imipridone action involves activation of the integrated stress response, which leads to selective apoptosis in cancer cells [ 73 ]. The PI3K/AKT/mTOR signaling pathway is frequently dysregulated in DMG, making it a target for therapy. Approximately 15–20% DMG cases present mutations in phosphatidylinositol 3-kinase (PIK3CA) gene. Current therapeutic strategies include testing the mTOR inhibitor, Everolimus and PI3K inhibitor, Paxalisib , in combination with other agents (e.g. NCT03387020 , NCT05009992 , NCT05843253 ) [ 74 ]. Fig. 4 summarizes the available DMG management strategies, including a comparison of their benefits and drawbacks.

Fig. 4 Current and Emerging Management Strategies for DMG: Overview of current (radiation, surgical resection, chemotherapy) and investigational (immunotherapy, next generation) strategies (Purple), showcasing their efficacy and constraints (Pink) and their mechanisms (Blue) in DMG management

CAR T cell therapy

The field of cancer immunotherapy has advanced significantly, leveraging the patient’s own immune system to combat malignancy. A well accepted strategy involves chimeric antigen receptor (CAR) T-cell therapy, which has achieved notable success in hematologic cancers and is currently being explored for solid tumors. CAR T cells are genetically engineered to express synthetic receptors that bind to specific tumor antigens, providing a mechanism to overcome the ability of cancer cells to escape attack by the innate immune system. Targeting the disialoganglioside GD2 with CAR T cells has emerged as a promising strategy for glioma therapy. Due to its selective overexpression in the malignant tissue of several cancer types and minimal presence in healthy tissue, GD2 serves as an ideal tumor-associated antigen. Despite being a small cohort of patients, a recent study focusing on H3 K27-mutated gliomas ( NCT04196413 ) demonstrates the potential of GD2 directed CAR T cell therapy to induce significant clinical and radiographic improvements with tumor shrinkage of 50–98% observed in 7 of 11 patients and a median survival approaching 2 years, substantially exceeding historical expectations [ 75 ]. B7-H3, a transmembrane protein overexpressed on DMG cells, has also emerged as a viable target for CAR-T cell therapy. Engineered constructs directed against this molecule are now being evaluated in clinical trials [ 76 ]. Furthermore, the IL13Rα2 antigen is found to be overexpressed on about half of all pediatric brain tumors. A CAR T-cell therapy trial ( NCT04510051 ) specifically targeting IL13Rα2-positive, recurrent or refractory pediatric brain tumors posted on August 12, 2020 is also recruiting children with DMG [ 77 ]. However, CAR T-cell therapy for DMG carries critical safety risks, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), tumor-inflammation associated neurotoxicity (TIAN) and oedema. These can lead to pseudoprogression and severe increased intracranial pressure. Furthermore, on-target, off-tumor effects remain a significant concern due to potential antigen expression on healthy CNS tissue, necessitating the need for careful patient monitoring and specialized supportive management [ 75 , 78 ].

Vaccines

The rationale for using vaccines in pediatric brain tumors is to harness the immune system to fight cancer cells with greater specificity and reduced toxicity compared to traditional therapies [ 79 ]. After administration of autologous dendritic cell vaccines that activate T-cells, one clinical trial demonstrated a DIPG/DMG-specific immune response [ 80 ]. Similar anti-tumor responses have also been observed in small patient studies using the immune antibody Pidilizumab and genetically modified adenoviruses [ 81 , 82 ]. An ongoing phase I clinical trial ( NCT04943848 ) is testing a neoantigen peptide-based vaccine—combining a heat shock protein with 16 H3 K27-altered DMG-specific peptides—to evaluate its ability to boost immune recognition of tumor cells. While these results show potential, expanding patient cohorts and mitigation of adverse effects are necessary to facilitate clinical translation for DMG treatment.

Image-guided noninvasive therapies

Novel, image-guided multi-modal strategies are emerging to selectively target malignant tumors. Among these, sonodynamic therapy (SDT), combines low-intensity ultrasound with a prodrug, 5-aminolaevulinic acid (5-ALA) to target tumors. 5-ALA serves as a prodrug that preferentially accumulates in rapidly dividing tumor cells, where it is metabolized into the photosensitizer protoporphyrin IX (PpIX) by disrupting the heme biosynthetic pathway while sparing the healthy tissue. Subsequent excitation of PpIX by MRI-guided focused ultrasound generates cytotoxic reactive oxygen species (ROS), triggering apoptosis. Pre-clinical results from animal models showed inhibition of tumor growth and extended survival [ 83 , 84 ]. Following a successful Phase 0/1 safety trial ( NCT04559685 ) [ 85 ], a Phase 2 study ( NCT05123534 ) is currently underway to optimize protocols and evaluate clinical efficacy in DMG. Table 2 summarizes the major treatment strategies in clinical trial in the United States for DMG, including associated benefits and pitfalls [ 86 , 87 ]. Although some of these strategies have shown preclinical therapeutic efficacy, none have yet demonstrated considerable survival improvement for patients.

Table 2 Summary of Ongoing and Completed Clinical Trials including DMG Patients [ 86 , 87 ] Detailed description of the therapeutic/trials, including phase, ClinicalTrials.gov identifier, administration, mechanism, & indication Active Trials Drug/Trial # NCT# Phase Route of Administration Age Group Molecular Target/Mechanism Indication(s) Immunotherapy APX005M NCT03389802 I IV Pediatrics CD40 Agonist DMG, Recurrent/refractory CNS tumors B7-H3 CAR-T NCT04185038 I Intracranial Pediatrics Young Adults B7-H3 DMG Recurrent/refractory CNS tumors B7-H3, EGFR806, HER2, & IL13-Zetakine (Quad) CAR T Cells NCT05768880 I Intracranial Pediatrics Young Adults B7-H3 EGFR806 HER2 IL13Rα2 DMG, Recurrent/refractory CNS tumors C7R-GD2.CAR T Cells NCT04099797 I IV ± Intracranial Pediatrics Young Adults GD2 GD2-expressing brain tumors GD2 CAR T Cells NCT05298995 I Intracranial Pediatrics Young Adults GD2 GD2-expressing brain tumors Loc3CAR NCT05835687 I IV Pediatrics PD-1/PD-L1 axis Primary CNS tumors Pembrolizumab NCT02359565 I IV Pediatrics Young Adults PD-1 pathway DMG, Medulloblastoma, Refractory HGG, Ependymoma PNOC018 NCT05478837 I Intracranial Pediatrics Young Adults CAR-T H3.3K27M-Mutated Glioma ReMIND NCT03652545 I IV Pediatrics Adults WT1, PRAME, & survivin tumor-associated antigens CNS malignancies (including DMG) Targeted Therapy Abemaciclib NCT02644460 I PO Pediatrics Young Adults mTOR pathway DMG Abemaciclib NCT05298995 I Intracranial Pediatrics Young Adults GD2 DMG Solid brain/spinal tumors ACT001 NCT06838676 I PO Pediatrics PI3K/AKT/mTOR pathway DMG HGG AflacST1901 NCT04334863 I PO Pediatrics PI3K/mTOR Recurrent/ progressive malignant brain tumors, Melanoma CLR 131 NCT03433183 I PO Pediatrics CDK4/6 Relapsed/refractory solid & brain tumors Lymphoma Fimepinostat NCT03893487 I PO Pediatrics Young Adults HDAC inhibitor DMG, Medulloblastoma, HGG Larotrectinib NCT04655404 I PO Pediatrics DRD2 antagonist/DIpP agonist HGG Marizomab + Panobinostat NCT04341311 I PO Pediatrics EZH2 DMG ONC206 NCT04732065 I PO Pediatrics Young Adults DNA damage/ PARP pathway DMG, Recurrent malignant CNS tumors Precision Medicine and Adoptive Cellular Therapy (PEACH) NCT04837547 I PO Pediatrics Young Adults MAPK/ MEK pathway DMG Recurrent neuroblastoma Savolitinib (PBTC49) NCT03598244 I PO Pediatric Kinase inhibition DMG, Medulloblastoma HGG 9-ING-41 +/- irinotecan NCT04239092 I/II PO Pediatrics Young Adults Epigenetic modulation Refractory CNS tumors Avapritinib NCT04773782 I/II PO Pediatrics Kinase inhibition Relapsed/refractory solid tumors Cabozantinib NCT02885324 I/II PO Pediatrics Histone modification Recurrent/ progressive malignant brain tumors CBL0137 NCT01981525 I/II PO Pediatrics Targeted kinase pathway Progressive/refractory CNS tumors, Lymphoma Lutathera NCT05278208 I/II PO Pediatrics Young Adults VEGF CNS tumors Meningiomas Oral AMXT 1501 Dicaprate + IV DFMO NCT05500508 I/II PO Pediatrics PI3K/AKT pathway DMG Ribociclib + Everolimus NCT03387020 I/II PO Pediatrics Young Adults CDK4/6 DMG ONC201 + Panobinostat or Paxalisib NCT05009992 II IV ± Image-guided delivery Pediatrics Young Adults Drug delivery enhancement radiosensitization DMG ONC201 Following Radiotherapy (ACTION) NCT05580562 III PO Pediatrics Adults Targeted small-molecule therapy DMG Chemotherapy BXQ-350 NCT04771897 I IV Pediatrics Cytotoxic DMG Gemcitabine NCT02992015 I IV Pediatrics DNA synthesis inhibition DMG Unesbulin NCT03605550 I Oral ± IV Pediatrics Alkylating agent DMG, HGG Pediatric MATCH trial NCT03155620 II IV Pediatrics Cytotoxic Solid tumors, NHL Histiocytic disorders HIT-HGG-2013 NCT03243461 III IV Pediatrics Cytotoxic GBM, Anaplastic astrocytoma DMG, Gliomatosis cerebri Radiation Stereotactic Biopsy Split-Course Radiation Therapy NCT05077735 II External beam radiation Pediatrics DNA damage DMG Vaccine PEP-CMV NCT03299309 I Intradermal/ subQ Pediatrics Young Adults Tumor-specific neoantigens Medulloblastoma Grade III or IV gliomas SurVaxM (PBTC-060) NCT05163080 I Intradermal Pediatrics Tumor antigen-specific immune activation Medulloblastoma, Astrocytoma, DMG, GBM, Oligodendroglioma, Ependymoma Image-Guided Therapy Exablate Focused Ultrasound + Doxorubicin NCT05009992 I/II Image-guided; IV Pediatrics Young Adults Drug delivery enhancement DMG MTX110 delivered by convection-enhanced delivery (CED) NCT03566199 I/II Convection-enhanced delivery (CED); intracranial Pediatrics Young Adults Local drug delivery DMG SONALA-001 + Exablate 4000 Type 2.0 NCT05123534 II Oral + MRI-guided ultrasound Pediatrics Young Adults ROS generation DMG Combination Adavosertib + Local Radiation Therapy NCT01922076 I IV + radiation Pediatrics Chemo-radiation DMG Adoptive Cellular Therapy During Focal Radiotherapy +/- Temozolomide NCT03396575 I PO + radiation Pediatrics Young Adults Targeted + radiation synergy Brainstem gliomas Convection-Enhanced Delivery (CED) of MTX110 NCT03566199 I CED Pediatrics Local delivery DMG Focused Ultrasound (FUS) + oral panobinostat NCT04804709 I PO + IV Pediatrics Multi-pathway inhibition DMG FUS Etoposide NCT05762419 I PO + immunotherapy Pediatrics Targeted + immune therapy DMG HSC-DIPGVax + Balstilimab + Zalifrelimab NCT04943848 I Intradermal Pediatrics H3K27M neoantigen vaccine DMG Vorinostat + Temsirolimus +/- Radiation NCT02420613 I IV Pediatrics Chemotherapy DMG Abemaciclib (LY2835219) + temozolomide +/- irinotecan, Dinutuximab, GM-CSF NCT04238819 I/II PO Pediatrics Targeted + epigenetic Relapsed/refractory solid tumors Neuroblastoma H3.3K27M Peptide Vaccine + Nivolumab NCT02960230 I/II IV Pediatrics Young Adults Chemotherapy + radiation DMG Optune device + radiation NCT03033992 I/II PO Pediatrics Young Adults Targeted therapy combination HGG, Ependymoma DMG Palbociclib + Chemotherapy NCT03526250 I/II PO Pediatrics Young Adults Multi-pathway inhibition Recurrent/refractory solid tumors REGN2810 + Radiotherapy NCT03690869 I/II PO + IV Pediatrics Targeted + chemotherapy Relapsed/refractory solid or CNS tumors Selinexor + Radiation Therapy NCT05099003 I/II PO Pediatrics Young Adults Targeted Therapy HGG DMG Indoximod + Chemotherapy + Radiation NCT04049669 II PO Pediatrics Young Adults Targeted Therapy Progressive brain tumors DMG Methotrexate + radiation NCT00278278 II IV Pediatrics Chemotherapy HGG, DMG Completed Trials Immunotherapy Wild-type reovirus + sargramostim NCT02444546 I IV Pediatrics PD-1 Recurrent/refractory brain tumors Pomalidomide NCT03242460 I/II IV Pediatrics Young Adults PD-1/CTLA-4 Recurrent/progressive CNS tumors Pegylated Interferon Alfa 2b NCT07231276 II IV Pediatrics Immune checkpoint modulation DMG Targeted Therapy Abemaciclib NCT05413304 I Intracranial Pediatrics, Young Adults CAR-T/tumor-associated antigen Recurrent/refractory solid/brain tumors, DMG Crenolanib NCT01522469 I IV Pediatrics, Young Adults PD-1/PD-L1 axis DMG HGG Crizotinib + Dasatinib NCT01644773 I IV Pediatrics CTLA-4 DMG HGG GDC-0084 NCT03696355 I IV Pediatrics PD-1 checkpoint inhibition DMG INCB7839 NCT04295759 I IV Pediatrics Immune checkpoint inhibition/ T-cell activation HGG, DMG Panobinostat NCT02717455 I IV Pediatrics Immune checkpoint pathway DMG Recurrent/progressive HGG Ribociclib + Everolimus NCT05843253 I IV Pediatrics Young Adults Immune modulation DMG HGG Ad-RTS-hIL-12 + Veledimex NCT03330197 I/II IV Pediatrics Young Adults Immune checkpoint/ cytokine modulation DMG Panobinostat (MTX100) NCT03566199 I/II CED Pediatrics Local drug delivery DMG Depatuxizumab Mafoditin (ABT-414) +/- Temozolomide or Lomustine NCT02343406 II PO Pediatrics Adults Targeted kinase inhibition EGFR-amplified gliomas Chemotherapy Mebendazole NCT02644291 I PO Pediatrics Targeted small-molecule therapy Pediatric gliomas Intra-arterial delivery of Melphalan Hydrocholoride NCT01688401 I/II IV Pediatrics VEGF Recurrent/refractory CNS tumors Mebendazole + vincristine, carboplatin, and temozolomide NCT01837862 I/II PO Pediatrics Kinase pathway LGG, HGG Trametinib +/- Dabrafenib I/II Pediatrics MAPK pathway Relapsed/refractory cancer Nivolumab +/- Ipilumumab NCT03130959 II PO Pediatrics Young Adults Epigenetic modulation High grade CNS tumors Nimotuzumab II/III Pediatrics DMG Radiation Finding maximum dose of reirradiation NCT02709226 I/II PO Pediatrics Targeted DNA damage DMG Hypofractionated Radiotherapy NCT05077735 II External beam radiation Pediatrics DNA damage DMG Re-irridation of progressive or recurrent DMG II Pediatrics Adults Targeted DNA damage DMG Re-irradiation versus RT and Multiple elective RT courses NCT03620032 II PO Pediatrics Young Adults Targeted DNA Damage DMG Vaccines Immune Modulatory DC Vaccine NCT03914768 I PO Pediatrics Adults Targeted kinase pathway GBM DMG Image-Guided Therapy CED of 124I-omburtamab NCT01502917 I CED Pediatrics Chemotherapy DMG Combination Bevacizumab +/- temozolomide +/- irinotecan NCT01114555 I/II CED Pediatrics Cytotoxic Drug Delivery DMG HGG Indoximod + Temozolomide NCT04049669 I/II PO Pediatrics Targeted Therapy DMG Recurrent/refractory CNS tumors Irinotecan Liposome Injection using real time imaging w/ gadolinium NCT03088813 I CED Pediatrics Local Drug Delivery DMG Lenalidomide + radiation NCT01226940 I IV Pediatrics Chemotherapy DMG, HGG Temozolomide + radiation NCT05009992 I/II IV ± image-guided Pediatrics Drug delivery/ Radiosensitization DMG Valproic acid, radiation, and bevacizumab NCT00879437 II IV Pediatrics Cytotoxic Chemotherapy DMG, HGG Vandetanib + Dasatinib + radiation NCT00996723 I IV Pediatrics Chemotherapy DMG Vorinostat + radiation NCT01189266 I/II PO Pediatrics Kinase inhibition DMG Mindfulness-based Intervention NCT05336916 N/A IV Pediatrics, Young Adults Immunotherapy/checkpoint modulation DMG High risk cancers HGG (high grade glioma) | MB (medulloblastoma) | GBM (glioblastoma multiforme) | NHL (Non-Hodgkin Lymphoma)

Preclinical investigation of targeted strategies

As the primary driver of DMG, the H3K27M mutated oncohistone protein triggers widespread epigenetic reprogramming by binding to and inhibiting the Polycomb Repressive Complex 2 (PRC2) methyltransferase. This inhibition leads to a drastic reduction in repressive H3K27 trimethylation (H3K27me3), while concurrently inducing an aberrant increase in H3K27 acetylation (H3K27ac) that activates silenced oncogenes. To counteract this, the HDAC inhibitor Panobinostat functions as a targeted therapy, reversing the disrupted landscape by restoring H3K27 trimethylation and reducing tumor-promoting effects [ 88 – 90 ]. Current pre-clinical research is focused on more effective strategies for treating DMG by targeting the mutated histone H3. Synergistic antitumor effects that prolonged survival in mice were observed when Panobinostat was combined with GSKJ4 (a drug that prevents the demethylation of the mutated H3 histone) [ 91 ] and CBL0137 (a compound promoting chromatin transcription and DNA repair) [ 92 ].

Strategies targeting activating mutations in activin A receptor type I (ACVR1), found in over 30% of DMG, have shown promise. ACVR1 encodes the serine/threonine activin receptor-like kinase-2 (ALK2), which is vital for tumorigenesis [ 57 ]. Targeting ALK2 with the pyrazolo[5-a]pyrimidine ALK2 inhibitor, LDN-193,189, and the pyridine derivative, LDN-214,117 demonstrated in vivo efficacy, significantly prolonging survival in mice with brainstem xenografts of H3K27M and ACVR1 mutated DMG cells [ 93 ]. The dual MEK1/2 and ACVR1 inhibitor, E2601 reduced viability of DMG cells carrying ACVR1 mutation and also extended survival in genetically engineered mice developing spontaneous ACVR1 mutated brainstem gliomas [ 94 ]. ACVR1 mutations induce varying effects on in vitro proliferation and survival. DMG cell lines carrying the highly potent ACVR1 R206H mutation were sensitive to the ACVR1 inhibitor LDN212854, and treatment with this inhibitor improved survival in mice [ 19 ].

A distinct, less common subtype of H3 K27-altered DMG exists in patients with wild-type H3, characterized by the overexpression of EZHIP. It functions as an oncohistone mimic and intrinsic inhibitor of PRC2, leading to a consequential loss of H3K27me3. This finding establishes EZH2 as a viable therapeutic target. EZH2 inhibitors prevent tumor growth via the activation of the p16 tumor suppressor protein [ 95 ]. Preclinical in vivo studies have supported the tumor-suppressive effects of EZH2 inhibitors [ 96 ], although research remains ongoing to better understand the impact of EZH2 monotherapy.

Protein Kinase C (PKC) is a key regulator of cell growth, differentiation, and survival, and its activation promotes aggressive tumor cell behavior. Inhibition of the PI3K pathway in H3 K27-altered DMG produces compensatory activation of PKC signaling, fueling tumor survival and resistance. To overcome this, a therapeutic strategy supporting dual blockade was investigated for DMG by combining Paxalisib (an investigational small molecule that inhibits the PI3K pathway) with the PKC inhibitor, Enzastaurin to achieve a synergistic effect. Despite moderate BBB penetration (> 50%) of Paxalisib, and limited efficacy (15–17%) Enzastaurin, the combination extended mouse survival by 22% [ 74 ]. These findings highlight the need for superior BBB-permeant PKC inhibitors to optimize this combination strategy.

Resistance to radiotherapy in DMG is partly driven by the tumor’s hypoxic environment. To overcome this, therapeutic strategies have employed diverse radiosensitizers designed to enhance tumor sensitivity while sparing surrounding healthy tissue [ 97 ]. One promising approach involves repurposing compounds such as the BBB-permeable lipophilic diabetes drug, phenformin, to inhibit mitochondrial oxygen consumption within tumor cells. Phenformin was additionally combined with dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, to mitigate phenformin-induced lactic acid accumulation, thus increasing tumor metabolic stress and sensitivity to radiation. Although this pre-clinical investigation resulted in treatment-limiting weight loss in an orthotopic murine model, further dose optimization or development of alternative mitochondrial inhibitors for use with PDK blockade represent potential next steps toward improved radiosensitization [ 98 ].

The combination of anti-parasitic drugs and radiotherapy has also been suggested as novel approach towards the management of DMG and improve patient survival outcomes. Increasing evidence of the role of anti-parasitic drugs in inducing mitochondrial dysfunction and activating DNA damage pathways, makes them attractive candidates for repurposing them to enhance radiosensitivity in DMG [ 99 ].

Principles of nanoparticle-based tumor therapy

Nanoparticles (NPs), defined as particles under 100 nm in diameter, are established cancer therapies with potential for treating DMG [ 100 , 101 ]. The therapeutic promise of nanoparticle-based drug delivery lies in in two key mechanisms: passive accumulation via the Enhanced Permeability and Retention (EPR) effect, driven by leaky tumor vasculature, and Active Transport and Retention (ATR) or Enhanced Transcytosis and Retention (ETR), which utilize cellular transcytosis to cross endothelial barriers [ 102 ]. By optimizing particle size and surface modifications to trigger receptor-mediated transcytosis, nanoparticles can preferentially accumulate in tumor tissues while limiting diffusion into healthy organs, thereby reducing systemic toxicity [ 103 ]. The ATR principle offers a framework for engineering NP trafficking (entry, exit, and retention) in BBB-intact tumors like DMG [ 104 ]. NPs must be sufficiently small to avoid capture by the reticulo-endothelial system, but large enough to escape filtration by the kidneys. Achieving optimal particle size can therefore prolong retention time within the bloodstream or the tumor. Increasing the circulation time of NPs is critical for many applications, including drug delivery [ 105 ]. The surface conjugation of NP with polyethylene glycol (PEG) is an established strategy to increase persistence in circulation. By generating a neutral surface charge, PEGylation creates a “stealth” effect that camouflages the NPs from detection and rapid clearance by the immune system [ 76 ]. While extending the half-life of NP in vivo this process improves NP solubility and facilitates the attachment of specific targeting ligands [ 106 ].

Significant adaptability of nps for biomedical applications

The inherent adaptability of nanoparticles makes them highly promising for a range of biomedical applications, including drug delivery systems, advanced imaging, and guided therapeutic interventions [ 107 ]. Their physical and chemical properties can be precisely engineered to promote biocompatibility and enhance retention in specific tumor tissues [ 108 ]. This is achieved through several key modifications including: (i) Targeting and co-delivery : Their small size and high surface-area-to-volume ratio allows for conjugation with multiple ligands for ultra-specific targeting and the simultaneous encapsulation of multiple drugs [ 109 ]. (ii) Controlled release : Coatings of acids and polymers can control the release of therapeutics, delivering drugs optimally in the acidic environment of tumors [ 110 ]. (iii) Enhanced retention : Adjusting the size and shape of nanoparticles can enhance cellular retention and influence permeability within tumors [ 105 ]. (iv) Improved drug properties : Modification can also improve the solubility of chemotherapeutics and control their release kinetics. (v) Imaging capabilities : In addition to therapeutic delivery, nanoparticles can be conjugated with fluorophores or manufactured with magnetic properties to enable fluorescent or magnetic resonance imaging [ 101 , 108 ]. This section explores how NPs are revolutionizing medicine through their use in optimized delivery methods, advanced diagnostics, novel imaging techniques, and drug repositioning.

Delivery and safety

NP delivery methods can be optimized for specific applications and to avoid toxicity. For example, biodegradable and biocompatible liposomal nanoformulations can be administered intravenously, intraperitoneally, subcutaneously, or topically [ 101 ]. Topical administration offers an alternative to avoid systemic toxicities by preventing them from entering the bloodstream [ 111 ].

Diagnoses

Beyond therapeutics, NPs are widely used for diagnostics [ 73 ]. For instance, they are commonly employed in biosensing assays to accurately detect the presence of various antigens in ex vivo patient samples in a noninvasive, accurate, and cost effective manner [ 112 ]. Their ability to conjugate with other molecules enhances signal sensitivity, enabling the detection of biomarkers for diseases, metabolic conditions, thromboses, pulmonary embolisms, and various cancers in both urine and blood samples [ 101 ].

Contrast agents for imaging

NPs show promise as agents for guiding imaging platforms [ 113 ]. Surgical resection is a primary treatment for many cancers, but incomplete tumor removal and subsequent recurrence are common due to the difficulty in accurately identifying tumor margins [ 114 ]. NPs designed to target and accumulate at tumor sites, are used as contrast agents to better delineate a tumor’s exact location [ 113 ] Iron oxide, silica, and gold NPs have demonstrated success in enhancing tumor detection sensitivity using various techniques, including Computed Tomography (CT), Positron Emission Tomography (PET), magnetic resonance and fluorescence imaging, for both pre-operative and intra-operative use. Finally, these similar mechanisms also allow for the evaluation of treatment response by tracking tumor shrinkage following therapy [ 101 , 115 ].

Repositioning Nps - from first-approved doxil to the future of cancer therapy

The repurposing of nanomedicines, exemplified by the evolution of Doxil, demonstrates a powerful strategy for expanding the therapeutic applications of existing drugs in oncology. Doxil, a liposomal nanoparticle encapsulating doxorubicin, was initially approved for Kaposi’s Sarcoma but has since been repurposed and gained FDA approval for a wider array of cancers, including ovarian cancer and multiple myeloma [ 101 ]. The success of Doxil has paved the way for further innovation, with 13 different nanoparticle formulations now FDA-approved for various types of cancer. These advanced treatments include targeted therapies for breast cancer, pancreatic cancer, and acute lymphoblastic leukemia, illustrating how the strategic use of nanoparticles has broadened the therapeutic landscape for oncology [ 116 , 117 ]. The continued development and repurpose of nanoparticle formulations promise more targeted and cost-effective path to new treatments.

Nanoparticle formulations for targeted and sustained drug delivery in brain tumors

.NPs are a promising strategy for enhancing CNS drug delivery, designed to circumvent the therapeutic limitations of the BBB. While the BBB restricts most small molecules, functionalized NPs that are PEGylated—can evade rapid immune clearance to achieve prolonged circulation times. This improved pharmacokinetic profile allows NPs to accumulate at the brain tumor site, leveraging the compromised vasculature of the blood-tumor barrier (BTB) through the EPR effect or active mechanisms like transcytosis and interaction with the TME (tumor-associated endothelial cells) via ATR/ETR route. Furthermore, these platforms can be decorated with ligands to specifically target tumor cells, enhancing penetration into the brain parenchyma [ 106 ]. Below, we summarize categories of brain-penetrating NPs for use in diagnosis and treatment of brain tumors (Fig. 5 ) and research findings that show improved drug delivery with less toxicity.

Fig. 5 Schematic of Multifunctional nanoplatforms for Brain Tumor Diagnosis and Therapy. The figure illustrates the advantages and multimodality of various nanoplatforms (organic, inorganic, and carbon-based) for brain tumor management. Their structural and functional composition post-functionalization with polyethylene glycol (PEG) allows the NPs to traverse the blood-brain barrier (BBB), while active targeting moieties facilitate specific accumulation in tumor cells for combined diagnostic and therapeutic applications

Inorganic NPs

Typically features a solid core of metallic (e.g., gold and silver) or metal oxide (e.g., iron oxide and gadolinium oxide) material. While metallic NPs are often synthesized through chemical reduction in the presence of a capping ligand, metal oxide NPs are produced using different chemical methods, such as co-precipitation [ 118 ]. Iron oxide nanoparticles (IONPs) are frequently used for brain imaging and targeted gene/drug delivery due to their inherent biocompatibility, biodegradability, adaptable surface chemistry for bioconjugation, and distinct magnetic characteristics. Superior therapeutic effects and low systemic toxicity have been demonstrated with the use of IONPs to co-deliver cisplatin and glutathione peroxidase-targeting siRNA for combinatorial GBM therapy [ 119 ]. A similar IONP system was developed for the targeted delivery of siRNAs to overcome drug resistance mediated by the DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) during temozolomide therapy in GBM. This system effectively overcame biological barriers, specifically bound to tumor cells, and reduced MGMT expression in mouse models bearing patient-derived GBM xenografts [ 120 ]. Time-resolved MRI assessment demonstrated that chlorotoxin-conjugated IONPs facilitated efficient convection-enhanced delivery and specifically targeted cancer cells in a human glioblastoma mouse model [ 121 ]. However, many of these preclinical studies demonstrating therapeutic efficacy are based on GBM models rather than DMG, highlighting a current gap in DMG-specific research.

Gold nanoparticles (AuNPs) have been explored for treating gliomas through several approaches. PEGylated AuNPs were able to successfully deliver doxorubicin to glioma cells by targeting the overexpressed LRP1 receptor, leading to significantly prolonged survival in mice [ 122 ]. In separate applications, the light-absorbing properties of AuNPs have been leveraged for photothermal therapy, with multiple studies exploring their conjugation with photosensitizers like integrins and silicon phthalocyanine [ 100 , 123 ]. For theranostic and adjuvant applications, coupling of AuNP with ionizing radiation has demonstrated increased cellular DNA damage in GBM, boosting survival and reducing systemic toxicity from high-dose radiation This radiosensitization effect is primarily mediated by the high atomic number of gold, which enhances the photoelectric effect and generates secondary electrons that amplify localized DNA damage within tumor cells [ 124 , 125 ]. However, the non-biodegradability of AuNPs remains a key challenge, prompting research into alternative methods of administration, including topical, intrarectal, and oral routes, to mitigate systemic toxicity concerns [ 101 , 126 ].

Silver nanoparticles (AgNPs) have shown significant promise for treating GBM, primarily through the release of silver ions that induce DNA damage and disrupt membrane permeability by producing reactive oxygen species [ 127 ]. The ability of smaller AgNPs to infiltrate nuclear pores and cause chromosomal aberration further contributes to their therapeutic effects [ 127 ]. Like gold, AgNPs can act as effective radiosensitizers [ 128 ]. Numerous studies have demonstrated the benefits of AgNPs in promoting apoptosis and autophagy, enabling radioenhancement in the treatment of GBM [ 108 , 129 , 130 ]. Additionally, AgNPs exhibit similar therapeutic enhancement in both photo- and thermal-based treatments [ 131 , 132 ]. However, concerns regarding potential toxicity remain, as AgNPs can induce oxidative stress and damage in healthy neural tissue, necessitating rigorous dose optimization and biocompatibility assessments [ 113 ].

Copper Nanoparticles (CuNPs) have emerged as versatile, cost-effective agents for antitumor therapy over the past decade. Leveraging their unique physicochemical properties, functionalized CuNPs effectively traverse the BBB to treat neurological tumors. They induce selective cancer cell death via cuproptosis—a copper-dependent form of oxidative stress—while their high surface-area-to-volume ratio optimizes drug delivery and photothermal therapy (PTT). Furthermore, their rapid clearance minimizes off-target toxicity, highlighting their potential as a highly selective theranostic platform [ 133 – 136 ].

Organic NP s are nanostructures composed of amphiphilic molecules that self-organize into spherical shapes in an aqueous environment. This process is driven by the molecules’ dual nature, which includes a water-loving (hydrophilic) and a water-hating (hydrophobic) part. This unique self-assembly property makes organic NPs valuable for applications like targeted drug delivery. This category includes micelles, liposomes, polymeric NPs, and dendrimers [ 137 ]. They are noted for their biocompatibility, biodegradability, and ability to enable controlled drug release making them ideal for neuro-oncologic applications like drug delivery [ 138 ].

Liposomes are spherical vesicles made of one or more phospholipid bilayers that enclose an aqueous core and are a promising strategy for delivering drugs to brain tumors. By exploiting the tumor’s leaky vasculature, these nanocarriers passively accumulate through the EPR effect and are retained longer due to poor lymphatic drainage [ 139 ]. However, for more effective targeting, liposomes can be functionalized for active targeting. This involves conjugating ligands to the liposome’s surface that can bind to receptors overexpressed on cancer cells or the cells of the BBB via ATR effect. Examples of these targeting ligands include transferrin, insulin, and endothelial growth factor. This receptor-mediated endocytosis facilitates the liposomes’ passage across the BBB [ 140 , 141 ]. A notable challenge for systemically administered liposomes is their rapid uptake by the reticuloendothelial system (RES), primarily in the liver and spleen, which can diminish their therapeutic effect. This can be addressed through modifications like PEGylation [ 142 ]. Further advances include targeted therapies using specific receptors. For example, the development of high-density lipoprotein mimicking liposomal NPs to target the scavenger receptor class B type 1 (SCARB1) on medulloblastoma cells. This approach was shown to reduce tumor cell proliferation [ 143 ].

Polymer-based NPs are a promising strategy for delivering therapeutics to brain tumors due to their modifiable formulations. Poly(lactic-co-glycolic acid) (PLGA), an FDA-approved, biodegradable, and biocompatible polymer, is frequently used for this application because of its straightforward synthesis [ 144 ]. In one study, morusin-loaded PLGA NPs were conjugated with chlorotoxin, a peptide derived from scorpion venom to specifically target chloride channels on glioma cells, which led to significant cell death in multiple GBM cell lines [ 145 ]. Polyanhydride is another polymer commonly used in cancer therapy, notably in the FDA-approved Gliadel wafer for local chemotherapy in GBM. Emerging research indicates that polyanhydrides can cross the BBB, suggesting that combining NPs with Gliadel wafers is an exciting avenue for future development [ 146 ]. Furthermore, biodegradable poly (β-amino ester) (PBAE) NPs have recently shown merit in delivering the Herpes simplex virus I thymidine kinase suicide gene to medulloblastoma and atypical teratoid/rhabdoid tumors. This treatment resulted in high levels of gene transfection with substantial cell death in these cancer cell lines and significantly enhanced survival in mice bearing orthotopic tumor xenografts [ 147 ].

Dendrimers are organic NPs defined by a central core attached to symmetrical, branching structures with functional groups on their surface. For brain tumor targeting, conjugations with transferrin and EGFR are common, a strategy also seen with other organic NP formulations [ 128 ]. Poly-amidoamine (PAMAM) is the most frequently synthesized dendrimer, and studies have investigated how different conjugations can increase its diffusion into the CNS tissue [ 148 ]. Though EGFR-conjugated PAMAM dendrimers encapsulating doxorubicin increased drug delivery in glioma-bearing mice, in vivo translation has yet to provide convincing results [ 149 , 150 ].

Polymeric micelles are self-assembled amphiphilic copolymers that show significant promise—and in certain preclinical contexts, superior performance to other nanocarriers—due to their small size and structural stability. Although they may have lower drug-loading capacities than other carriers, they demonstrate an exceptional ability to encapsulate hydrophobic drugs, offering high solubilization and easy, low-cost preparation [ 151 – 153 ].

Carbon-based NPs, including carbon nanotubes (CNTs), carbon dots (CDs), fullerenes, and graphene oxide (GO), have shown promise for treating brain cancer in preclinical studies. These NPs cross the BBB, deliver therapeutics directly to tumors, and can be modified for specific treatments like chemotherapy and phototherapy. Recent studies highlight promising results for Carbon-based NP-based targeted delivery to CNS.

Carbon nanotubes (CNTs) are cylindrical, hexagonal-lattice carbon structures that are being investigated as a highly promising platform for brain-targeted drug delivery. Their unique properties, such as high surface area, biocompatibility, and ability to be tailored through functionalization make them ideal for carrying diverse drug payloads. Furthermore, optimized functionalization strategies enable them to cross the BBB efficiently [ 154 ]. A mechanical approach has been developed for the treatment of chemoresistant GBM in the mouse cortex. This method utilizes magnetic CNTs functionalized with an anti-CD44 antibody. The functionalized CNTs specifically target GBM cells—which are enriched with the CD44 antigen on their surface—and treat them with elevated efficacy upon the application of an external magnetic field [ 155 ]. This approach may also be applied to inoperable brain tumors such as DMG.

Carbon dots (CDs) represent a new class of fluorescent, zero-dimensional carbon nanomaterials, characterized by their small size, typically under 10 nm. This carbon-based modality offers numerous advantages, including low production costs, high reproducibility, and the ability to be robustly modified for specific molecular targeting. This tunability allows for imaging and targeted drug delivery, which can minimize peripheral toxicity in cancer treatment [ 156 ]. Conjugating CDs with transferrin was shown to enable the formation of strong covalent bonds with chemotherapeutic drugs like doxorubicin, enhancing their delivery to various brain tumor cell lines [ 157 ]. Similarly, the benefits of this strategy were reinforced by showing that transferrin-targeting carbon nitride dots (CNDs) markedly enhanced the delivery of gemcitabine to pediatric glioma cells. CNDs are a type of CD that incorporates nitrogen atoms in their structure to improve their fluorescent properties [ 158 ]. This enhancement was observed when compared to delivery by non-functionalized NPs or gemcitabine administered alone.

Graphene oxide (GO)— a novel, single atomic-thickness, two-dimensional carbon nanomaterial derived from graphene with promising applications in glioma treatment. Due to its exceptional physical and chemical properties, GO is being explored for four main applications in glioma treatment: direct killing, drug delivery, immunotherapy, and phototherapy. However, concerns regarding neurotoxicity and oxidative stress have been reported in preclinical studies, highlighting the need for further investigation into its safety profile before clinical translation [ 159 – 161 ].

Fullerenes (C 60 ) excel as photosensitizers in photodynamic therapy (PDT) and reactive oxygen species (ROS) generation, facilitating superior tumor-specific apoptosis compared to graphene or nanotubes [ 162 – 164 ]. Beyond directly inducing apoptosis, fullerene derivatives exhibit potent antiangiogenic properties by inhibiting vascular endothelial growth factor (VEGF). This makes them promising agents for glioma treatment, as they can reduce tumor vasculature while simultaneously protecting surrounding healthy brain tissue through their inherent antioxidant activity [ 165 ].

Nanoparticle-based theranostic approaches in brain cancer

NPs have become commonplace in both oncologic and non-oncologic therapeutics; however, their application in diagnosing brain malignancies, such as DMG, remains limited. NP-based theranostic approaches, as depicted in Fig. 6 , offer a versatile platform for simultaneous diagnosis, real-time monitoring, and treatment of brain malignancies. The deep-seated midline location of DMG within the brain presents exceptional diagnostic challenges, as performing a definitive biopsy in this critical area is inherently difficult and carries significant risks. Consequently, diagnosis typically relies on a combination of a child’s rapid neurological decline and characteristic MRI findings. A key difficulty, however, is that these symptoms and imaging results can overlap with other brain tumors, hindering accurate differentiation [ 166 ]. The aggressiveness of DIPG and the expansive nature of its invasion make delineating tumor margins especially difficult. Furthermore, while gadolinium is the most common contrast agent for MRI, its potential for nephrotoxicity limits its use in patients with renal impairment [ 167 ]. These concerns make the use of NPs for diagnostic purposes particularly compelling. The multi-modality of NPs—allowing for their utility in both diagnosis and therapy—is the most promising aspect of nanomedicine. This capability has led to the term ‘theranostics’, a powerful approach for improving drug delivery initiatives in brain cancer.

Fig. 6 Schematic Illustrating the Application of NP based approaches in Diagnosis and Therapy of Brain Malignancies. These include enhanced tumor contrast, improved margin delineation, multimodal imaging, and image-guided delivery of therapeutic agents. These integrated capabilities support more precise treatment and have the potential to improve outcomes while reducing systemic toxicity

Clinically, several nanoparticle-based platforms have already demonstrated theranostic potential, supporting their translational relevance. For instance, Ferumoxytol, an FDA-approved iron oxide NP (IONP), is widely used as an MRI contrast agent and has been repurposed for tracking tumor-associated macrophage activity and treatment response in brain tumors [ 168 ]. Similarly, liposomal formulations like Doxil (liposomal doxorubicin) highlight the feasibility of nanoparticle-mediated drug delivery in oncology [ 169 ]. While these clinically approved systems underscore the potential for integrating diagnostic imaging with therapeutic delivery, their translation to DMG remains limited.

The distinct paramagnetic properties of magnetic nanoparticles (NPs) position them as valuable agents for magnetic resonance imaging (MRI). Their utility in cancer imaging and therapy has been demonstrated across multiple studies. One study highlighted the efficacy of targeted iron oxide NPs (IONPs), which accumulated in glioblastoma cells with nine times greater efficiency than their untargeted counterparts, facilitating optimal tumor imaging while minimizing uptake by healthy tissue. This system was also adapted for theranostic applications, leveraging the NPs to enable the hyperthermic treatment of tumors [ 170 ]. Expanding on this potential, multifunctional IONPs conjugated with an F3 peptide achieved a three-fold prolonged tumor transit time and doubled the contrast-to-noise ratio in rat glioma cells. The co-delivery of the photoactivated drug Photofrin within these NPs significantly increased survival rates relative to non-targeted or systemically administered Photofrin [ 171 ]. In a different application, ferumoxytol IONPs served as an MRI contrast agent to monitor monocyte infiltration into glioblastoma cells post-amphotericin B treatment, revealing a markedly amplified uptake of ferumoxytol by monocytes in the treated tumor environment [ 172 ].

Gold nanoparticles (AuNPs) can be chelated with gadolinium to extend their short half-life and facilitate tumor tissue targeting. This approach enhances the properties of both materials within a single nanoplatform. In one study, researchers conjugated AuNPs with a transactivator of transcription (TAT) peptide, which improved brain tumor imaging compared to free gadolinium alone. This approach also proved beneficial for encapsulating and delivering doxorubicin to glioma tumor cells [ 173 ]. A significant challenge with AuNPs is their nonbiodegradability, which has spurred investigations into non-systemic administration methods. For instance, topical administration of surface-enhanced Raman scattering (SERS) NPs rapidly delineated breast cancer tumor margins in excised tissue. The results from this method compared favorably with established techniques like flow cytometry and immunochemistry. While this specific application addressed breast cancer, it demonstrates how varied NP administration methods offer distinct advantages and overcome limitations associated with more traditional therapies [ 111 ].

NP imaging offers high versatility, extending to simultaneous use with multiple imaging modalities. To leverage this, a combined SERS and multispectral optoacoustic tomography (MSOT) system was developed. This system achieved highly precise tumor margin delineation in glioma-bearing mice using gold nanostars by capitalizing on the high resolution of SERS and the deeper penetration of MSOT [ 174 ]. In another approach, researchers created a multimodal system incorporating MRI, photoacoustic imaging, and Raman imaging. This method used SERS NPs to target glioblastoma tumors in mice, exploiting the complementary sensitivity and spatial resolution of each modality [ 175 ]. These findings underscore the broad applicability of AuNP imaging and the significant potential for integrating different systems to enhance tumor identification. While multimodal systems are a key focus, NPs also show promise in fluorescence imaging. Specifically, zirconium-labeled liposomal NPs facilitate passive targeting, leading to enhanced uptake and optimal PET imaging in breast cancer models [ 176 ]. A translational study using PET imaging of ⁶⁴Cu-labeled HER2-targeted liposomal doxorubicin demonstrated substantial variability in tumor accumulation in patients and showed that higher nanoparticle deposition correlated with improved therapeutic response, highlighting its potential as a theranostic platform [ 177 ]. In a separate study, researchers used fluorescently-labeled silver nanoplate clusters, conjugated with an F3 peptide, to target rat glioma cell types, achieving a contrast enhancement of over 90% [ 178 ].

Organic nanoparticles, despite lacking intrinsic magnetic properties, offer significant diagnostic capabilities. In photoacoustic imaging, organic materials are valuable because they contain chromophores that produce size-independent photophysical properties—a distinct advantage over size-dependent metallic particles. This allows for the creation of nanoparticles (NPs) of a similar size that produce various signal intensities and absorption wavelengths. The EPR/ATR effect facilitates the accumulation of fluorescent liposomes in brain tumors, enabling their use as contrast agents [ 179 ].

To address the shortcomings of common contrast dyes like cyanine—specifically their poor photostability and limited retention in tumor tissue—researchers are exploring their incorporation into organic NPs for cancer diagnosis [ 180 , 181 ]. For instance, Yang et al. developed liposomal NPs with magnetic nanocrystals and a PEG/fatty acid copolymer, a design that minimized toxicity and enhanced imaging in various cancer cell lines [ 182 ].

CNDs, a new generation of carbon dots (CD) featuring nitrogen heteroatom doping in their structure, can emit in a wide range of wavelengths, enabling various uses in imaging studies. The development of CDs and CNDs as carriers for contrast agents, such as gadolinium, also offers a promising way to reduce the dosage and toxicity of these otherwise toxic or non-biocompatible substances [ 183 , 184 ].

A novel PEGylated polymeric nanoplatform incorporating a photosensitizer has been developed and evaluated for its potential in tri-modal imaging (fluorescence, MRI, and photoacoustic) of brain tumors in a murine model [ 185 ]. Dendrimers have been similarly successful when conjugated with gadolinium and fluorescent dyes [ 186 , 187 ].

While the potential for improved diagnostic accuracy via NPs in cancer detection—particularly in preclinical models—is well-documented, significant challenges to clinical implementation persist. Researchers still need to addres s critical issues regarding long-term toxicity, low hepatic clearance, and high variability in human tumor accumulation [ 188 ].

Nanomedicine for DMG: overcoming barriers with current strategies and prospects

DMG presents unique and heightened challenges to effective treatment. Common to most brain tumors is the limited ability of therapeutics to cross the BBB, a problem particularly pronounced in DMG. Additional barriers, such as drug efflux transporters and anisotropic effects, further impede drug infiltration. Finally, the distinct TME of DMG is deficient in critical immune mediators (e.g., CD3 + and CD8 + T-lymphocytes and PD-1), making many immunotherapies ineffective. NPs may offer a viable solution by potentially surmounting these obstacles and providing selective targeting for both diagnostic and therapeutic applications. Despite this potential, NP-based DMG research is currently limited, largely overshadowed by studies on GBM and other high-grade gliomas [ 100 ]. While numerous DMG treatment strategies have been developed (Table 1), remarkably few—only three studies to date—have investigated NP-based therapies. The research includes: (i) NP formulations (apoferritin and liposomal) that encapsulate N(3)-propragyl analogue (N3P) , a drug used to treat temozolomide resistant cancers, demonstrating significant increase in drug uptake and therapeutic efficiency compared to free N3P in DMG cell cultures [ 189 ]; (ii) Doxorubicin- loaded AuNPs showed potent in vitro cytotoxicity; however, their failure to produce a significant antitumor effect or improve survival in rat models indicated poor BBB penetration remains a major challenge [ 190 ]. (iii) Finally, Spherical nucleic acids (SNAs) —AuNPs functionalized with highly oriented small interfering RNA duplexes—were tested for targeting and inhibiting the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1), which is overexpressed in DMG cell lines [ 191 ]. This limited research suggests that leveraging the unique properties of NPs is a promising future direction.

The specific advantages that nanotechnology offers for DMG treatment are highlighted below

Molecular targeting

Genetic studies have been instrumental in identifying potential gene targets in DMG. Recent large-scale genomic analyses have identified alterations in the retinoblastoma (RB) cell cycle regulatory pathway in approximately 20–30% of DMG cases, including CDK4/6 amplification, CDKN2A/B deletion, and RB1 mutations [ 26 , 192 – 195 ]. Given that CDK4/6 inhibitors are already being investigated for other brain tumors, using NPs to enhance the delivery of these agents to DMG tumors represents a compelling treatment strategy. Other genomic analyses have revealed aberrations in PDGFRα and PARP1 expression within DMG biopsies [ 196 ], while inhibition of another cell cycle regulator, Wee1, has enhanced survival in DMG mouse models [ 197 ]. While the precise nature and prevalence of these mutations warrant further investigation, these examples highlight the potential efficacy of inhibiting key genes involved in DMG tumor proliferation and underscore the need for effective delivery agents, such as NPs, to ensure adequate targeting.

A separate study using 3D co-cultures generated in vitro tumor tissue analogs and identified a set of 14 proteins/genes overexpressed in DMG cells. These were curated into a non-canonical oncogenic signaling pathway activated by tumor-stroma interactions. Nine of these—including STAT3, SOD2, CEBP, ITGA5, MVP, LGALS1, CLIC1, LGALS3, and VCAM1—showed significantly increased expression in GBM/glioma patient tissues compared to normal brain tissue. However, five of the candidate proteins from the 3D model (CEBPB, PLSCR1, COL6A1, TIMP1, and NFkB1Z) did not show significant expression changes in the GBM/glioma cohorts [ 198 ]. This suggests that DMG may possess molecular characteristics distinct from more general gliomas and GBMs, offering opportunities for more selective targeting with NPs.

In addition, chlorotoxin, a peptide derived from scorpion venom, specifically targets cell surface receptors found on brain tumor cells. These receptors—including matrix metalloproteinase-2 (MMP-2) and several chloride channels, such as CLIC1—were also demonstrated to be overexpressed in DMG cells in vitro and in a 3D co-culture tumor-permissive microenvironment [ 198 , 199 ]. Various studies, primarily conducted in GBM models, have demonstrated that NP drug formulations conjugated with chlorotoxin can promote anti-tumor effects in gliomas [ 145 , 200 – 203 ]. Given recent studies investigating the prevalence of these receptors on DIPG cells, chlorotoxin-conjugated NPs are a promising strategy for specific and effective DMG tumor targeting.

Finally, a recent study identified the upregulation of several potential immune targets on the surface of DMG cells. These include Cluster of Differentiation 27 (CD276), B7 homolog 3 protein (B7H3), Interleukin 13 alpha receptor 2 (IL-13Rα2), Human Epidermal Growth Factor Receptor 2 (HER2), Ephrin Type-A Receptor 2 (EphA2), and Ephrin Type-A Receptor 3 (EphA3) [ 204 ].

Improved drug retention and extended release

In addition to targeted drug delivery, NP functionalization is a promising strategy for increasing drug half-life in the brain—a critical advantage for treating DMG. Functionalization with hydrophilic polymers, such as PEG, enhances half-life by preventing immunogenic clearance, which allows for extended retention of the drug at the tumor site. This prolonged exposure is significant for effectively treating the fast-growing and persistent cells of DMG and offers the potential for less frequent therapy administration [ 205 – 207 ].

For imaging purposes, gadolinium enhancement also extends the half-life of NPs [ 208 ]. Beyond functionalization, other factors affect half-life, including nanoparticle size—smaller NPs face rapid renal excretion, while larger ones are subject to phagocytosis via the complement system—as well as core components, surface charge, and targeting moieties [ 209 – 211 ]. Ongoing research focuses on optimizing NP design by modifying these variables to maximize half-life for improved DMG therapeutic strategies [ 212 ].

Furthermore, nanoparticle-based drug delivery is a transformative approach that provides a sustained, low-dose exposure of therapeutic agents to the TME. This strategy can be used for metronomic chemotherapy in DMG, leveraging the controlled release and EPR or ATR effect for preferential delivery. This minimizes systemic side effects and lowers the risk of developing drug resistance [ 213 , 214 ].

Gold nanoparticles can be chelated to gadolinium to extend their normally short half-life and can be targeted to tumor tissue.

Radiosensitizers

Radiation therapy is the established standard of care for DMG and is initiated promptly following diagnosis. A significant risk associated with this treatment is the potential for collateral damage to healthy cells, a concern that is especially acute in the sensitive tissue of the brain [ 215 ]. For aggressive tumors like DIPG, a reduced radiation dose—aimed at protecting healthy tissue—lowers the probability of effectively neutralizing the cancer. NPs can overcome this limitation by providing multiple methods to enhance the effectiveness of radiation within DMG cells. Their inherent ability to specifically target tumors helps to minimize radiation-mediated damage to healthy tissue [ 216 ]. In addition, due to the EPR or ATR effect in the tumor tissue, NPs can increase radiotherapy-focused DNA damage and inhibit DNA repair [ 217 , 218 ]. Crucially, NPs can serve multiple roles. They can function as delivery vehicles for radiosensitizing agents or as intrinsic radiosensitizers themselves, depending on their composition, design, and desired purpose [ 219 ]. Among various options, AuNPs are particularly effective in amplifying the absorbed radiation dose for treating brain cancer, due to their stability, biocompatibility, and high atomic number (Z = 79). Gold’s high Z makes it highly efficient at absorbing X-rays (radiotherapy) [ 220 – 222 ] or high-energy protons (proton therapy) [ 223 ]. This absorption causes the gold atoms to release secondary and Auger electrons, which induce localized, high-energy damage to adjacent cancer cells. This mechanism is a key principle of a cancer treatment strategy called ‘nanoparticle radio-enhancement’.

Imaging/treatment response

NPs hold an intriguing potential for more accurate and thorough cancer detection. Research has already demonstrated that various organic and inorganic NPs enhance tumor imaging for GBM, suggesting a promising role in detecting DMG. The tumor-targeting capabilities of NPs are especially vital for comprehensively delineating DMG tumor margins, which is critical due to the disease’s rapid spread throughout the brain [ 100 , 224 ]. This rapid progression also amplifies the importance of theranostic applications, which can simultaneously deliver therapy and monitor treatment response. The continued development of these advanced imaging modalities offers a promising avenue for improving the prognosis of DMG patients.

Improving drug delivery across the BBB

Focused ultrasound (FUS) combined with intravenously administered microbubbles has emerged as a promising, non-invasive strategy to transiently and locally disrupt the BBB, thereby enhancing drug delivery to Diffuse Midline Gliomas (DMG) [ 225 ]. The technique relies on acoustic cavitation, in which oscillating microbubbles induce mechanical stress on endothelial tight junctions, creating reversible BBB permeability. Preclinical studies show this method significantly increases the accumulation of chemotherapeutics and nanoparticles, highlighting its synergy with nanomedicine [ 226 – 228 ] Furthermore, low-intensity pulsed ultrasound via skull-implantable devices has demonstrated successful BBB opening for agents such as albumin-bound paclitaxel, with promising early-phase trials in recurrent glioblastoma (GBM; NCT04528680 ) [ 229 ]. These studies confirm the safety and feasibility of FUS-mediated disruption as a complementary approach to overcome one of the most significant pharmacological barriers in DMG therapy.

Conclusion

Key lessons learned. Nanoparticle-based platforms hold significant potential to improve diagnosis and treatment of DMG, yet their translation is hindered by the unique biology of the disease. While preclinical drug delivery results are promising, the intact BBB, active efflux pumps, intratumoral heterogeneity and the diffusely infiltrative nature of DMG present major obstacles. To move from promising, small-scale results to tangible clinical impact, the field must prioritize tailored, multifunctional systems designed to actively cross the BBB and distribute uniformly within the infiltrating tumor.

Furthermore, while the EPR effect is often cited as the primary mechanism for nanoparticle accumulation in solid tumors, it is increasingly recognized as highly heterogeneous. In the specific case of DMG, the BBB often remains intact or only partially compromised, resulting in low accumulation of conventional passive NPs. Therefore, benchmarking drug delivery requires moving beyond reliance on passive accumulation to prioritize active transport mechanisms or methods —such as focused ultrasound (FUS) or convection-enhanced delivery—to ensure therapeutic concentration within DMG lesions.

Outlook and Future perspective. To successfully translate these strategies from bench to bedside, future research must focus on optimizing NP design to ensure superior BBB penetration and enhanced retention within the TME. Parallel to this, efforts should prioritize the development of targeted, stimulus-responsive theranostic platforms that utilize tumor-specific biomarkers for simultaneous, real-time monitoring of therapeutic efficacy. To maximize clinical impact, these NP systems must be integrated with the standard of care, radiotherapy, utilizing NPs as radiosensitizers to improve tumor control while minimizing off-target side effects. Finally, overcoming persistent translational challenges, specifically by addressing manufacturing scalability and successfully navigating the regulatory landscape for complex nanomedicines, remains crucial for clinical implementation.

Ultimately, successful DMG therapy depends on a collaborative, multidisciplinary approach that combines advanced materials science with clinical and radiological oncology. By engineering delivery systems tailored specifically to the unique constraints of DMG, we can reshape the treatment from purely palliative care to precise, targeted interventions for pediatric patients.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

We thank BioRender for illustration tools and the DDTR journal team for editorial support.

Author contributions

M.U. and A.M. conceptualized the study, performed literature searches, and interpreted the data. Figures and schematic illustrations were prepared by M.U., A.M., R.P., and V.R.D. The clinical trial treatment table was compiled by A.M. and A.L. under the supervision of A.S.M. The manuscript was drafted by M.U. and A.M., with critical revisions, edits, and input provided by R.A.M., V.R.D., M.K., A.S.M., and P.A.C. All authors have approved the final version.

Funding

We gratefully acknowledge support for writing this review from funds from the National Institutes of Health (R25 CA225513 to AM), the Department of Defense office of the CDMRP (RA210290 to MU), the NIH National Institute of Neurological Disorders & Stroke (K08NS125175-01A1 to PC), and the Children’s Cancer Research Fund (PC & MU), Alternatives in Research & Development Foundation (MU & PC), Wipe out Kids Cancer (MU), and The Margaret E Early Medical Research Trust (MU). This work was also supported by the generous philanthropy from Andrew & Gislaine Schwartz, Harmon & Elaine Schwartz, and the CHLA community.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical Approval

This article does not include studies with human or animal participants, performed by any of the authors.

Competing interests

The authors declare no competing interests.

References

1. Aziz-Bose R Monje M Diffuse intrinsic pontine glioma: molecular landscape and emerging therapeutic targets Curr Opin Oncol 2019 31 6 522 30 10.1097/CCO.0000000000000577 31464759 PMC7242222 Aziz-Bose R, Monje M. Diffuse intrinsic pontine glioma: molecular landscape and emerging therapeutic targets. Curr Opin Oncol. 2019;31(6):522–30. 31464759 10.1097/CCO.0000000000000577 PMC7242222

2. Bradley KA Zhou T McNall-Knapp RY Jakacki RI Levy AS Vezina G Motexafin-gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a children’s oncology group phase 2 study Int J Radiat Oncol Biol Phys 2013 85 1 e55 60 10.1016/j.ijrobp.2012.09.004 23092726 PMC3529324 Bradley KA, Zhou T, McNall-Knapp RY, Jakacki RI, Levy AS, Vezina G, et al. Motexafin-gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a children’s oncology group phase 2 study. Int J Radiat Oncol Biol Phys. 2013;85(1):e55–60. 23092726 10.1016/j.ijrobp.2012.09.004 PMC3529324

3. Cooney T Lane A Bartels U Bouffet E Goldman S Leary SES Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study Neuro-oncology 2017 19 9 1279 80 10.1093/neuonc/nox107 28821206 PMC5570207 Cooney T, Lane A, Bartels U, Bouffet E, Goldman S, Leary SES, et al. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro-oncology. 2017;19(9):1279–80. 28821206 10.1093/neuonc/nox107 PMC5570207

4. Hoffman LM Veldhuijzen van Zanten SEM Colditz N Baugh J Chaney B Hoffmann M Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018 36 19 1963 72 10.1200/JCO.2017.75.9308 29746225 PMC6075859 Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, Baugh J, Chaney B, Hoffmann M, et al. Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;36(19):1963–72. 29746225 10.1200/JCO.2017.75.9308 PMC6075859

5. Veldhuijzen van Zanten SE Jansen MH Sanchez Aliaga E van Vuurden DG Vandertop WP Kaspers GJ A twenty-year review of diagnosing and treating children with diffuse intrinsic pontine glioma in The Netherlands Expert Rev Anticancer Ther 2015 15 2 157 64 10.1586/14737140.2015.974563 25435089 Veldhuijzen van Zanten SE, Jansen MH, Sanchez Aliaga E, van Vuurden DG, Vandertop WP, Kaspers GJ. A twenty-year review of diagnosing and treating children with diffuse intrinsic pontine glioma in The Netherlands. Expert Rev Anticancer Ther. 2015;15(2):157–64. 25435089 10.1586/14737140.2015.974563

6. Coleman C Chen K Lu A Seashore E Stoller S Davis T Interdisciplinary care of children with diffuse midline glioma Neoplasia 2023 35 100851 10.1016/j.neo.2022.100851 36410226 PMC9676429 Coleman C, Chen K, Lu A, Seashore E, Stoller S, Davis T, et al. Interdisciplinary care of children with diffuse midline glioma. Neoplasia. 2023;35:100851. 36410226 10.1016/j.neo.2022.100851 PMC9676429

7. Fisher PG Breiter SN Carson BS Wharam MD Williams JA Weingart JD A clinicopathologic reappraisal of brain stem tumor classification Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer 2000 89 7 1569 76 11013373 10.1002/1097-0142(20001001)89:7<1569::aid-cncr22>3.0.co;2-0 Fisher PG, Breiter SN, Carson BS, Wharam MD, Williams JA, Weingart JD, et al. A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer. 2000;89(7):1569–76. 11013373 10.1002/1097-0142(20001001)89:7<1569::aid-cncr22>3.0.co;2-0

8. De Martino L Picariello S Russo C Errico ME Spennato P Papa MR Extra-neural metastases in pediatric diffuse midline gliomas, H3 K27-altered: presentation of two cases and literature review Front Mol Neurosci 2023 16 1152430 10.3389/fnmol.2023.1152430 37547920 PMC10398382 De Martino L, Picariello S, Russo C, Errico ME, Spennato P, Papa MR, et al. Extra-neural metastases in pediatric diffuse midline gliomas, H3 K27-altered: presentation of two cases and literature review. Front Mol Neurosci. 2023;16:1152430. 37547920 10.3389/fnmol.2023.1152430 PMC10398382

9. Ge X Yang Y Wang W Tian L Zhang G Tian Z Pediatric H3K27M‑mutant diffuse midline glioma with vertebral metastasis: A case report and literature review Oncol Lett 2024 27 2 48 10.3892/ol.2023.14181 38192660 PMC10773191 Ge X, Yang Y, Wang W, Tian L, Zhang G, Tian Z, et al. Pediatric H3K27M‑mutant diffuse midline glioma with vertebral metastasis: A case report and literature review. Oncol Lett. 2024;27(2):48. 38192660 10.3892/ol.2023.14181 PMC10773191

10. Giantini-Larsen AM Garton ALA Rivera M Han R Pisapia DJ Sait SF Diffuse midline glioma with extra central nervous system metastases in the pediatric, adolescent, and young adult population Child’s nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2025 41 1 306 10.1007/s00381-025-06903-4 41055765 PMC12504370 Giantini-Larsen AM, Garton ALA, Rivera M, Han R, Pisapia DJ, Sait SF, et al. Diffuse midline glioma with extra central nervous system metastases in the pediatric, adolescent, and young adult population. Child’s nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2025;41(1):306. 41055765 10.1007/s00381-025-06903-4 PMC12504370

11. Buczkowicz P Bartels U Bouffet E Becher O Hawkins C Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications Acta neuropathologica 2014 128 4 573 81 10.1007/s00401-014-1319-6 25047029 PMC4159563 Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta neuropathologica. 2014;128(4):573–81. 25047029 10.1007/s00401-014-1319-6 PMC4159563

12. Caretti V Bugiani M Freret M Schellen P Jansen M van Vuurden D Subventricular spread of diffuse intrinsic pontine glioma Acta neuropathologica 2014 128 4 605 7 10.1007/s00401-014-1307-x 24929912 PMC4161623 Caretti V, Bugiani M, Freret M, Schellen P, Jansen M, van Vuurden D, et al. Subventricular spread of diffuse intrinsic pontine glioma. Acta neuropathologica. 2014;128(4):605–7. 24929912 10.1007/s00401-014-1307-x PMC4161623

13. Khuong-Quang DA Buczkowicz P Rakopoulos P Liu XY Fontebasso AM Bouffet E K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas Acta neuropathologica 2012 124 3 439 47 10.1007/s00401-012-0998-0 22661320 PMC3422615 Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta neuropathologica. 2012;124(3):439–47. 22661320 10.1007/s00401-012-0998-0 PMC3422615

14. Schwartzentruber J Korshunov A Liu XY Jones DT Pfaff E Jacob K Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma Nature 2012 482 7384 226 31 10.1038/nature10833 22286061 Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482(7384):226–31. 22286061 10.1038/nature10833

15. Chan KM Fang D Gan H Hashizume R Yu C Schroeder M The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression Genes Dev 2013 27 9 985 90 10.1101/gad.217778.113 23603901 PMC3656328 Chan KM, Fang D, Gan H, Hashizume R, Yu C, Schroeder M, et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 2013;27(9):985–90. 23603901 10.1101/gad.217778.113 PMC3656328

16. Findlay IJ De Iuliis GN Duchatel RJ Jackson ER Vitanza NA Cain JE Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies Oncogene 2022 41 4 461 75 10.1038/s41388-021-02102-y 34759345 PMC8782719 Findlay IJ, De Iuliis GN, Duchatel RJ, Jackson ER, Vitanza NA, Cain JE, et al. Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies. Oncogene. 2022;41(4):461–75. 34759345 10.1038/s41388-021-02102-y PMC8782719

17. Nikolaev A, Fiveash JB, Yang ES: Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG. Int J Mol Sci 2020, 21(2). 10.3390/ijms21020490 PMC7014308 31940975

18. Vuong HG Ngo TNM Le HT Jea A Hrachova M Battiste J Prognostic Implication of Patient Age in H3K27M-Mutant Midline Gliomas Frontiers in oncology 2022 12 858148 10.3389/fonc.2022.858148 35371982 PMC8971724 Vuong HG, Ngo TNM, Le HT, Jea A, Hrachova M, Battiste J, et al. Prognostic Implication of Patient Age in H3K27M-Mutant Midline Gliomas. Frontiers in oncology. 2022;12:858148. 35371982 10.3389/fonc.2022.858148 PMC8971724

19. Hoeman CM Cordero FJ Hu G Misuraca K Romero MM Cardona HJ ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis Nature communications 2019 10 1 1023 10.1038/s41467-019-08823-9 30833574 PMC6399349 Hoeman CM, Cordero FJ, Hu G, Misuraca K, Romero MM, Cardona HJ, et al. ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis. Nature communications. 2019;10(1):1023. 30833574 10.1038/s41467-019-08823-9 PMC6399349

20. Fontebasso AM Papillon-Cavanagh S Schwartzentruber J Nikbakht H Gerges N Fiset PO Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma Nat Genet 2014 46 5 462 6 10.1038/ng.2950 24705250 PMC4282994 Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO, et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet. 2014;46(5):462–6. 24705250 10.1038/ng.2950 PMC4282994

21. Mackay A Burford A Carvalho D Izquierdo E Fazal-Salom J Taylor KR Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma Cancer Cell 2017 32 4 520 37.e525 10.1016/j.ccell.2017.08.017 28966033 PMC5637314 Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, et al. Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell. 2017;32(4):520–37.e525. 28966033 10.1016/j.ccell.2017.08.017 PMC5637314

22. Duchatel RJ Jackson ER Alvaro F Nixon B Hondermarck H Dun MD Signal Transduction in Diffuse Intrinsic Pontine Glioma Proteomics 2019 19 21–22 e1800479 10.1002/pmic.201800479 31328874 Duchatel RJ, Jackson ER, Alvaro F, Nixon B, Hondermarck H, Dun MD. Signal Transduction in Diffuse Intrinsic Pontine Glioma. Proteomics. 2019;19(21–22):e1800479. 31328874 10.1002/pmic.201800479

23. Koschmann C Zamler D MacKay A Robinson D Wu YM Doherty R Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma Oncotarget 2016 7 40 65696 706 10.18632/oncotarget.11602 27582545 PMC5323185 Koschmann C, Zamler D, MacKay A, Robinson D, Wu YM, Doherty R, et al. Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma. Oncotarget. 2016;7(40):65696–706. 27582545 10.18632/oncotarget.11602 PMC5323185

24. Mayr L Neyazi S Schwark K Trissal M Beck A Labelle J Effective targeting of PDGFRA-altered high-grade glioma with avapritinib Cancer Cell 2025 43 4 740 56.e748 10.1016/j.ccell.2025.02.018 40086436 PMC12121847 Mayr L, Neyazi S, Schwark K, Trissal M, Beck A, Labelle J, et al. Effective targeting of PDGFRA-altered high-grade glioma with avapritinib. Cancer Cell. 2025;43(4):740–56.e748. 40086436 10.1016/j.ccell.2025.02.018 PMC12121847

25. Khadka P Reitman ZJ Lu S Buchan G Gionet G Dubois F PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation Nature communications 2022 13 1 604 10.1038/s41467-022-28198-8 35105861 PMC8807747 Khadka P, Reitman ZJ, Lu S, Buchan G, Gionet G, Dubois F, et al. PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation. Nature communications. 2022;13(1):604. 35105861 10.1038/s41467-022-28198-8 PMC8807747

26. Paugh BS Broniscer A Qu C Miller CP Zhang J Tatevossian RG Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011 29 30 3999 4006 10.1200/JCO.2011.35.5677 21931021 PMC3209696 Paugh BS, Broniscer A, Qu C, Miller CP, Zhang J, Tatevossian RG, et al. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(30):3999–4006. 21931021 10.1200/JCO.2011.35.5677 PMC3209696

27. Guo Y Li Z Parsels LA Wang Z Parsels JD Dalvi A H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition Neuro-oncology 2025 27 8 2129 46 10.1093/neuonc/noaf097 40207661 PMC12448828 Guo Y, Li Z, Parsels LA, Wang Z, Parsels JD, Dalvi A, et al. H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition. Neuro-oncology. 2025;27(8):2129–46. 40207661 10.1093/neuonc/noaf097 PMC12448828

28. Cassim A Dun MD Gallego-Ortega D Valdes-Mora F EZHIP’s role in diffuse midline glioma: echoes of oncohistones? Trends Cancer 2024 10 12 1095 105 10.1016/j.trecan.2024.09.002 39343635 Cassim A, Dun MD, Gallego-Ortega D, Valdes-Mora F. EZHIP’s role in diffuse midline glioma: echoes of oncohistones? Trends Cancer. 2024;10(12):1095–105. 39343635 10.1016/j.trecan.2024.09.002

29. Bailey CP, Wang R, Figueroa M, Zhang S, Wang L, Chandra J: Computational immune infiltration analysis of pediatric high-grade gliomas (pHGGs) reveals differences in immunosuppression and prognosis by tumor location. Comput Syst Oncol 2021, 1(3). 10.1002/cso2.1016 PMC8553216 34723252

30. Lin GL Nagaraja S Filbin MG Suva ML Vogel H Monje M Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma Acta Neuropathol Commun 2018 6 1 51 10.1186/s40478-018-0553-x 29954445 PMC6022714 Lin GL, Nagaraja S, Filbin MG, Suva ML, Vogel H, Monje M. Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma. Acta Neuropathol Commun. 2018;6(1):51. 29954445 10.1186/s40478-018-0553-x PMC6022714

31. Lieberman NAP DeGolier K Kovar HM Davis A Hoglund V Stevens J Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy Neuro-oncology 2019 21 1 83 94 10.1093/neuonc/noy145 30169876 PMC6303470 Lieberman NAP, DeGolier K, Kovar HM, Davis A, Hoglund V, Stevens J, et al. Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: implications for development of immunotherapy. Neuro-oncology. 2019;21(1):83–94. 30169876 10.1093/neuonc/noy145 PMC6303470

32. Bockmayr M Klauschen F Maire CL Rutkowski S Westphal M Lamszus K Immunologic Profiling of Mutational and Transcriptional Subgroups in Pediatric and Adult High-Grade Gliomas Cancer Immunol Res 2019 7 9 1401 11 10.1158/2326-6066.CIR-18-0939 31266783 Bockmayr M, Klauschen F, Maire CL, Rutkowski S, Westphal M, Lamszus K, et al. Immunologic Profiling of Mutational and Transcriptional Subgroups in Pediatric and Adult High-Grade Gliomas. Cancer Immunol Res. 2019;7(9):1401–11. 31266783 10.1158/2326-6066.CIR-18-0939

33. Vitanza NA Monje M Diffuse Intrinsic Pontine Glioma: From Diagnosis to Next-Generation Clinical Trials Curr Treat Options Neurol 2019 21 8 37 10.1007/s11940-019-0577-y 31290035 PMC10234769 Vitanza NA, Monje M. Diffuse Intrinsic Pontine Glioma: From Diagnosis to Next-Generation Clinical Trials. Curr Treat Options Neurol. 2019;21(8):37. 31290035 10.1007/s11940-019-0577-y PMC10234769

34. Jansen MH Veldhuijzen van Zanten SE Sanchez Aliaga E Heymans MW Warmuth-Metz M Hargrave D Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria Neuro-oncology 2015 17 1 160 6 10.1093/neuonc/nou104 24903904 PMC4483042 Jansen MH, Veldhuijzen van Zanten SE, Sanchez Aliaga E, Heymans MW, Warmuth-Metz M, Hargrave D, et al. Survival prediction model of children with diffuse intrinsic pontine glioma based on clinical and radiological criteria. Neuro-oncology. 2015;17(1):160–6. 24903904 10.1093/neuonc/nou104 PMC4483042

35. Fischbein NJ Prados MD Wara W Russo C Edwards MS Barkovich AJ Radiologic classification of brain stem tumors: correlation of magnetic resonance imaging appearance with clinical outcome Pediatric neurosurgery 1996 24 1 9 23 8817611 10.1159/000121010 Fischbein NJ, Prados MD, Wara W, Russo C, Edwards MS, Barkovich AJ. Radiologic classification of brain stem tumors: correlation of magnetic resonance imaging appearance with clinical outcome. Pediatric neurosurgery. 1996;24(1):9–23. 8817611 10.1159/000121010

36. Albright AL Packer RJ Zimmerman R Rorke LB Boyett J Hammond GD Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children’s Cancer Group Neurosurgery 1993 33 6 1026 9 8133987 10.1227/00006123-199312000-00010 Albright AL, Packer RJ, Zimmerman R, Rorke LB, Boyett J, Hammond GD. Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children’s Cancer Group. Neurosurgery. 1993;33(6):1026–9. ; discussion 1029–1030 8133987 10.1227/00006123-199312000-00010

37. Puget S, Blauwblomme T, Grill J: Is biopsy safe in children with newly diagnosed diffuse intrinsic pontine glioma? Am Soc Clin Oncol Educ Book 2012:629-33. 10.14694/EdBook_AM.2012.32.59 24451809

38. Wang ZJ Rao L Bhambhani K Miller K Poulik J Altinok D Diffuse intrinsic pontine glioma biopsy: a single institution experience Pediatr Blood Cancer 2015 62 1 163 5 10.1002/pbc.25224 25263768 Wang ZJ, Rao L, Bhambhani K, Miller K, Poulik J, Altinok D, et al. Diffuse intrinsic pontine glioma biopsy: a single institution experience. Pediatr Blood Cancer. 2015;62(1):163–5. 25263768 10.1002/pbc.25224

39. Sheikh SR Patel NJ Recinos VMR Safety and Technical Efficacy of Pediatric Brainstem Biopsies: An Updated Meta-Analysis of 1000 + Children World Neurosurg 2024 189 428 38.e422 10.1016/j.wneu.2024.06.163 38968995 Sheikh SR, Patel NJ, Recinos VMR. Safety and Technical Efficacy of Pediatric Brainstem Biopsies: An Updated Meta-Analysis of 1000 + Children. World Neurosurg. 2024;189:428–38.e422. 38968995 10.1016/j.wneu.2024.06.163

40. Gupta N Goumnerova LC Manley P Chi SN Neuberg D Puligandla M Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma Neuro-oncology 2018 20 11 1547 55 10.1093/neuonc/noy070 29741745 PMC6176802 Gupta N, Goumnerova LC, Manley P, Chi SN, Neuberg D, Puligandla M, et al. Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro-oncology. 2018;20(11):1547–55. 29741745 10.1093/neuonc/noy070 PMC6176802

41. McVeigh L, Patel T, Miclea M, Schwark K, Ajaero D, Momen F, et al : Updates in Diagnostic Techniques and Experimental Therapies for Diffuse Intrinsic Pontine Glioma. Cancers (Basel) 2025, 17(6). 10.3390/cancers17060931 PMC11940218 40149267

42. Sheikh SR Recinos VMR Thompson EM Mangum R Wright-Nadkarni M Gampel B The role of brainstem biopsy and targeted therapies in pediatric diffuse midline glioma/diffuse intrinsic pontine glioma Frontiers in oncology 2024 14 1504440 10.3389/fonc.2024.1504440 39763605 PMC11701219 Sheikh SR, Recinos VMR, Thompson EM, Mangum R, Wright-Nadkarni M, Gampel B, et al. The role of brainstem biopsy and targeted therapies in pediatric diffuse midline glioma/diffuse intrinsic pontine glioma. Frontiers in oncology. 2024;14:1504440. 39763605 10.3389/fonc.2024.1504440 PMC11701219

43. Cantor E Wierzbicki K Tarapore RS Ravi K Thomas C Cartaxo R Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma Neuro-oncology 2022 24 8 1366 74 10.1093/neuonc/noac030 35137228 PMC9340643 Cantor E, Wierzbicki K, Tarapore RS, Ravi K, Thomas C, Cartaxo R, et al. Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma. Neuro-oncology. 2022;24(8):1366–74. 35137228 10.1093/neuonc/noac030 PMC9340643

44. Li D Bonner ER Wierzbicki K Panditharatna E Huang T Lulla R Standardization of the liquid biopsy for pediatric diffuse midline glioma using ddPCR Scientific reports 2021 11 1 5098 10.1038/s41598-021-84513-1 33658570 PMC7930089 Li D, Bonner ER, Wierzbicki K, Panditharatna E, Huang T, Lulla R, et al. Standardization of the liquid biopsy for pediatric diffuse midline glioma using ddPCR. Scientific reports. 2021;11(1):5098. 33658570 10.1038/s41598-021-84513-1 PMC7930089

45. Panditharatna E Kilburn LB Aboian MS Kambhampati M Gordish-Dressman H Magge SN Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy Clinical cancer research : an official journal of the American Association for Cancer Research 2018 24 23 5850 9 10.1158/1078-0432.CCR-18-1345 30322880 PMC6279526 Panditharatna E, Kilburn LB, Aboian MS, Kambhampati M, Gordish-Dressman H, Magge SN, et al. Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018;24(23):5850–9. 30322880 10.1158/1078-0432.CCR-18-1345 PMC6279526

46. Patel J Aittaleb R Doherty R Gera A Lau B Messinger D Liquid biopsy in H3K27M diffuse midline glioma Neuro-oncology 2024 26 Supplement_2 S101 s109 10.1093/neuonc/noad229 38096156 PMC11066927 Patel J, Aittaleb R, Doherty R, Gera A, Lau B, Messinger D, et al. Liquid biopsy in H3K27M diffuse midline glioma. Neuro-oncology. 2024;26(Supplement_2):S101–s109. 38096156 10.1093/neuonc/noad229 PMC11066927

47. Warren KE Beyond the Blood:Brain Barrier: The Importance of Central Nervous System (CNS) Pharmacokinetics for the Treatment of CNS Tumors, Including Diffuse Intrinsic Pontine Glioma Frontiers in oncology 2018 8 239 10.3389/fonc.2018.00239 30018882 PMC6037693 Warren KE. Beyond the Blood:Brain Barrier: The Importance of Central Nervous System (CNS) Pharmacokinetics for the Treatment of CNS Tumors, Including Diffuse Intrinsic Pontine Glioma. Frontiers in oncology. 2018;8:239. 30018882 10.3389/fonc.2018.00239 PMC6037693

48. Veringa SJ Biesmans D van Vuurden DG Jansen MH Wedekind LE Horsman I In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma PLoS One 2013 8 4 e61512 10.1371/journal.pone.0061512 23637844 PMC3639279 Veringa SJ, Biesmans D, van Vuurden DG, Jansen MH, Wedekind LE, Horsman I, et al. In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma. PLoS One. 2013;8(4):e61512. 23637844 10.1371/journal.pone.0061512 PMC3639279

49. Sandberg DI Edgar MA Souweidane MM Convection-enhanced delivery into the rat brainstem J Neurosurg 2002 96 5 885 91 10.3171/jns.2002.96.5.0885 12005396 Sandberg DI, Edgar MA, Souweidane MM. Convection-enhanced delivery into the rat brainstem. J Neurosurg. 2002;96(5):885–91. 12005396 10.3171/jns.2002.96.5.0885

50. Frazier JL Lee J Thomale UW Noggle JC Cohen KJ Jallo GI Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies J Neurosurg Pediatr 2009 3 4 259 69 10.3171/2008.11.PEDS08281 19338403 Frazier JL, Lee J, Thomale UW, Noggle JC, Cohen KJ, Jallo GI. Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies. J Neurosurg Pediatr. 2009;3(4):259–69. 19338403 10.3171/2008.11.PEDS08281

51. Kebudi R Cakir FB Management of diffuse pontine gliomas in children: recent developments Paediatr Drugs 2013 15 5 351 62 10.1007/s40272-013-0033-5 23719782 Kebudi R, Cakir FB. Management of diffuse pontine gliomas in children: recent developments. Paediatr Drugs. 2013;15(5):351–62. 23719782 10.1007/s40272-013-0033-5

52. Jenkin RD Boesel C Ertel I Evans A Hittle R Ortega J Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the Childrens Cancer Study Group J Neurosurg 1987 66 2 227 33 10.3171/jns.1987.66.2.0227 3806204 Jenkin RD, Boesel C, Ertel I, Evans A, Hittle R, Ortega J, et al. Brain-stem tumors in childhood: a prospective randomized trial of irradiation with and without adjuvant CCNU, VCR, and prednisone. A report of the Childrens Cancer Study Group. J Neurosurg. 1987;66(2):227–33. 3806204 10.3171/jns.1987.66.2.0227

53. Packer RJ Boyett JM Zimmerman RA Albright AL Kaplan AM Rorke LB Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial Cancer 1994 74 6 1827 34 10.1002/1097-0142(19940915)74:6<1827::AID-CNCR2820740628>3.0.CO;2-Q 8082086 Packer RJ, Boyett JM, Zimmerman RA, Albright AL, Kaplan AM, Rorke LB, et al. Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial. Cancer. 1994;74(6):1827–34. 8082086 10.1002/1097-0142(19940915)74:6<1827::aid-cncr2820740628>3.0.co;2-q

54. Janssens GO Gandola L Bolle S Mandeville H Ramos-Albiac M van Beek K Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group Eur J Cancer 2017 73 38 47 10.1016/j.ejca.2016.12.007 28161497 Janssens GO, Gandola L, Bolle S, Mandeville H, Ramos-Albiac M, van Beek K, et al. Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group. Eur J Cancer. 2017;73:38–47. 28161497 10.1016/j.ejca.2016.12.007

55. Valvi S Manoharan N Mateos MK Hassall TE Ziegler DS McCowage GB Management of patients with diffuse intrinsic pontine glioma in Australia and New Zealand: Australian and New Zealand Children’s Haematology/Oncology Group position statement Med J Aust 2024 220 10 533 8 10.5694/mja2.52295 38699949 Valvi S, Manoharan N, Mateos MK, Hassall TE, Ziegler DS, McCowage GB, et al. Management of patients with diffuse intrinsic pontine glioma in Australia and New Zealand: Australian and New Zealand Children’s Haematology/Oncology Group position statement. Med J Aust. 2024;220(10):533–8. 38699949 10.5694/mja2.52295

56. Zaghloul MS Bishr MK Refaat A Hemaly AE Ayadi MA Ahmed S Re-Irradiation for the Progressive Pediatric Diffuse Intrinsic Pontine Glioma: A Report on 109 Children From a Single Center Pediatr Blood Cancer 2025 72 4 e31587 10.1002/pbc.31587 39905588 Zaghloul MS, Bishr MK, Refaat A, Hemaly AE, Ayadi MA, Ahmed S, et al. Re-Irradiation for the Progressive Pediatric Diffuse Intrinsic Pontine Glioma: A Report on 109 Children From a Single Center. Pediatr Blood Cancer. 2025;72(4):e31587. 39905588 10.1002/pbc.31587

57. Vanan MI Underhill DA Eisenstat DD Targeting Epigenetic Pathways in the Treatment of Pediatric Diffuse (High Grade) Gliomas Neurotherapeutics 2017 14 2 274 83 10.1007/s13311-017-0514-2 28233220 PMC5398987 Vanan MI, Underhill DA, Eisenstat DD. Targeting Epigenetic Pathways in the Treatment of Pediatric Diffuse (High Grade) Gliomas. Neurotherapeutics. 2017;14(2):274–83. 28233220 10.1007/s13311-017-0514-2 PMC5398987

58. Mandell LR Kadota R Freeman C Douglass EC Fontanesi J Cohen ME There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy Int J Radiat Oncol Biol Phys 1999 43 5 959 64 10.1016/S0360-3016(98)00501-X 10192340 Mandell LR, Kadota R, Freeman C, Douglass EC, Fontanesi J, Cohen ME, et al. There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys. 1999;43(5):959–64. 10192340 10.1016/s0360-3016(98)00501-x

59. Doz F Neuenschwander S Bouffet E Gentet JC Schneider P Kalifa C Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d’Oncologie Pédiatrique Eur J Cancer 2002 38 6 815 9 10.1016/S0959-8049(02)00029-1 11937316 Doz F, Neuenschwander S, Bouffet E, Gentet JC, Schneider P, Kalifa C, et al. Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: a study by the Société Française d’Oncologie Pédiatrique. Eur J Cancer. 2002;38(6):815–9. 11937316 10.1016/s0959-8049(02)00029-1

60. Cohen KJ Heideman RL Zhou T Holmes EJ Lavey RS Bouffet E Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children’s Oncology Group Neuro-oncology 2011 13 4 410 6 10.1093/neuonc/noq205 21345842 PMC3064697 Cohen KJ, Heideman RL, Zhou T, Holmes EJ, Lavey RS, Bouffet E, et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children’s Oncology Group. Neuro-oncology. 2011;13(4):410–6. 21345842 10.1093/neuonc/noq205 PMC3064697

61. Michalski A Bouffet E Taylor RE Hargrave D Walker D Picton S The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma Journal of Neuro-Oncology 2010 100 1 81 88 10.1007/s11060-010-0141-9 20238235 Michalski A, Bouffet E, Taylor RE, Hargrave D, Walker D, Picton S, et al. The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma. Journal of Neuro-Oncology. 2010;100(1):81–88. 20238235 10.1007/s11060-010-0141-9

62. Wolff JE Kortmann RD Wolff B Pietsch T Peters O Schmid HJ High dose methotrexate for pediatric high grade glioma: results of the HIT-GBM-D pilot study Journal of Neuro-Oncology 2011 102 3 433 42 10.1007/s11060-010-0334-2 20694800 Wolff JE, Kortmann RD, Wolff B, Pietsch T, Peters O, Schmid HJ, et al. High dose methotrexate for pediatric high grade glioma: results of the HIT-GBM-D pilot study. Journal of Neuro-Oncology. 2011;102(3):433–42. 20694800 10.1007/s11060-010-0334-2

63. Gallitto M Lazarev S Wasserman I Stafford JM Wolden SL Terezakis SA Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review Adv Radiat Oncol 2019 4 3 520 31 10.1016/j.adro.2019.03.009 31360809 PMC6639749 Gallitto M, Lazarev S, Wasserman I, Stafford JM, Wolden SL, Terezakis SA, et al. Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review. Adv Radiat Oncol. 2019;4(3):520–31. 31360809 10.1016/j.adro.2019.03.009 PMC6639749

64. Massimino M Spreafico F Biassoni V Simonetti F Riva D Trecate G Diffuse pontine gliomas in children: changing strategies, changing results? A mono-institutional 20-year experience Journal of Neuro-Oncology 2008 87 3 355 61 10.1007/s11060-008-9525-5 18217208 Massimino M, Spreafico F, Biassoni V, Simonetti F, Riva D, Trecate G, et al. Diffuse pontine gliomas in children: changing strategies, changing results? A mono-institutional 20-year experience. Journal of Neuro-Oncology. 2008;87(3):355–61. 18217208 10.1007/s11060-008-9525-5

65. Sirachainan N Pakakasama S Visudithbhan A Chiamchanya S Tuntiyatorn L Dhanachai M Concurrent radiotherapy with temozolomide followed by adjuvant temozolomide and cis-retinoic acid in children with diffuse intrinsic pontine glioma Neuro-Oncology 2008 10 4 577 82 10.1215/15228517-2008-025 18559468 PMC2666231 Sirachainan N, Pakakasama S, Visudithbhan A, Chiamchanya S, Tuntiyatorn L, Dhanachai M, et al. Concurrent radiotherapy with temozolomide followed by adjuvant temozolomide and cis-retinoic acid in children with diffuse intrinsic pontine glioma. Neuro-Oncology. 2008;10(4):577–82. 18559468 10.1215/15228517-2008-025 PMC2666231

66. Di Ruscio V Del Baldo G Fabozzi F Vinci M Cacchione A de Billy E Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle Diagnostics (Basel) 2022 12 2064 10.3390/diagnostics12092064 36140466 PMC9497626 Di Ruscio V, Del Baldo G, Fabozzi F, Vinci M, Cacchione A, de Billy E, et al. Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle. Diagnostics (Basel). 2022;12:2064. 36140466 10.3390/diagnostics12092064 PMC9497626

67. Bailey S Howman A Wheatley K Wherton D Boota N Pizer B Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy–results of a United Kingdom phase II trial (CNS 2007 04) Eur J Cancer 2013 49 18 3856 62 10.1016/j.ejca.2013.08.006 24011536 PMC3853623 Bailey S, Howman A, Wheatley K, Wherton D, Boota N, Pizer B, et al. Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy–results of a United Kingdom phase II trial (CNS 2007 04). Eur J Cancer. 2013;49(18):3856–62. 24011536 10.1016/j.ejca.2013.08.006 PMC3853623

68. MacDonald TJ Arenson EB Ater J Sposto R Bevan HE Bruner J Phase II study of high-dose chemotherapy before radiation in children with newly diagnosed high-grade astrocytoma: final analysis of Children’s Cancer Group Study 9933 Cancer 2005 104 12 2862 71 10.1002/cncr.21593 16315242 MacDonald TJ, Arenson EB, Ater J, Sposto R, Bevan HE, Bruner J, et al. Phase II study of high-dose chemotherapy before radiation in children with newly diagnosed high-grade astrocytoma: final analysis of Children’s Cancer Group Study 9933. Cancer. 2005;104(12):2862–71. 16315242 10.1002/cncr.21593

69. Finlay JL Boyett JM Yates AJ Wisoff JH Milstein JM Geyer JR Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group Journal of Clinical Oncology 1995 13 1 112 23 10.1200/JCO.1995.13.1.112 7799011 Finlay JL, Boyett JM, Yates AJ, Wisoff JH, Milstein JM, Geyer JR, et al. Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group. Journal of Clinical Oncology. 1995;13(1):112–23. 7799011 10.1200/JCO.1995.13.1.112

70. Pollack IF Agnihotri S Broniscer A Childhood brain tumors: current management, biological insights, and future directions J Neurosurg Pediatr 2019 23 3 261 73 10.3171/2018.10.PEDS18377 30835699 PMC6823600 Pollack IF, Agnihotri S, Broniscer A. Childhood brain tumors: current management, biological insights, and future directions. J Neurosurg Pediatr. 2019;23(3):261–73. 30835699 10.3171/2018.10.PEDS18377 PMC6823600

71. Haas-Kogan DA Banerjee A Poussaint TY Kocak M Prados MD Geyer JR Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas Neuro-Oncology 2011 13 3 298 306 10.1093/neuonc/noq202 21339191 PMC3064607 Haas-Kogan DA, Banerjee A, Poussaint TY, Kocak M, Prados MD, Geyer JR, et al. Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas. Neuro-Oncology. 2011;13(3):298–306. 21339191 10.1093/neuonc/noq202 PMC3064607

72. Jansen MH van Vuurden DG Vandertop WP Kaspers GJ Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology Cancer Treat Rev 2012 38 1 27 35 10.1016/j.ctrv.2011.06.007 21764221 Jansen MH, van Vuurden DG, Vandertop WP, Kaspers GJ. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev. 2012;38(1):27–35. 21764221 10.1016/j.ctrv.2011.06.007

73. Prabhu VV Morrow S Rahman Kawakibi A Zhou L Ralff M Ray J ONC201 and imipridones: Anti-cancer compounds with clinical efficacy Neoplasia 2020 22 12 725 44 10.1016/j.neo.2020.09.005 33142238 PMC7588802 Prabhu VV, Morrow S, Rahman Kawakibi A, Zhou L, Ralff M, Ray J, et al. ONC201 and imipridones: Anti-cancer compounds with clinical efficacy. Neoplasia. 2020;22(12):725–44. 33142238 10.1016/j.neo.2020.09.005 PMC7588802

74. Duchatel RJ Jackson ER Parackal SG Kiltschewskij D Findlay IJ Mannan A PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma J Clin Invest 2024 134 e170329 10.1172/JCI170329 38319732 PMC10940093 Duchatel RJ, Jackson ER, Parackal SG, Kiltschewskij D, Findlay IJ, Mannan A, et al. PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma. J Clin Invest. 2024;134:e170329. 38319732 10.1172/JCI170329 PMC10940093

75. Majzner RG Ramakrishna S Yeom KW Patel S Chinnasamy H Schultz LM GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas Nature 2022 603 7903 934 41 10.1038/s41586-022-04489-4 35130560 PMC8967714 Majzner RG, Ramakrishna S, Yeom KW, Patel S, Chinnasamy H, Schultz LM, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature. 2022;603(7903):934–41. 35130560 10.1038/s41586-022-04489-4 PMC8967714

76. Vitanza NA Wilson AL Huang W Seidel K Brown C Gustafson JA Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety Cancer Discov 2023 13 1 114 31 10.1158/2159-8290.CD-22-0750 36259971 PMC9827115 Vitanza NA, Wilson AL, Huang W, Seidel K, Brown C, Gustafson JA, et al. Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety. Cancer Discov. 2023;13(1):114–31. 36259971 10.1158/2159-8290.CD-22-0750 PMC9827115

77. Brown CE Alizadeh D Starr R Weng L Wagner JR Naranjo A Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy N Engl J Med 2016 375 26 2561 9 10.1056/NEJMoa1610497 28029927 PMC5390684 Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med. 2016;375(26):2561–9. 28029927 10.1056/NEJMoa1610497 PMC5390684

78. Vitanza NA Ronsley R Choe M Seidel K Huang W Rawlings-Rhea SD Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial Nature Medicine 2025 31 3 861 8 10.1038/s41591-024-03451-3 39775044 PMC11922736 Vitanza NA, Ronsley R, Choe M, Seidel K, Huang W, Rawlings-Rhea SD, et al. Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial. Nature Medicine. 2025;31(3):861–8. 39775044 10.1038/s41591-024-03451-3 PMC11922736

79. Olsen HE Lynn GM Valdes PA Cerecedo Lopez CD Ishizuka AS Arnaout O Therapeutic cancer vaccines for pediatric malignancies: advances, challenges, and emerging technologies Neuro-Oncology Advances 2021 3 1 vdab027 10.1093/noajnl/vdab027 33860227 PMC8034661 Olsen HE, Lynn GM, Valdes PA, Cerecedo Lopez CD, Ishizuka AS, Arnaout O, et al. Therapeutic cancer vaccines for pediatric malignancies: advances, challenges, and emerging technologies. Neuro-Oncology Advances. 2021;3(1):vdab027. 33860227 10.1093/noajnl/vdab027 PMC8034661

80. Benitez-Ribas D Cabezon R Florez-Grau G Molero MC Puerta P Guillen A Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma Frontiers in Oncology 2018 8 127 10.3389/fonc.2018.00127 29755954 PMC5932163 Benitez-Ribas D, Cabezon R, Florez-Grau G, Molero MC, Puerta P, Guillen A, et al. Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma. Frontiers in Oncology. 2018;8:127. 29755954 10.3389/fonc.2018.00127 PMC5932163

81. Fried I Lossos A Ben Ami T Dvir R Toledano H Ben Arush MW Preliminary results of immune modulating antibody MDV9300 (pidilizumab) treatment in children with diffuse intrinsic pontine glioma Journal of Neuro-Oncology 2018 136 1 189 95 10.1007/s11060-017-2643-1 29143272 Fried I, Lossos A, Ben Ami T, Dvir R, Toledano H, Ben Arush MW, et al. Preliminary results of immune modulating antibody MDV9300 (pidilizumab) treatment in children with diffuse intrinsic pontine glioma. Journal of Neuro-Oncology. 2018;136(1):189–95. 29143272 10.1007/s11060-017-2643-1

82. Martinez-Velez N Garcia-Moure M Marigil M Gonzalez-Huarriz M Puigdelloses M Gallego Perez-Larraya J The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models Nature Communications 2019 10 1 2235 10.1038/s41467-019-10043-0 31138805 PMC6538754 Martinez-Velez N, Garcia-Moure M, Marigil M, Gonzalez-Huarriz M, Puigdelloses M, Gallego Perez-Larraya J, et al. The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Nature Communications. 2019;10(1):2235. 31138805 10.1038/s41467-019-10043-0 PMC6538754

83. Sheehan K Sheehan D Sulaiman M Padilla F Moore D Sheehan J Investigation of the tumoricidal effects of sonodynamic therapy in malignant glioblastoma brain tumors Journal of Neuro-Oncology 2020 148 1 9 16 10.1007/s11060-020-03504-w 32361864 Sheehan K, Sheehan D, Sulaiman M, Padilla F, Moore D, Sheehan J, et al. Investigation of the tumoricidal effects of sonodynamic therapy in malignant glioblastoma brain tumors. Journal of Neuro-Oncology. 2020;148(1):9–16. 32361864 10.1007/s11060-020-03504-w

84. Wu SK Santos MA Marcus SL Hynynen K MR-guided Focused Ultrasound Facilitates Sonodynamic Therapy with 5-Aminolevulinic Acid in a Rat Glioma Model Scientific Reports 2019 9 1 10465 10.1038/s41598-019-46832-2 31320671 PMC6639400 Wu SK, Santos MA, Marcus SL, Hynynen K. MR-guided Focused Ultrasound Facilitates Sonodynamic Therapy with 5-Aminolevulinic Acid in a Rat Glioma Model. Scientific Reports. 2019;9(1):10465. 31320671 10.1038/s41598-019-46832-2 PMC6639400

85. Sanai N Tovmasyan A Tien AC Chang YW Margaryan T Knight W An early clinical trial of 5-ALA sonodynamic therapy in recurrent high-grade glioma Science translational medicine 2025 17 826 eads5813 10.1126/scitranslmed.ads5813 41296829 Sanai N, Tovmasyan A, Tien AC, Chang YW, Margaryan T, Knight W, et al. An early clinical trial of 5-ALA sonodynamic therapy in recurrent high-grade glioma. Science translational medicine. 2025;17(826):eads5813. 41296829 10.1126/scitranslmed.ads5813

86. DIPG.org: DMG/DIPG Trial Finder. In.; 2025.

87. Clinicaltrials.gov: Diffuse Midline Glioma (DMG) and Diffuse Intrinsic Pontine Glioma (DIPG) Clinical Trials. In., 2025 edn. National Library of Medicine (NIH).

88. Hashizume R Epigenetic Targeted Therapy for Diffuse Intrinsic Pontine Glioma Neurol Med Chir (Tokyo) 2017 57 7 331 42 10.2176/nmc.ra.2017-0018 28592748 PMC5566706 Hashizume R. Epigenetic Targeted Therapy for Diffuse Intrinsic Pontine Glioma. Neurol Med Chir (Tokyo). 2017;57(7):331–42. 28592748 10.2176/nmc.ra.2017-0018 PMC5566706

89. Hennika T Hu G Olaciregui NG Barton KL Ehteda A Chitranjan A Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models PLoS One 2017 12 1 e0169485 10.1371/journal.pone.0169485 28052119 PMC5215670 Hennika T, Hu G, Olaciregui NG, Barton KL, Ehteda A, Chitranjan A, et al. Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models. PLoS One. 2017;12(1):e0169485. 28052119 10.1371/journal.pone.0169485 PMC5215670

90. Wang Z Zang C Cui K Schones DE Barski A Peng W Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes Cell 2009 138 5 1019 31 10.1016/j.cell.2009.06.049 19698979 PMC2750862 Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell. 2009;138(5):1019–31. 19698979 10.1016/j.cell.2009.06.049 PMC2750862

91. Hashizume R Andor N Ihara Y Lerner R Gan H Chen X Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma Nature medicine 2014 20 12 1394 6 10.1038/nm.3716 25401693 PMC4257862 Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nature medicine. 2014;20(12):1394–6. 25401693 10.1038/nm.3716 PMC4257862

92. Ehteda A Simon S Franshaw L Giorgi FM Liu J Joshi S Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG Cell Rep 2021 35 2 108994 10.1016/j.celrep.2021.108994 33852836 Ehteda A, Simon S, Franshaw L, Giorgi FM, Liu J, Joshi S, et al. Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG. Cell Rep. 2021;35(2):108994. 33852836 10.1016/j.celrep.2021.108994

93. Carvalho D Taylor KR Olaciregui NG Molinari V Clarke M Mackay A ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma Commun Biol 2019 2 156 10.1038/s42003-019-0420-8 31098401 PMC6509210 Carvalho D, Taylor KR, Olaciregui NG, Molinari V, Clarke M, Mackay A, et al. ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma. Commun Biol. 2019;2:156. 31098401 10.1038/s42003-019-0420-8 PMC6509210

94. Fortin J Tian R Zarrabi I Hill G Williams E Sanchez-Duffhues G Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas Cancer Cell 2020 37 3 308 23 e312 10.1016/j.ccell.2020.02.002 32142668 PMC7105820 Fortin J, Tian R, Zarrabi I, Hill G, Williams E, Sanchez-Duffhues G, et al. Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas. Cancer Cell. 2020;37(3):308–23 e312. 32142668 10.1016/j.ccell.2020.02.002 PMC7105820

95. Mohammad F Weissmann S Leblanc B Pandey DP Hojfeldt JW Comet I EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas Nature medicine 2017 23 4 483 92 10.1038/nm.4293 28263309 Mohammad F, Weissmann S, Leblanc B, Pandey DP, Hojfeldt JW, Comet I, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nature medicine. 2017;23(4):483–92. 28263309 10.1038/nm.4293

96. Zhang Y Dong W Zhu J Wang L Wu X Shan H Combination of EZH2 inhibitor and BET inhibitor for treatment of diffuse intrinsic pontine glioma Cell Biosci 2017 7 56 10.1186/s13578-017-0184-0 29118968 PMC5663148 Zhang Y, Dong W, Zhu J, Wang L, Wu X, Shan H. Combination of EZH2 inhibitor and BET inhibitor for treatment of diffuse intrinsic pontine glioma. Cell Biosci. 2017;7:56. 29118968 10.1186/s13578-017-0184-0 PMC5663148

97. Shiridokht F Kehtari P Eskandani M Farajollahi A Vandghanooni S Advancing cancer radiotherapy: Harnessing radiosensitizers and nanotechnology for enhanced tumor control Int J Pharm X 2025 10 100419 41189671 10.1016/j.ijpx.2025.100419 PMC12581699 Shiridokht F, Kehtari P, Eskandani M, Farajollahi A, Vandghanooni S. Advancing cancer radiotherapy: Harnessing radiosensitizers and nanotechnology for enhanced tumor control. Int J Pharm X. 2025;10:100419. 41189671 10.1016/j.ijpx.2025.100419 PMC12581699

98. Shen H Huynh QS Mudassar F Chang C Gloss B Ing P Metabolic reprogramming in diffuse intrinsic pontine gliomas (DIPG): dual inhibition of mitochondrial oxidative phosphorylation and lactate metabolism to enhance anti-tumor and radiosensitizing effects in DIPG cells Cancer Metab 2025 13 1 43 10.1186/s40170-025-00411-4 41163069 PMC12570633 Shen H, Huynh QS, Mudassar F, Chang C, Gloss B, Ing P, et al. Metabolic reprogramming in diffuse intrinsic pontine gliomas (DIPG): dual inhibition of mitochondrial oxidative phosphorylation and lactate metabolism to enhance anti-tumor and radiosensitizing effects in DIPG cells. Cancer Metab. 2025;13(1):43. 41163069 10.1186/s40170-025-00411-4 PMC12570633

99. Mudassar F Shen H O'Neill G Hau E Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas J Exp Clin Cancer Res 2020 39 1 208 10.1186/s13046-020-01724-6 33028364 PMC7542384 Mudassar F, Shen H, O'Neill G, Hau E. Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas. J Exp Clin Cancer Res. 2020;39(1):208. 33028364 10.1186/s13046-020-01724-6 PMC7542384

100. Bredlau AL Dixit S Chen C Broome AM Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma Curr Neuropharmacol 2017 15 1 104 15 10.2174/1570159X14666160223121002 26903150 PMC5327462 Bredlau AL, Dixit S, Chen C, Broome AM. Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma. Curr Neuropharmacol. 2017;15(1):104–15. 26903150 10.2174/1570159X14666160223121002 PMC5327462

101. Miyasato DL Mohamed AW Zavaleta C A path toward the clinical translation of nano-based imaging contrast agents Wiley Interdiscip Rev Nanomed Nanobiotechnol 2021 13 6 e1721 10.1002/wnan.1721 33938151 Miyasato DL, Mohamed AW, Zavaleta C. A path toward the clinical translation of nano-based imaging contrast agents. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021;13(6):e1721. 33938151 10.1002/wnan.1721

102. Upreti M Jyoti A Sethi P Tumor microenvironment and nanotherapeutics Transl Cancer Res 2013 2 4 309 19 24634853 10.3978/j.issn.2218-676X.2013.08.11 PMC3951160 Upreti M, Jyoti A, Sethi P. Tumor microenvironment and nanotherapeutics. Transl Cancer Res. 2013;2(4):309–19. 24634853 10.3978/j.issn.2218-676X.2013.08.11 PMC3951160

103. Dasgupta A Sofias AM Kiessling F Lammers T Nanoparticle Delivery to Tumours: From EPR and ATR Mechanisms to Clinical Impact Nat Rev Bioeng 2024 2 9 714 6 10.1038/s44222-024-00203-3 39376248 PMC7616668 Dasgupta A, Sofias AM, Kiessling F, Lammers T. Nanoparticle Delivery to Tumours: From EPR and ATR Mechanisms to Clinical Impact. Nat Rev Bioeng. 2024;2(9):714–6. 39376248 10.1038/s44222-024-00203-3 PMC7616668

104. Wu JLY Ji Q Blackadar C Nguyen LNM Lin ZP Sepahi Z The pathways for nanoparticle transport across tumour endothelium Nat Nanotechnol 2025 20 5 672 82 10.1038/s41565-025-01877-5 40097646 Wu JLY, Ji Q, Blackadar C, Nguyen LNM, Lin ZP, Sepahi Z, et al. The pathways for nanoparticle transport across tumour endothelium. Nat Nanotechnol. 2025;20(5):672–82. 40097646 10.1038/s41565-025-01877-5

105. Hoshyar N Gray S Han H Bao G The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction Nanomedicine (Lond) 2016 11 6 673 92 10.2217/nnm.16.5 27003448 PMC5561790 Hoshyar N, Gray S, Han H, Bao G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine (Lond). 2016;11(6):673–92. 27003448 10.2217/nnm.16.5 PMC5561790

106. Gabizon AA Cancer nanomedicine from a clinician-scientist perspective: Lessons and prospects J Control Release 2025 382 113731 10.1016/j.jconrel.2025.113731 40228664 Gabizon AA. Cancer nanomedicine from a clinician-scientist perspective: Lessons and prospects. J Control Release. 2025;382:113731. 40228664 10.1016/j.jconrel.2025.113731

107. Edelman R Assaraf YG Slavkin A Dolev T Shahar T Livney YD Developing Body-Components-Based Theranostic Nanoparticles for Targeting Ovarian Cancer Pharmaceutics 2019 11 216 10.3390/pharmaceutics11050216 31060303 PMC6572588 Edelman R, Assaraf YG, Slavkin A, Dolev T, Shahar T, Livney YD. Developing Body-Components-Based Theranostic Nanoparticles for Targeting Ovarian Cancer. Pharmaceutics. 2019;11:216. 31060303 10.3390/pharmaceutics11050216 PMC6572588

108. Zhang Y Kohler N Zhang M Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake Biomaterials 2002 23 7 1553 61 10.1016/S0142-9612(01)00267-8 11922461 Zhang Y, Kohler N, Zhang M. Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials. 2002;23(7):1553–61. 11922461 10.1016/s0142-9612(01)00267-8

109. Davis ME Chen ZG Shin DM Nanoparticle therapeutics: an emerging treatment modality for cancer Nat Rev Drug Discov 2008 7 9 771 82 10.1038/nrd2614 18758474 Davis ME, Chen ZG, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008;7(9):771–82. 18758474 10.1038/nrd2614

110. Whitley MJ Cardona DM Lazarides AL Spasojevic I Ferrer JM Cahill J A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer Science translational medicine 2016 8 320 320ra324 10.1126/scitranslmed.aad0293 PMC4794335 26738797 Whitley MJ, Cardona DM, Lazarides AL, Spasojevic I, Ferrer JM, Cahill J, et al. A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Science translational medicine. 2016;8(320):320ra324. 10.1126/scitranslmed.aad0293 PMC4794335 26738797

111. Wang Y Kang S Khan A Ruttner G Leigh SY Murray M Quantitative molecular phenotyping with topically applied SERS nanoparticles for intraoperative guidance of breast cancer lumpectomy Scientific reports 2016 6 21242 10.1038/srep21242 26878888 PMC4754709 Wang Y, Kang S, Khan A, Ruttner G, Leigh SY, Murray M, et al. Quantitative molecular phenotyping with topically applied SERS nanoparticles for intraoperative guidance of breast cancer lumpectomy. Scientific reports. 2016;6:21242. 26878888 10.1038/srep21242 PMC4754709

112. Swierczewska M Liu G Lee S Chen X High-sensitivity nanosensors for biomarker detection Chem Soc Rev 2012 41 7 2641 55 10.1039/C1CS15238F 22187721 PMC3629948 Swierczewska M, Liu G, Lee S, Chen X. High-sensitivity nanosensors for biomarker detection. Chem Soc Rev. 2012;41(7):2641–55. 22187721 10.1039/c1cs15238f PMC3629948

113. Tipirneni KE Warram JM Moore LS Prince AC de Boer E Jani AH Oncologic Procedures Amenable to Fluorescence-guided Surgery Ann Surg 2017 266 1 36 47 10.1097/SLA.0000000000002127 28045715 PMC6280663 Tipirneni KE, Warram JM, Moore LS, Prince AC, de Boer E, Jani AH, et al. Oncologic Procedures Amenable to Fluorescence-guided Surgery. Ann Surg. 2017;266(1):36–47. 28045715 10.1097/SLA.0000000000002127 PMC6280663

114. Rodriguez K Wilkins GG Newcomb P Gwirtz PA Skrine R Risk Factors for Re-Excision Following Breast-Conserving Surgery Oncol Nurs Forum 2017 44 3 358 65 10.1188/17.ONF.358-365 28635983 Rodriguez K, Wilkins GG, Newcomb P, Gwirtz PA, Skrine R. Risk Factors for Re-Excision Following Breast-Conserving Surgery. Oncol Nurs Forum. 2017;44(3):358–65. 28635983 10.1188/17.ONF.358-365

115. Zhou B Shi B Jin D Liu X Controlling upconversion nanocrystals for emerging applications Nat Nanotechnol 2015 10 11 924 36 10.1038/nnano.2015.251 26530022 Zhou B, Shi B, Jin D, Liu X. Controlling upconversion nanocrystals for emerging applications. Nat Nanotechnol. 2015;10(11):924–36. 26530022 10.1038/nnano.2015.251

116. Cancer Nano-Therapies in the Clinic and Clinical Trials. In.: National Cancer Institute; 2023.

117. Morales CS Grodzinski P Current landscape of treating different cancers using nanomedicines: Trends and perspectives Wiley Interdiscip Rev Nanomed Nanobiotechnol 2024 16 1 e1927 10.1002/wnan.1927 37706362 Morales CS, Grodzinski P. Current landscape of treating different cancers using nanomedicines: Trends and perspectives. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2024;16(1):e1927. 37706362 10.1002/wnan.1927

118. Unnikrishnan G Joy A Megha M Kolanthai E Senthilkumar M Exploration of inorganic nanoparticles for revolutionary drug delivery applications: a critical review Discov Nano 2023 18 1 157 10.1186/s11671-023-03943-0 38112849 PMC10730791 Unnikrishnan G, Joy A, Megha M, Kolanthai E, Senthilkumar M. Exploration of inorganic nanoparticles for revolutionary drug delivery applications: a critical review. Discov Nano. 2023;18(1):157. 38112849 10.1186/s11671-023-03943-0 PMC10730791

119. Zhang Y Fu X Jia J Wikerholmen T Xi K Kong Y Glioblastoma Therapy Using Codelivery of Cisplatin and Glutathione Peroxidase Targeting siRNA from Iron Oxide Nanoparticles ACS Appl Mater Interfaces 2020 12 39 43408 21 10.1021/acsami.0c12042 32885649 Zhang Y, Fu X, Jia J, Wikerholmen T, Xi K, Kong Y, et al. Glioblastoma Therapy Using Codelivery of Cisplatin and Glutathione Peroxidase Targeting siRNA from Iron Oxide Nanoparticles. ACS Appl Mater Interfaces. 2020;12(39):43408–21. 32885649 10.1021/acsami.0c12042

120. Wang K Kievit FM Chiarelli PA Stephen ZR Lin G Silber JR siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model Adv Funct Mater 2021 31 2007166 10.1002/adfm.202007166 33708035 PMC7942690 Wang K, Kievit FM, Chiarelli PA, Stephen ZR, Lin G, Silber JR, et al. siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model. Adv Funct Mater. 2021;31:2007166. 33708035 10.1002/adfm.202007166 PMC7942690

121. Stephen ZR Chiarelli PA Revia RA Wang K Kievit F Dayringer C Assessment of Convection-Enhanced Delivery by Targeted and Nontargeted Nanoparticles in a Human Glioblastoma Mouse Model Cancer Research 2019 79 18 4776 86 10.1158/0008-5472.CAN-18-2998 31331912 PMC6744959 Stephen ZR, Chiarelli PA, Revia RA, Wang K, Kievit F, Dayringer C, et al. Assessment of Convection-Enhanced Delivery by Targeted and Nontargeted Nanoparticles in a Human Glioblastoma Mouse Model. Cancer Research. 2019;79(18):4776–86. 31331912 10.1158/0008-5472.CAN-18-2998 PMC6744959

122. Ruan S Qin L Xiao W Hu C Zhou Y Wang R Acid-Responsive Transferrin Dissociation and GLUT Mediated Exocytosis for Increased Blood–Brain Barrier Transcytosis and Programmed Glioma Targeting Delivery Advanced Functional Materials 2018 28 1802227 10.1002/adfm.201802227 Ruan S, Qin L, Xiao W, Hu C, Zhou Y, Wang R, et al. Acid-Responsive Transferrin Dissociation and GLUT Mediated Exocytosis for Increased Blood–Brain Barrier Transcytosis and Programmed Glioma Targeting Delivery. Advanced Functional Materials. 2018;28:1802227.

123. Huang X Jain PK El-Sayed IH El-Sayed MA Plasmonic photothermal therapy (PPTT) using gold nanoparticles Lasers Med Sci 2008 23 3 217 28 10.1007/s10103-007-0470-x 17674122 Huang X, Jain PK, El-Sayed IH, El-Sayed MA. Plasmonic photothermal therapy (PPTT) using gold nanoparticles. Lasers Med Sci. 2008;23(3):217–28. 17674122 10.1007/s10103-007-0470-x

124. Joh DY Sun L Stangl M Al Zaki A Murty S Santoiemma PP Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization PLoS One 2013 8 4 e62425 10.1371/journal.pone.0062425 23638079 PMC3640092 Joh DY, Sun L, Stangl M, Al Zaki A, Murty S, Santoiemma PP, et al. Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization. PLoS One. 2013;8(4):e62425. 23638079 10.1371/journal.pone.0062425 PMC3640092

125. Biswal P, Vijay GV, Krouse G, Mai PMQ, Lakshmisha BM, Shahbaz SK, et al : Tumor radiosensitization with gold nanoparticles: evolving strategies to improve tumoral gold uptake and catalyze future clinical translation. ACS Nano Med 2026. 10.1021/acsnanomed.5c00110 . PMC12931844 41743230

126. Campbell JL SoRelle ED Ilovich O Liba O James ML Qiu Z Multimodal assessment of SERS nanoparticle biodistribution post ingestion reveals new potential for clinical translation of Raman imaging Biomaterials 2017 135 42 52 10.1016/j.biomaterials.2017.04.045 28486147 PMC6252087 Campbell JL, SoRelle ED, Ilovich O, Liba O, James ML, Qiu Z, et al. Multimodal assessment of SERS nanoparticle biodistribution post ingestion reveals new potential for clinical translation of Raman imaging. Biomaterials. 2017;135:42–52. 28486147 10.1016/j.biomaterials.2017.04.045 PMC6252087

127. Yin IX Zhang J Zhao IS Mei ML Li Q Chu CH The Antibacterial Mechanism of Silver Nanoparticles and Its Application in Dentistry Int J Nanomedicine 2020 15 2555 62 10.2147/IJN.S246764 32368040 PMC7174845 Yin IX, Zhang J, Zhao IS, Mei ML, Li Q, Chu CH. The Antibacterial Mechanism of Silver Nanoparticles and Its Application in Dentistry. Int J Nanomedicine. 2020;15:2555–62. 32368040 10.2147/IJN.S246764 PMC7174845

128. Guido C Baldari C Maiorano G Mastronuzzi A Carai A Quintarelli C Nanoparticles for Diagnosis and Target Therapy in Pediatric Brain Cancers Diagnostics (Basel) 2022 12 173 10.3390/diagnostics12010173 35054340 PMC8774904 Guido C, Baldari C, Maiorano G, Mastronuzzi A, Carai A, Quintarelli C, et al. Nanoparticles for Diagnosis and Target Therapy in Pediatric Brain Cancers. Diagnostics (Basel). 2022;12:173. 35054340 10.3390/diagnostics12010173 PMC8774904

129. Liu P Huang Z Chen Z Xu R Wu H Zang F Silver nanoparticles: a novel radiation sensitizer for glioma? Nanoscale 2013 5 23 11829 36 10.1039/c3nr01351k 24126539 Liu P, Huang Z, Chen Z, Xu R, Wu H, Zang F, et al. Silver nanoparticles: a novel radiation sensitizer for glioma? Nanoscale. 2013;5(23):11829–36. 24126539 10.1039/c3nr01351k

130. Liu Z Tan H Zhang X Chen F Zhou Z Hu X Enhancement of radiotherapy efficacy by silver nanoparticles in hypoxic glioma cells Artif Cells Nanomed Biotechnol 2018 46 S922 S930 10.1080/21691401.2018.1518912 30307330 Liu Z, Tan H, Zhang X, Chen F, Zhou Z, Hu X, et al. Enhancement of radiotherapy efficacy by silver nanoparticles in hypoxic glioma cells. Artif Cells Nanomed Biotechnol. 2018;46:S922–S930. sup3 30307330 10.1080/21691401.2018.1518912

131. Wang R Chen C Yang W Shi S Wang C Chen J Enhancement effect of cytotoxicity response of silver nanoparticles combined with thermotherapy on C6 rat glioma cells J Nanosci Nanotechnol 2013 13 6 3851 4 10.1166/jnn.2013.7156 23862417 Wang R, Chen C, Yang W, Shi S, Wang C, Chen J. Enhancement effect of cytotoxicity response of silver nanoparticles combined with thermotherapy on C6 rat glioma cells. J Nanosci Nanotechnol. 2013;13(6):3851–4. 23862417 10.1166/jnn.2013.7156

132. Jiang H Wang C Guo Z Wang Z Liu L Silver nanocrystals mediated combination therapy of radiation with magnetic hyperthermia on glioma cells J Nanosci Nanotechnol 2012 12 11 8276 81 10.1166/jnn.2012.6626 23421206 Jiang H, Wang C, Guo Z, Wang Z, Liu L. Silver nanocrystals mediated combination therapy of radiation with magnetic hyperthermia on glioma cells. J Nanosci Nanotechnol. 2012;12(11):8276–81. 23421206 10.1166/jnn.2012.6626

133. Abdolmaleki S Aliabadi A Khaksar S Unveiling the promising anticancer effect of copper-based compounds: a comprehensive review J Cancer Res Clin Oncol 2024 150 4 213 10.1007/s00432-024-05641-5 38662225 PMC11045632 Abdolmaleki S, Aliabadi A, Khaksar S. Unveiling the promising anticancer effect of copper-based compounds: a comprehensive review. J Cancer Res Clin Oncol. 2024;150(4):213. 38662225 10.1007/s00432-024-05641-5 PMC11045632

134. Cazzoli R Zamborlin A Ermini ML Salerno A Curcio M Nicoletta FP Evolving approaches in glioma treatment: harnessing the potential of copper metabolism modulation RSC Adv 2023 13 48 34045 56 10.1039/D3RA06434D 38020008 PMC10661684 Cazzoli R, Zamborlin A, Ermini ML, Salerno A, Curcio M, Nicoletta FP, et al. Evolving approaches in glioma treatment: harnessing the potential of copper metabolism modulation. RSC Adv. 2023;13(48):34045–56. 38020008 10.1039/d3ra06434d PMC10661684

135. Gebreslassie YT Gebremeskel FG Green and cost-effective biofabrication of copper oxide nanoparticles: Exploring antimicrobial and anticancer applications Biotechnol Rep (Amst) 2024 41 e00828 10.1016/j.btre.2024.e00828 38312482 PMC10835232 Gebreslassie YT, Gebremeskel FG. Green and cost-effective biofabrication of copper oxide nanoparticles: Exploring antimicrobial and anticancer applications. Biotechnol Rep (Amst). 2024;41:e00828. 38312482 10.1016/j.btre.2024.e00828 PMC10835232

136. Li SR Tao SY Li Q Hu CY Sun ZJ Harnessing nanomaterials for copper-induced cell death Biomaterials 2025 313 122805 10.1016/j.biomaterials.2024.122805 39250865 Li SR, Tao SY, Li Q, Hu CY, Sun ZJ. Harnessing nanomaterials for copper-induced cell death. Biomaterials. 2025;313:122805. 39250865 10.1016/j.biomaterials.2024.122805

137. Zottel A Videtič Paska A Jovčevska I Nanotechnology Meets Oncology: Nanomaterials in Brain Cancer Research, Diagnosis and Therapy Materials (Basel) 2019 12 1588 10.3390/ma12101588 31096609 PMC6567262 Zottel A, Videtič Paska A, Jovčevska I. Nanotechnology Meets Oncology: Nanomaterials in Brain Cancer Research, Diagnosis and Therapy. Materials (Basel). 2019;12:1588. 31096609 10.3390/ma12101588 PMC6567262

138. Joudeh N Linke D Nanoparticle classification, physicochemical properties, characterization, and applications: a comprehensive review for biologists J Nanobiotechnology 2022 20 1 262 10.1186/s12951-022-01477-8 35672712 PMC9171489 Joudeh N, Linke D. Nanoparticle classification, physicochemical properties, characterization, and applications: a comprehensive review for biologists. J Nanobiotechnology. 2022;20(1):262. 35672712 10.1186/s12951-022-01477-8 PMC9171489

139. Nakamura T Harashima H Integration of nano drug-delivery system with cancer immunotherapy Ther Deliv 2017 8 11 987 1000 10.4155/tde-2017-0071 29061103 Nakamura T, Harashima H. Integration of nano drug-delivery system with cancer immunotherapy. Ther Deliv. 2017;8(11):987–1000. 29061103 10.4155/tde-2017-0071

140. Smith MW Gumbleton M Endocytosis at the blood-brain barrier: from basic understanding to drug delivery strategies J Drug Target 2006 14 4 191 214 10.1080/10611860600650086 16777679 Smith MW, Gumbleton M. Endocytosis at the blood-brain barrier: from basic understanding to drug delivery strategies. J Drug Target. 2006;14(4):191–214. 16777679 10.1080/10611860600650086

141. Zhan Q Yi K Yang S Hong B Su D Zhao J LPC-engineered liposomes activate transcytosis for paclitaxel brain delivery and potentiation of TTFields/TMZ via TALECT regimen in glioblastoma Theranostics 2026 16 5 2249 68 10.7150/thno.122658 41424865 PMC12712795 Zhan Q, Yi K, Yang S, Hong B, Su D, Zhao J, et al. LPC-engineered liposomes activate transcytosis for paclitaxel brain delivery and potentiation of TTFields/TMZ via TALECT regimen in glioblastoma. Theranostics. 2026;16(5):2249–68. 41424865 10.7150/thno.122658 PMC12712795

142. da Cruz MT Simoes S de Lima MC Improving lipoplex-mediated gene transfer into C6 glioma cells and primary neurons Exp Neurol 2004 187 1 65 75 10.1016/j.expneurol.2003.12.013 15081589 da Cruz MT, Simoes S, de Lima MC. Improving lipoplex-mediated gene transfer into C6 glioma cells and primary neurons. Exp Neurol. 2004;187(1):65–75. 15081589 10.1016/j.expneurol.2003.12.013

143. Bell JB Rink JS Eckerdt F Clymer J Goldman S Thaxton CS HDL nanoparticles targeting sonic hedgehog subtype medulloblastoma Scientific reports 2018 8 1 1211 10.1038/s41598-017-18100-8 29352211 PMC5775338 Bell JB, Rink JS, Eckerdt F, Clymer J, Goldman S, Thaxton CS, et al. HDL nanoparticles targeting sonic hedgehog subtype medulloblastoma. Scientific reports. 2018;8(1):1211. 29352211 10.1038/s41598-017-18100-8 PMC5775338

144. Caraway CA Gaitsch H Wicks EE Kalluri A Kunadi N Tyler BM Polymeric Nanoparticles in Brain Cancer Therapy: A Review of Current Approaches Polymers (Basel) 2022 14 2963 10.3390/polym14142963 35890738 PMC9322801 Caraway CA, Gaitsch H, Wicks EE, Kalluri A, Kunadi N, Tyler BM. Polymeric Nanoparticles in Brain Cancer Therapy: A Review of Current Approaches. Polymers (Basel). 2022;14:2963. 35890738 10.3390/polym14142963 PMC9322801

145. Agarwal S Mohamed MS Mizuki T Maekawa T Sakthi Kumar D Chlorotoxin modified morusin-PLGA nanoparticles for targeted glioblastoma therapy J Mater Chem B 2019 7 39 5896 919 10.1039/C9TB01131E 31423502 Agarwal S, Mohamed MS, Mizuki T, Maekawa T, Sakthi Kumar D. Chlorotoxin modified morusin-PLGA nanoparticles for targeted glioblastoma therapy. J Mater Chem B. 2019;7(39):5896–919. 31423502 10.1039/c9tb01131e

146. Brenza TM Schlichtmann BW Bhargavan B Vela Ramirez JE Nelson RD Panthani MG Biodegradable polyanhydride-based nanomedicines for blood to brain drug delivery J Biomed Mater Res A 2018 106 11 2881 90 10.1002/jbm.a.36477 30369055 PMC6366942 Brenza TM, Schlichtmann BW, Bhargavan B, Vela Ramirez JE, Nelson RD, Panthani MG, et al. Biodegradable polyanhydride-based nanomedicines for blood to brain drug delivery. J Biomed Mater Res A. 2018;106(11):2881–90. 30369055 10.1002/jbm.a.36477 PMC6366942

147. Choi J Rui Y Kim J Gorelick N Wilson DR Kozielski K Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies Nanomedicine : Nanotechnology, Biology, and Medicine 2020 23 102115 10.1016/j.nano.2019.102115 31655205 PMC7027378 Choi J, Rui Y, Kim J, Gorelick N, Wilson DR, Kozielski K, et al. Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies. Nanomedicine : Nanotechnology, Biology, and Medicine. 2020;23:102115. 31655205 10.1016/j.nano.2019.102115 PMC7027378

148. Albertazzi L Gherardini L Brondi M Sulis Sato S Bifone A Pizzorusso T In vivo distribution and toxicity of PAMAM dendrimers in the central nervous system depend on their surface chemistry Mol Pharm 2013 10 1 249 60 10.1021/mp300391v 23163881 Albertazzi L, Gherardini L, Brondi M, Sulis Sato S, Bifone A, Pizzorusso T, et al. In vivo distribution and toxicity of PAMAM dendrimers in the central nervous system depend on their surface chemistry. Mol Pharm. 2013;10(1):249–60. 23163881 10.1021/mp300391v

149. Liu C Zhao Z Gao H Rostami I You Q Jia X Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas Nanotheranostics 2019 3 4 311 30 10.7150/ntno.38954 31687320 PMC6821994 Liu C, Zhao Z, Gao H, Rostami I, You Q, Jia X, et al. Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas. Nanotheranostics. 2019;3(4):311–30. 31687320 10.7150/ntno.38954 PMC6821994

150. Infante P Malfanti A Quaglio D Balducci S De Martin S Bufalieri F Glabrescione B delivery by self-assembling micelles efficiently inhibits tumor growth in preclinical models of Hedgehog-dependent medulloblastoma Cancer Lett 2021 499 220 31 10.1016/j.canlet.2020.11.028 33249196 Infante P, Malfanti A, Quaglio D, Balducci S, De Martin S, Bufalieri F, et al. Glabrescione B delivery by self-assembling micelles efficiently inhibits tumor growth in preclinical models of Hedgehog-dependent medulloblastoma. Cancer Lett. 2021;499:220–31. 33249196 10.1016/j.canlet.2020.11.028

151. Bryaskova RG Staykov KG Ganchev DS Advances in Polymer Micelles for Cancer Therapy: From Conventional to Smart Delivery Systems Pharmaceutics 2026 18 177 10.3390/pharmaceutics18020177 41754919 PMC12944056 Bryaskova RG, Staykov KG, Ganchev DS. Advances in Polymer Micelles for Cancer Therapy: From Conventional to Smart Delivery Systems. Pharmaceutics. 2026;18:177. 41754919 10.3390/pharmaceutics18020177 PMC12944056

152. German-Cortés J Herrero R Torroglosa N Pumarola A Fischer-Albiol N Campos-Moreno S Preclinical evaluation of several polymeric micelles identifies Soluplus®-docetaxel as the most effective candidate in multiple glioblastoma models J Control Release 2025 381 113616 10.1016/j.jconrel.2025.113616 40073942 German-Cortés J, Herrero R, Torroglosa N, Pumarola A, Fischer-Albiol N, Campos-Moreno S, et al. Preclinical evaluation of several polymeric micelles identifies Soluplus®-docetaxel as the most effective candidate in multiple glioblastoma models. J Control Release. 2025;381:113616. 40073942 10.1016/j.jconrel.2025.113616

153. Zhang Z Xu X Du J Chen X Xue Y Zhang J Redox-responsive polymer micelles co-encapsulating immune checkpoint inhibitors and chemotherapeutic agents for glioblastoma therapy Nature Communications 2024 15 1 1118 10.1038/s41467-024-44963-3 38320994 PMC10847518 Zhang Z, Xu X, Du J, Chen X, Xue Y, Zhang J, et al. Redox-responsive polymer micelles co-encapsulating immune checkpoint inhibitors and chemotherapeutic agents for glioblastoma therapy. Nature Communications. 2024;15(1):1118. 38320994 10.1038/s41467-024-44963-3 PMC10847518

154. Elsori D Rashid G Khan NA Sachdeva P Jindal R Kayenat F Nanotube breakthroughs: unveiling the potential of carbon nanotubes as a dual therapeutic arsenal for Alzheimer’s disease and brain tumors Frontiers in Oncology 2023 13 1265347 10.3389/fonc.2023.1265347 37799472 PMC10548133 Elsori D, Rashid G, Khan NA, Sachdeva P, Jindal R, Kayenat F, et al. Nanotube breakthroughs: unveiling the potential of carbon nanotubes as a dual therapeutic arsenal for Alzheimer’s disease and brain tumors. Frontiers in Oncology. 2023;13:1265347. 37799472 10.3389/fonc.2023.1265347 PMC10548133

155. Wang X Gong Z Wang T Law J Chen X Wanggou S Mechanical nanosurgery of chemoresistant glioblastoma using magnetically controlled carbon nanotubes Sci Adv 2023 9 13 eade5321 10.1126/sciadv.ade5321 36989359 PMC10058241 Wang X, Gong Z, Wang T, Law J, Chen X, Wanggou S, et al. Mechanical nanosurgery of chemoresistant glioblastoma using magnetically controlled carbon nanotubes. Sci Adv. 2023;9(13):eade5321. 36989359 10.1126/sciadv.ade5321 PMC10058241

156. Vallejo FA Sigdel G Veliz EA Leblanc RM Vanni S Graham RM Carbon Dots in Treatment of Pediatric Brain Tumors: Past, Present, and Future Directions Int J Mol Sci 2023 24 9562 10.3390/ijms24119562 37298513 PMC10253800 Vallejo FA, Sigdel G, Veliz EA, Leblanc RM, Vanni S, Graham RM. Carbon Dots in Treatment of Pediatric Brain Tumors: Past, Present, and Future Directions. Int J Mol Sci. 2023;24:9562. 37298513 10.3390/ijms24119562 PMC10253800

157. Li S Amat D Peng Z Vanni S Raskin S De Angulo G Transferrin conjugated nontoxic carbon dots for doxorubicin delivery to target pediatric brain tumor cells Nanoscale 2016 8 37 16662 9 10.1039/C6NR05055G 27714111 Li S, Amat D, Peng Z, Vanni S, Raskin S, De Angulo G, et al. Transferrin conjugated nontoxic carbon dots for doxorubicin delivery to target pediatric brain tumor cells. Nanoscale. 2016;8(37):16662–9. 27714111 10.1039/c6nr05055g

158. Liyanage PY Zhou Y Al-Youbi AO Bashammakh AS El-Shahawi MS Vanni S Pediatric glioblastoma target-specific efficient delivery of gemcitabine across the blood-brain barrier via carbon nitride dots Nanoscale 2020 12 14 7927 38 10.1039/D0NR01647K 32232249 Liyanage PY, Zhou Y, Al-Youbi AO, Bashammakh AS, El-Shahawi MS, Vanni S, et al. Pediatric glioblastoma target-specific efficient delivery of gemcitabine across the blood-brain barrier via carbon nitride dots. Nanoscale. 2020;12(14):7927–38. 32232249 10.1039/d0nr01647k

159. Patel SC Lee S Lalwani G Suhrland C Chowdhury SM Sitharaman B Graphene-based platforms for cancer therapeutics Ther Deliv 2016 7 2 101 16 10.4155/tde.15.93 26769305 PMC4976992 Patel SC, Lee S, Lalwani G, Suhrland C, Chowdhury SM, Sitharaman B. Graphene-based platforms for cancer therapeutics. Ther Deliv. 2016;7(2):101–16. 26769305 10.4155/tde.15.93 PMC4976992

160. Sharp PS Stylianou M Arellano LM Neves JC Gravagnuolo AM Dodd A Graphene Oxide Nanoscale Platform Enhances the Anti-Cancer Properties of Bortezomib in Glioblastoma Models Adv Healthc Mater 2023 12 3 e2201968 10.1002/adhm.202201968 36300643 PMC11468189 Sharp PS, Stylianou M, Arellano LM, Neves JC, Gravagnuolo AM, Dodd A, et al. Graphene Oxide Nanoscale Platform Enhances the Anti-Cancer Properties of Bortezomib in Glioblastoma Models. Adv Healthc Mater. 2023;12(3):e2201968. 36300643 10.1002/adhm.202201968 PMC11468189

161. Taşdemir Ş Morçimen ZG Doğan AA Görgün C Şendemir A Surface Area of Graphene Governs Its Neurotoxicity ACS Biomater Sci Eng 2023 9 6 3297 305 10.1021/acsbiomaterials.3c00104 37201186 PMC10265580 Taşdemir Ş, Morçimen ZG, Doğan AA, Görgün C, Şendemir A. Surface Area of Graphene Governs Its Neurotoxicity. ACS Biomater Sci Eng. 2023;9(6):3297–305. 37201186 10.1021/acsbiomaterials.3c00104 PMC10265580

162. Hou W Shen L Zhu Y Wang X Du T Yang F Fullerene Derivatives for Tumor Treatment: Mechanisms and Application Int J Nanomedicine 2024 19 9771 97 10.2147/IJN.S476601 39345909 PMC11430870 Hou W, Shen L, Zhu Y, Wang X, Du T, Yang F, et al. Fullerene Derivatives for Tumor Treatment: Mechanisms and Application. Int J Nanomedicine. 2024;19:9771–97. 39345909 10.2147/IJN.S476601 PMC11430870

163. Serda M Gawecki R Dulski M Sajewicz M Talik E Szubka M Synthesis and applications of [60]fullerene nanoconjugate with 5-aminolevulinic acid and its glycoconjugate as drug delivery vehicles RSC Adv 2022 12 11 6377 88 10.1039/D1RA08499B 35424628 PMC8981668 Serda M, Gawecki R, Dulski M, Sajewicz M, Talik E, Szubka M, et al. Synthesis and applications of [60]fullerene nanoconjugate with 5-aminolevulinic acid and its glycoconjugate as drug delivery vehicles. RSC Adv. 2022;12(11):6377–88. 35424628 10.1039/d1ra08499b PMC8981668

164. Zhang B Yang L Jin Y Lu Y Li J Tang G Ferritin-Based Supramolecular Assembly Drug Delivery System for Aminated Fullerene Derivatives to Enhance Tumor-Targeted Therapy Adv Sci (Weinh) 2025 12 8 e2413389 10.1002/advs.202413389 39737845 PMC11848615 Zhang B, Yang L, Jin Y, Lu Y, Li J, Tang G, et al. Ferritin-Based Supramolecular Assembly Drug Delivery System for Aminated Fullerene Derivatives to Enhance Tumor-Targeted Therapy. Adv Sci (Weinh). 2025;12(8):e2413389. 39737845 10.1002/advs.202413389 PMC11848615

165. Hsieh FY Zhilenkov AV Voronov II Khakina EA Mischenko DV Troshin PA Water-Soluble Fullerene Derivatives as Brain Medicine: Surface Chemistry Determines If They Are Neuroprotective and Antitumor ACS Appl Mater Interfaces 2017 9 13 11482 92 10.1021/acsami.7b01077 28263053 Hsieh FY, Zhilenkov AV, Voronov II, Khakina EA, Mischenko DV, Troshin PA, et al. Water-Soluble Fullerene Derivatives as Brain Medicine: Surface Chemistry Determines If They Are Neuroprotective and Antitumor. ACS Appl Mater Interfaces. 2017;9(13):11482–92. 28263053 10.1021/acsami.7b01077

166. Warren KE Diffuse intrinsic pontine glioma: poised for progress Frontiers in Oncology 2012 2 205 10.3389/fonc.2012.00205 23293772 PMC3531714 Warren KE. Diffuse intrinsic pontine glioma: poised for progress. Frontiers in Oncology. 2012;2:205. 23293772 10.3389/fonc.2012.00205 PMC3531714

167. Perazella MA Gadolinium-contrast toxicity in patients with kidney disease: nephrotoxicity and nephrogenic systemic fibrosis Curr Drug Saf 2008 3 1 67 75 10.2174/157488608783333989 18690983 Perazella MA. Gadolinium-contrast toxicity in patients with kidney disease: nephrotoxicity and nephrogenic systemic fibrosis. Curr Drug Saf. 2008;3(1):67–75. 18690983 10.2174/157488608783333989

168. Adams LC Jayapal P Ramasamy SK Morakote W Yeom K Baratto L Ferumoxytol-Enhanced MRI in Children and Young Adults: State of the Art AJR Am J Roentgenol 2023 220 4 590 603 10.2214/AJR.22.28453 36197052 PMC10038879 Adams LC, Jayapal P, Ramasamy SK, Morakote W, Yeom K, Baratto L, et al. Ferumoxytol-Enhanced MRI in Children and Young Adults: State of the Art. AJR Am J Roentgenol. 2023;220(4):590–603. 36197052 10.2214/AJR.22.28453 PMC10038879

169. Barenholz Y Doxil®- -the first FDA-approved nano-drug: lessons learned J Control Release 2012 160 2 117 34 10.1016/j.jconrel.2012.03.020 22484195 Barenholz Y. Doxil®--the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34. 22484195 10.1016/j.jconrel.2012.03.020

170. Tsiapa I Efthimiadou EK Fragogeorgi E Loudos G Varvarigou AD Bouziotis P (99m)Tc-labeled aminosilane-coated iron oxide nanoparticles for molecular imaging of alphanubeta3-mediated tumor expression and feasibility for hyperthermia treatment J Colloid Interface Sci 2014 433 163 75 10.1016/j.jcis.2014.07.032 25128864 Tsiapa I, Efthimiadou EK, Fragogeorgi E, Loudos G, Varvarigou AD, Bouziotis P, et al. (99m)Tc-labeled aminosilane-coated iron oxide nanoparticles for molecular imaging of alphanubeta3-mediated tumor expression and feasibility for hyperthermia treatment. J Colloid Interface Sci. 2014;433:163–75. 25128864 10.1016/j.jcis.2014.07.032

171. Reddy GR Bhojani MS McConville P Moody J Moffat BA Hall DE Vascular targeted nanoparticles for imaging and treatment of brain tumors Clinical Cancer Research 2006 12 22 6677 86 10.1158/1078-0432.CCR-06-0946 17121886 Reddy GR, Bhojani MS, McConville P, Moody J, Moffat BA, Hall DE, et al. Vascular targeted nanoparticles for imaging and treatment of brain tumors. Clinical Cancer Research. 2006;12(22):6677–86. 17121886 10.1158/1078-0432.CCR-06-0946

172. Yang R Sarkar S Korchinski DJ Wu Y Yong VW Dunn JF MRI monitoring of monocytes to detect immune stimulating treatment response in brain tumor Neuro-Oncology 2017 19 3 364 71 27571884 10.1093/neuonc/now180 PMC5464321 Yang R, Sarkar S, Korchinski DJ, Wu Y, Yong VW, Dunn JF. MRI monitoring of monocytes to detect immune stimulating treatment response in brain tumor. Neuro-Oncology. 2017;19(3):364–71. 27571884 10.1093/neuonc/now180 PMC5464321

173. Cheng Y Dai Q Morshed RA Fan X Wegscheid ML Wainwright DA Blood-brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging Small 2014 10 24 5137 50 10.1002/smll.201400654 25104165 PMC4268041 Cheng Y, Dai Q, Morshed RA, Fan X, Wegscheid ML, Wainwright DA, et al. Blood-brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging. Small. 2014;10(24):5137–50. 25104165 10.1002/smll.201400654 PMC4268041

174. Neuschmelting V Harmsen S Beziere N Lockau H Hsu HT Huang R Dual-Modality Surface-Enhanced Resonance Raman Scattering and Multispectral Optoacoustic Tomography Nanoparticle Approach for Brain Tumor Delineation Small 2018 14 23 e1800740 10.1002/smll.201800740 29726109 PMC6541212 Neuschmelting V, Harmsen S, Beziere N, Lockau H, Hsu HT, Huang R, et al. Dual-Modality Surface-Enhanced Resonance Raman Scattering and Multispectral Optoacoustic Tomography Nanoparticle Approach for Brain Tumor Delineation. Small. 2018;14(23):e1800740. 29726109 10.1002/smll.201800740 PMC6541212

175. Kircher MF de la Zerda A Jokerst JV Zavaleta CL Kempen PJ Mittra E A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle Nature medicine 2012 18 5 829 34 10.1038/nm.2721 22504484 PMC3422133 Kircher MF, de la Zerda A, Jokerst JV, Zavaleta CL, Kempen PJ, Mittra E, et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nature medicine. 2012;18(5):829–34. 22504484 10.1038/nm.2721 PMC3422133

176. Perez-Medina C Abdel-Atti D Zhang Y Longo VA Irwin CP Binderup T A modular labeling strategy for in vivo PET and near-infrared fluorescence imaging of nanoparticle tumor targeting J Nucl Med 2014 55 10 1706 11 10.2967/jnumed.114.141861 25060196 PMC4381653 Perez-Medina C, Abdel-Atti D, Zhang Y, Longo VA, Irwin CP, Binderup T, et al. A modular labeling strategy for in vivo PET and near-infrared fluorescence imaging of nanoparticle tumor targeting. J Nucl Med. 2014;55(10):1706–11. 25060196 10.2967/jnumed.114.141861 PMC4381653

177. Lee H Gaddy D Ventura M Bernards N de Souza R Kirpotin D Companion Diagnostic (64)Cu-Liposome Positron Emission Tomography Enables Characterization of Drug Delivery to Tumors and Predicts Response to Cancer Nanomedicines Theranostics 2018 8 9 2300 12 10.7150/thno.21670 29721081 PMC5928891 Lee H, Gaddy D, Ventura M, Bernards N, de Souza R, Kirpotin D, et al. Companion Diagnostic (64)Cu-Liposome Positron Emission Tomography Enables Characterization of Drug Delivery to Tumors and Predicts Response to Cancer Nanomedicines. Theranostics. 2018;8(9):2300–12. 29721081 10.7150/thno.21670 PMC5928891

178. Ray A Mukundan A Xie Z Karamchand L Wang X Kopelman R Highly stable polymer coated nano-clustered silver plates: a multimodal optical contrast agent for biomedical imaging Nanotechnology 2014 25 44 445104 10.1088/0957-4484/25/44/445104 25325364 PMC4244271 Ray A, Mukundan A, Xie Z, Karamchand L, Wang X, Kopelman R. Highly stable polymer coated nano-clustered silver plates: a multimodal optical contrast agent for biomedical imaging. Nanotechnology. 2014;25(44):445104. 25325364 10.1088/0957-4484/25/44/445104 PMC4244271

179. Frohlich E The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles Int J Nanomedicine 2012 7 5577 91 10.2147/IJN.S36111 23144561 PMC3493258 Frohlich E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomedicine. 2012;7:5577–91. 23144561 10.2147/IJN.S36111 PMC3493258

180. Kanazaki K Sano K Makino A Takahashi A Deguchi J Ohashi M Development of human serum albumin conjugated with near-infrared dye for photoacoustic tumor imaging J Biomed Opt 2014 19 9 96002 10.1117/1.JBO.19.9.096002 25191833 Kanazaki K, Sano K, Makino A, Takahashi A, Deguchi J, Ohashi M, et al. Development of human serum albumin conjugated with near-infrared dye for photoacoustic tumor imaging. J Biomed Opt. 2014;19(9):96002. 25191833 10.1117/1.JBO.19.9.096002

181. Biju V Chemical modifications and bioconjugate reactions of nanomaterials for sensing, imaging, drug delivery and therapy Chem Soc Rev 2014 43 3 744 64 10.1039/C3CS60273G 24220322 Biju V. Chemical modifications and bioconjugate reactions of nanomaterials for sensing, imaging, drug delivery and therapy. Chem Soc Rev. 2014;43(3):744–64. 24220322 10.1039/c3cs60273g

182. Yang J Gunn J Dave SR Zhang M Wang YA Gao X Ultrasensitive detection and molecular imaging with magnetic nanoparticles Analyst 2008 133 2 154 60 10.1039/B700091J 18227935 Yang J, Gunn J, Dave SR, Zhang M, Wang YA, Gao X. Ultrasensitive detection and molecular imaging with magnetic nanoparticles. Analyst. 2008;133(2):154–60. 18227935 10.1039/b700091j

183. Zhylkybayeva N Paliienko K Topchylo A Zaderko A Géloën A Borisova T Size dependent properties of Gd(3+)-free versus Gd(3+)-doped carbon dots for bioimaging application Scientific reports 2024 14 1 27812 10.1038/s41598-024-76500-z 39537704 PMC11561127 Zhylkybayeva N, Paliienko K, Topchylo A, Zaderko A, Géloën A, Borisova T, et al. Size dependent properties of Gd(3+)-free versus Gd(3+)-doped carbon dots for bioimaging application. Scientific reports. 2024;14(1):27812. 39537704 10.1038/s41598-024-76500-z PMC11561127

184. He X Luo Q Zhang J Chen P Wang HJ Luo K Gadolinium-doped carbon dots as nano-theranostic agents for MR/FL diagnosis and gene delivery Nanoscale 2019 11 27 12973 82 10.1039/C9NR03988K 31263818 He X, Luo Q, Zhang J, Chen P, Wang HJ, Luo K, et al. Gadolinium-doped carbon dots as nano-theranostic agents for MR/FL diagnosis and gene delivery. Nanoscale. 2019;11(27):12973–82. 31263818 10.1039/c9nr03988k

185. Gong H Dong Z Liu Y Yin S Cheng L Xi W Engineering of Multifunctional Nano-Micelles for Combined Photothermal and Photodynamic Therapy Under the Guidance of Multimodal Imaging Advanced Functional Materials 2014 24 41 6492 502 10.1002/adfm.201401451 Gong H, Dong Z, Liu Y, Yin S, Cheng L, Xi W, et al. Engineering of Multifunctional Nano-Micelles for Combined Photothermal and Photodynamic Therapy Under the Guidance of Multimodal Imaging. Advanced Functional Materials. 2014;24(41):6492–502.

186. Gamage NH Jing L Worsham MJ Ali MM Targeted Theranostic Approach for Glioma Using Dendrimer-Based Curcumin Nanoparticle J Nanomed Nanotechnol 2016 7 393 27699139 10.4172/2157-7439.1000393 PMC5040461 Gamage NH, Jing L, Worsham MJ, Ali MM. Targeted Theranostic Approach for Glioma Using Dendrimer-Based Curcumin Nanoparticle. J Nanomed Nanotechnol. 2016;7:393. 27699139 10.4172/2157-7439.1000393 PMC5040461

187. Sarin H Kanevsky AS Wu H Sousa AA Wilson CM Aronova MA Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors J Transl Med 2009 7 51 10.1186/1479-5876-7-51 19549317 PMC2706803 Sarin H, Kanevsky AS, Wu H, Sousa AA, Wilson CM, Aronova MA, et al. Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors. J Transl Med. 2009;7:51. 19549317 10.1186/1479-5876-7-51 PMC2706803

188. Liu CH Grodzinski P Nanotechnology for Cancer Imaging: Advances, Challenges, and Clinical Opportunities Radiol Imaging Cancer 2021 3 3 e200052 10.1148/rycan.2021200052 34047667 PMC8183257 Liu CH, Grodzinski P. Nanotechnology for Cancer Imaging: Advances, Challenges, and Clinical Opportunities. Radiol Imaging Cancer. 2021;3(3):e200052. 34047667 10.1148/rycan.2021200052 PMC8183257

189. Heravi Shargh V Luckett J Bouzinab K Paisey S Turyanska L Singleton WGB Chemosensitization of Temozolomide-Resistant Pediatric Diffuse Midline Glioma Using Potent Nanoencapsulated Forms of a N(3)-Propargyl Analogue ACS Appl Mater Interfaces 2021 13 30 35266 80 10.1021/acsami.1c04164 34310112 Heravi Shargh V, Luckett J, Bouzinab K, Paisey S, Turyanska L, Singleton WGB, et al. Chemosensitization of Temozolomide-Resistant Pediatric Diffuse Midline Glioma Using Potent Nanoencapsulated Forms of a N(3)-Propargyl Analogue. ACS Appl Mater Interfaces. 2021;13(30):35266–80. 34310112 10.1021/acsami.1c04164

190. Ung C Tsoli M Liu J Cassano D Pocovi-Martinez S Upton DH Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma Cancers (Basel) 2021 13 1278 10.3390/cancers13061278 33805713 PMC7999568 Ung C, Tsoli M, Liu J, Cassano D, Pocovi-Martinez S, Upton DH, et al. Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma. Cancers (Basel). 2021;13:1278. 33805713 10.3390/cancers13061278 PMC7999568

191. Lenzen A Cole L Lauing KL Zhai L Ladomersky E Lulla RR IMMU-24. IMMUNOTHERAPEUTIC NANOTECHNOLOGY TARGETING IDO1 FOR PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA Neuro Oncology 2018 20 i103 10.1093/neuonc/noy059.340 Lenzen A, Cole L, Lauing KL, Zhai L, Ladomersky E, Lulla RR, et al. IMMU-24. IMMUNOTHERAPEUTIC NANOTECHNOLOGY TARGETING IDO1 FOR PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA. Neuro Oncology. 2018;20:i103.

192. Warren KE Killian K Suuriniemi M Wang Y Quezado M Meltzer PS Genomic aberrations in pediatric diffuse intrinsic pontine gliomas Neuro-Oncology 2012 14 3 326 32 10.1093/neuonc/nor190 22064882 PMC3280796 Warren KE, Killian K, Suuriniemi M, Wang Y, Quezado M, Meltzer PS. Genomic aberrations in pediatric diffuse intrinsic pontine gliomas. Neuro-Oncology. 2012;14(3):326–32. 22064882 10.1093/neuonc/nor190 PMC3280796

193. Barton KL Misuraca K Cordero F Dobrikova E Min HD Gromeier M PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma PLoS One 2013 8 10 e77639 10.1371/journal.pone.0077639 24098593 PMC3788718 Barton KL, Misuraca K, Cordero F, Dobrikova E, Min HD, Gromeier M, et al. PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma. PLoS One. 2013;8(10):e77639. 24098593 10.1371/journal.pone.0077639 PMC3788718

194. Williams EA Brastianos PK Wakimoto H Zolal A Filbin MG Cahill DP A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4 Acta neuropathologica 2023 146 3 515 25 10.1007/s00401-023-02609-6 37524847 PMC10412483 Williams EA, Brastianos PK, Wakimoto H, Zolal A, Filbin MG, Cahill DP, et al. A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4. Acta neuropathologica. 2023;146(3):515–25. 37524847 10.1007/s00401-023-02609-6 PMC10412483

195. Chai RC Yan H An SY Pang B Chen HY Mu QH Genomic profiling and prognostic factors of H3 K27M-mutant spinal cord diffuse glioma Brain Pathol 2023 33 4 e13153 10.1111/bpa.13153 36751054 PMC10307522 Chai RC, Yan H, An SY, Pang B, Chen HY, Mu QH, et al. Genomic profiling and prognostic factors of H3 K27M-mutant spinal cord diffuse glioma. Brain Pathol. 2023;33(4):e13153. 36751054 10.1111/bpa.13153 PMC10307522

196. Zarghooni M Bartels U Lee E Buczkowicz P Morrison A Huang A Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets Journal of Clinical Oncology 2010 28 8 1337 44 10.1200/JCO.2009.25.5463 20142589 Zarghooni M, Bartels U, Lee E, Buczkowicz P, Morrison A, Huang A, et al. Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. Journal of Clinical Oncology. 2010;28(8):1337–44. 20142589 10.1200/JCO.2009.25.5463

197. Mueller S Hashizume R Yang X Kolkowitz I Olow AK Phillips J Targeting Wee1 for the treatment of pediatric high-grade gliomas Neuro-Oncology 2014 16 3 352 60 10.1093/neuonc/not220 24305702 PMC3922515 Mueller S, Hashizume R, Yang X, Kolkowitz I, Olow AK, Phillips J, et al. Targeting Wee1 for the treatment of pediatric high-grade gliomas. Neuro-Oncology. 2014;16(3):352–60. 24305702 10.1093/neuonc/not220 PMC3922515

198. Upreti M Petrosyan A Thornton ME Hovsepyan A Fernandez GE Koos DS Multicellular tumor-stromal interactions recapitulate aspects of therapeutic response and human oncogenic signaling in a 3D disease model for H3K27M-altered DIPG Oncogene 2025 44 39 3694 712 10.1038/s41388-025-03533-7 40914769 PMC12454143 Upreti M, Petrosyan A, Thornton ME, Hovsepyan A, Fernandez GE, Koos DS, et al. Multicellular tumor-stromal interactions recapitulate aspects of therapeutic response and human oncogenic signaling in a 3D disease model for H3K27M-altered DIPG. Oncogene. 2025;44(39):3694–712. 40914769 10.1038/s41388-025-03533-7 PMC12454143

199. Deshane J Garner CC Sontheimer H Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2 J Biol Chem 2003 278 6 4135 44 10.1074/jbc.M205662200 12454020 Deshane J, Garner CC, Sontheimer H. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem. 2003;278(6):4135–44. 12454020 10.1074/jbc.M205662200

200. Zhao L Li Y Zhu J Sun N Song N Xing Y Chlorotoxin peptide-functionalized polyethylenimine-entrapped gold nanoparticles for glioma SPECT/CT imaging and radionuclide therapy J Nanobiotechnology 2019 17 1 30 10.1186/s12951-019-0462-6 30782154 PMC6380014 Zhao L, Li Y, Zhu J, Sun N, Song N, Xing Y, et al. Chlorotoxin peptide-functionalized polyethylenimine-entrapped gold nanoparticles for glioma SPECT/CT imaging and radionuclide therapy. J Nanobiotechnology. 2019;17(1):30. 30782154 10.1186/s12951-019-0462-6 PMC6380014

201. Huang R Ke W Han L Li J Liu S Jiang C Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration Biomaterials 2011 32 9 2399 406 10.1016/j.biomaterials.2010.11.079 21185076 Huang R, Ke W, Han L, Li J, Liu S, Jiang C. Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration. Biomaterials. 2011;32(9):2399–406. 21185076 10.1016/j.biomaterials.2010.11.079

202. Boltman T Meyer M Ekpo O Diagnostic and Therapeutic Approaches for Glioblastoma and Neuroblastoma Cancers Using Chlorotoxin Nanoparticles Cancers (Basel) 2023 15 3388 10.3390/cancers15133388 37444498 PMC10341066 Boltman T, Meyer M, Ekpo O. Diagnostic and Therapeutic Approaches for Glioblastoma and Neuroblastoma Cancers Using Chlorotoxin Nanoparticles. Cancers (Basel). 2023;15:3388. 37444498 10.3390/cancers15133388 PMC10341066

203. Costa PM Cardoso AL Mendonca LS Serani A Custodia C Conceicao M Tumor-targeted Chlorotoxin-coupled Nanoparticles for Nucleic Acid Delivery to Glioblastoma Cells: A Promising System for Glioblastoma Treatment Mol Ther Nucleic Acids 2013 2 6 e100 10.1038/mtna.2013.30 23778499 PMC3696908 Costa PM, Cardoso AL, Mendonca LS, Serani A, Custodia C, Conceicao M, et al. Tumor-targeted Chlorotoxin-coupled Nanoparticles for Nucleic Acid Delivery to Glioblastoma Cells: A Promising System for Glioblastoma Treatment. Mol Ther Nucleic Acids. 2013;2(6):e100. 23778499 10.1038/mtna.2013.30 PMC3696908

204. Pandey K Wang SS Mifsud NA Faridi P Davenport AJ Webb AI A combined immunopeptidomics, proteomics, and cell surface proteomics approach to identify immunotherapy targets for diffuse intrinsic pontine glioma Frontiers in Oncology 2023 13 1192448 10.3389/fonc.2023.1192448 37637064 PMC10455951 Pandey K, Wang SS, Mifsud NA, Faridi P, Davenport AJ, Webb AI, et al. A combined immunopeptidomics, proteomics, and cell surface proteomics approach to identify immunotherapy targets for diffuse intrinsic pontine glioma. Frontiers in Oncology. 2023;13:1192448. 37637064 10.3389/fonc.2023.1192448 PMC10455951

205. Riccardi C Napolitano F Montesarchio D Sampaolo S Melone MAB Nanoparticle-Guided Brain Drug Delivery: Expanding the Therapeutic Approach to Neurodegenerative Diseases Pharmaceutics 2021 13 1897 10.3390/pharmaceutics13111897 34834311 PMC8623286 Riccardi C, Napolitano F, Montesarchio D, Sampaolo S, Melone MAB. Nanoparticle-Guided Brain Drug Delivery: Expanding the Therapeutic Approach to Neurodegenerative Diseases. Pharmaceutics. 2021;13:1897. 34834311 10.3390/pharmaceutics13111897 PMC8623286

206. Singh R Lillard JW Jr Nanoparticle-based targeted drug delivery Exp Mol Pathol 2009 86 3 215 23 10.1016/j.yexmp.2008.12.004 19186176 PMC3249419 Singh R, Lillard JW Jr. Nanoparticle-based targeted drug delivery. Exp Mol Pathol. 2009;86(3):215–23. 19186176 10.1016/j.yexmp.2008.12.004 PMC3249419

207. Suk JS Xu Q Kim N Hanes J Ensign LM PEGylation as a strategy for improving nanoparticle-based drug and gene delivery Adv Drug Deliv Rev 2016 99 28 51 10.1016/j.addr.2015.09.012 26456916 PMC4798869 Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99:28–51. Pt A 26456916 10.1016/j.addr.2015.09.012 PMC4798869

208. Xia Y Xu C Zhang X Ning P Wang Z Tian J Liposome-based probes for molecular imaging: from basic research to the bedside Nanoscale 2019 11 13 5822 38 10.1039/C9NR00207C 30888379 Xia Y, Xu C, Zhang X, Ning P, Wang Z, Tian J, et al. Liposome-based probes for molecular imaging: from basic research to the bedside. Nanoscale. 2019;11(13):5822–38. 30888379 10.1039/c9nr00207c

209. Choi CH Zuckerman JE Webster P Davis ME Targeting kidney mesangium by nanoparticles of defined size Proceedings of the National Academy of Sciences of the United States of America 2011 108 16 6656 61 10.1073/pnas.1103573108 21464325 PMC3080986 Choi CH, Zuckerman JE, Webster P, Davis ME. Targeting kidney mesangium by nanoparticles of defined size. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(16):6656–61. 21464325 10.1073/pnas.1103573108 PMC3080986

210. Perrault SD Walkey C Jennings T Fischer HC Chan WC Mediating tumor targeting efficiency of nanoparticles through design Nano Lett 2009 9 5 1909 15 10.1021/nl900031y 19344179 Perrault SD, Walkey C, Jennings T, Fischer HC, Chan WC. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett. 2009;9(5):1909–15. 19344179 10.1021/nl900031y

211. Popovic Z Liu W Chauhan VP Lee J Wong C Greytak AB A nanoparticle size series for in vivo fluorescence imaging Angew Chem Int Ed Engl 2010 49 46 8649 52 10.1002/anie.201003142 20886481 PMC3035057 Popovic Z, Liu W, Chauhan VP, Lee J, Wong C, Greytak AB, et al. A nanoparticle size series for in vivo fluorescence imaging. Angew Chem Int Ed Engl. 2010;49(46):8649–52. 20886481 10.1002/anie.201003142 PMC3035057

212. Alexis F Pridgen E Molnar LK Farokhzad OC Factors affecting the clearance and biodistribution of polymeric nanoparticles Mol Pharm 2008 5 4 505 15 10.1021/mp800051m 18672949 PMC2663893 Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008;5(4):505–15. 18672949 10.1021/mp800051m PMC2663893

213. Jyoti A Fugit KD Sethi P McGarry RC Anderson BD Upreti M An in vitro assessment of liposomal topotecan simulating metronomic chemotherapy in combination with radiation in tumor-endothelial spheroids Scientific reports 2015 5 15236 10.1038/srep15236 26468877 PMC4606561 Jyoti A, Fugit KD, Sethi P, McGarry RC, Anderson BD, Upreti M. An in vitro assessment of liposomal topotecan simulating metronomic chemotherapy in combination with radiation in tumor-endothelial spheroids. Scientific reports. 2015;5:15236. 26468877 10.1038/srep15236 PMC4606561

214. Kirti A Simnani FZ Jena S Lenka SS Kalalpitiya C Naser SS Nanoparticle-mediated metronomic chemotherapy in cancer: A paradigm of precision and persistence Cancer Lett 2024 594 216990 10.1016/j.canlet.2024.216990 38801886 Kirti A, Simnani FZ, Jena S, Lenka SS, Kalalpitiya C, Naser SS, et al. Nanoparticle-mediated metronomic chemotherapy in cancer: A paradigm of precision and persistence. Cancer Lett. 2024;594:216990. 38801886 10.1016/j.canlet.2024.216990

215. Chen HHW Kuo MT Improving radiotherapy in cancer treatment: Promises and challenges Oncotarget 2017 8 37 62742 58 10.18632/oncotarget.18409 28977985 PMC5617545 Chen HHW, Kuo MT. Improving radiotherapy in cancer treatment: Promises and challenges. Oncotarget. 2017;8(37):62742–58. 28977985 10.18632/oncotarget.18409 PMC5617545

216. Haque M Shakil MS Mahmud KM The Promise of Nanoparticles-Based Radiotherapy in Cancer Treatment Cancers (Basel) 2023 15 1892 10.3390/cancers15061892 36980778 PMC10047050 Haque M, Shakil MS, Mahmud KM. The Promise of Nanoparticles-Based Radiotherapy in Cancer Treatment. Cancers (Basel). 2023;15:1892. 36980778 10.3390/cancers15061892 PMC10047050

217. Mahmud KM Niloy MS Shakil MS Islam MA Ruthenium Complexes: An Alternative to Platinum Drugs in Colorectal Cancer Treatment Pharmaceutics 2021 13 1295 10.3390/pharmaceutics13081295 34452256 PMC8398452 Mahmud KM, Niloy MS, Shakil MS, Islam MA. Ruthenium Complexes: An Alternative to Platinum Drugs in Colorectal Cancer Treatment. Pharmaceutics. 2021;13:1295. 34452256 10.3390/pharmaceutics13081295 PMC8398452

218. Yao H Qiu H Shao Z Wang G Wang J Yao Y Nanoparticle formulation of small DNA molecules, Dbait, improves the sensitivity of hormone-independent prostate cancer to radiotherapy Nanomedicine: Nanotechnology, Biology, and Medicine 2016 12 8 2261 71 10.1016/j.nano.2016.06.010 27389144 Yao H, Qiu H, Shao Z, Wang G, Wang J, Yao Y, et al. Nanoparticle formulation of small DNA molecules, Dbait, improves the sensitivity of hormone-independent prostate cancer to radiotherapy. Nanomedicine: Nanotechnology, Biology, and Medicine. 2016;12(8):2261–71. 27389144 10.1016/j.nano.2016.06.010

219. Kuncic Z Lacombe S Nanoparticle radio-enhancement: principles, progress and application to cancer treatment Phys Med Biol 2018 63 2 02TR01 10.1088/1361-6560/aa99ce 29125831 Kuncic Z, Lacombe S. Nanoparticle radio-enhancement: principles, progress and application to cancer treatment. Phys Med Biol. 2018;63(2):02TR01. 29125831 10.1088/1361-6560/aa99ce

220. Kefayat A Ghahremani F Motaghi H Amouheidari A Ultra-small but ultra-effective: Folic acid-targeted gold nanoclusters for enhancement of intracranial glioma tumors’ radiation therapy efficacy Nanomedicine : Nanotechnology, Biology, and Medicine 2019 16 173 84 10.1016/j.nano.2018.12.007 30594659 Kefayat A, Ghahremani F, Motaghi H, Amouheidari A. Ultra-small but ultra-effective: Folic acid-targeted gold nanoclusters for enhancement of intracranial glioma tumors’ radiation therapy efficacy. Nanomedicine : Nanotechnology, Biology, and Medicine. 2019;16:173–84. 30594659 10.1016/j.nano.2018.12.007

221. Kazmi F Vallis KA Vellayappan BA Bandla A Yukun D Carlisle R Megavoltage Radiosensitization of Gold Nanoparticles on a Glioblastoma Cancer Cell Line Using a Clinical Platform Int J Mol Sci 2020 21 429 10.3390/ijms21020429 31936587 PMC7013825 Kazmi F, Vallis KA, Vellayappan BA, Bandla A, Yukun D, Carlisle R. Megavoltage Radiosensitization of Gold Nanoparticles on a Glioblastoma Cancer Cell Line Using a Clinical Platform. Int J Mol Sci. 2020;21:429. 31936587 10.3390/ijms21020429 PMC7013825

222. Kunoh T Shimura T Kasai T Matsumoto S Mahmud H Khayrani AC Use of DNA-generated gold nanoparticles to radiosensitize and eradicate radioresistant glioma stem cells Nanotechnology 2019 30 5 055101 10.1088/1361-6528/aaedd5 30499457 Kunoh T, Shimura T, Kasai T, Matsumoto S, Mahmud H, Khayrani AC, et al. Use of DNA-generated gold nanoparticles to radiosensitize and eradicate radioresistant glioma stem cells. Nanotechnology. 2019;30(5):055101. 30499457 10.1088/1361-6528/aaedd5

223. Carbone GG Mariano S Gabriele A Cennamo S Primiceri V Aziz MR Exploring the Potential of Gold Nanoparticles in Proton Therapy: Mechanisms, Advances, and Clinical Horizons Pharmaceutics 2025 17 176 10.3390/pharmaceutics17020176 40006543 PMC11859620 Carbone GG, Mariano S, Gabriele A, Cennamo S, Primiceri V, Aziz MR, et al. Exploring the Potential of Gold Nanoparticles in Proton Therapy: Mechanisms, Advances, and Clinical Horizons. Pharmaceutics. 2025;17:176. 40006543 10.3390/pharmaceutics17020176 PMC11859620

224. Ruiz-Garcia H Ramirez-Loera C Malouff TD Seneviratne DS Palmer JD Trifiletti DM Novel Strategies for Nanoparticle-Based Radiosensitization in Glioblastoma Int J Mol Sci 2021 22 9673 10.3390/ijms22189673 34575840 PMC8465220 Ruiz-Garcia H, Ramirez-Loera C, Malouff TD, Seneviratne DS, Palmer JD, Trifiletti DM. Novel Strategies for Nanoparticle-Based Radiosensitization in Glioblastoma. Int J Mol Sci. 2021;22:9673. 34575840 10.3390/ijms22189673 PMC8465220

225. Wu CC Szalontay L Pouliopoulos AN Bae S Berg X Wei HJ Blood-brain barrier opening with neuronavigation-guided focused ultrasound in pediatric patients with diffuse midline glioma Science Translational Medicine 2025 17 824 eadq6645 10.1126/scitranslmed.adq6645 41223245 Wu CC, Szalontay L, Pouliopoulos AN, Bae S, Berg X, Wei HJ, et al. Blood-brain barrier opening with neuronavigation-guided focused ultrasound in pediatric patients with diffuse midline glioma. Science Translational Medicine. 2025;17(824):eadq6645. 41223245 10.1126/scitranslmed.adq6645

226. Barzegar-Fallah A Gandhi K Rizwan SB Slatter TL Reynolds JNJ Harnessing Ultrasound for Targeting Drug Delivery to the Brain and Breaching the Blood-Brain Tumour Barrier Pharmaceutics 2022 14 2231 10.3390/pharmaceutics14102231 36297666 PMC9607160 Barzegar-Fallah A, Gandhi K, Rizwan SB, Slatter TL, Reynolds JNJ. Harnessing Ultrasound for Targeting Drug Delivery to the Brain and Breaching the Blood-Brain Tumour Barrier. Pharmaceutics. 2022;14:2231. 36297666 10.3390/pharmaceutics14102231 PMC9607160

227. Dasgupta A Liu M Ojha T Storm G Kiessling F Lammers T Ultrasound-mediated drug delivery to the brain: principles, progress and prospects Drug Discov Today Technol 2016 20 41 48 10.1016/j.ddtec.2016.07.007 27986222 PMC5166975 Dasgupta A, Liu M, Ojha T, Storm G, Kiessling F, Lammers T. Ultrasound-mediated drug delivery to the brain: principles, progress and prospects. Drug Discov Today Technol. 2016;20:41–48. 27986222 10.1016/j.ddtec.2016.07.007 PMC5166975

228. ElNemer W Lee D Selim O Slika H Farias AS Suvarnapathaki S Focused ultrasound mediated gene therapy for glioblastoma: A preclinical in vivo systematic review and meta-analysis Biomed Pharmacother 2026 198 119325 10.1016/j.biopha.2026.119325 41955864 ElNemer W, Lee D, Selim O, Slika H, Farias AS, Suvarnapathaki S, et al. Focused ultrasound mediated gene therapy for glioblastoma: A preclinical in vivo systematic review and meta-analysis. Biomed Pharmacother. 2026;198:119325. 41955864 10.1016/j.biopha.2026.119325

229. Sonabend AM Gould A Amidei C Ward R Schmidt KA Zhang DY Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial The Lancet Oncology 2023 24 5 509 22 10.1016/S1470-2045(23)00112-2 37142373 PMC10256454 Sonabend AM, Gould A, Amidei C, Ward R, Schmidt KA, Zhang DY, et al. Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. The Lancet Oncology. 2023;24(5):509–22. 37142373 10.1016/S1470-2045(23)00112-2 PMC10256454