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Engineering precision nanoparticles for drug delivery.

In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers - systemic, microenvironmental and cellular - that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-

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… Strategies for nuclear targeting generally fall into two categories: using particles that are small enough to pass through the nuclear pore complex, or incorporating functionality that is used after endosomal escape 214 , 279 . …

Anti-cancer mechanisms of action of therapeutic alternating electric fields (tumor treating fields [TTFields]).

Despite improved survival outcomes across many cancer types, the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer. Invariably in these cancers, the control achieved by time-limited interventions such as traditional surgical resection, radiation therapy, and chemotherapy is short-lived. A new form of anti-cancer therapy called therapeutic alternating electric fields (AEFs) or tumor treating fields (TTFields) has been shown, either by itself or in combination with chemotherapy, to have anti-cancer effects that translate to improved survival outc

Multiple Myeloma Therapy: Emerging Trends and Challenges.

Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergenc

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… Exportin Inhibitors The nuclear pore complexes (NPC) are large cylindrical channels, composed of several copies of >30 different proteins called nucleoporins [ 247 ]. …

Advances in Molecularly Imprinted Polymers for Bone Biomarker Detection and Therapeutic Applications.

This review explores the application of molecularly imprinted polymers (MIPs) in detecting bone turnover biomarkers and advancing osteogenic treatment strategies. MIPs, designed to mimic biological recognition sites, offer innovative solutions for precise molecular recognition in bone health management. Chemical methodologies for MIPs synthesis and their integration into diagnostic systems for detecting bone resorption markers are highlighted. Furthermore, MIP-driven therapeutic advancements, including controlled drug release, cell imprinting for osteogenic differentiation, and functional scaf

Alendronate-coated long-circulating liposomes containing 99mtechnetium-ceftizoxime used to identify osteomyelitis.

Osteomyelitis is a progressive destruction of bones caused by microorganisms. Inadequate or absent treatment increases the risk of bone growth inhibition, fractures, and sepsis. Among the diagnostic techniques, functional images are the most sensitive in detecting osteomyelitis in its early stages. However, these techniques do not have adequate specificity. By contrast, radiolabeled antibiotics could improve selectivity, since they are specifically recognized by the bacteria. The incorporation of these radiopharmaceuticals in drug-delivery systems with high affinity for bones could improve the

Mediterranean Diet Food Components as Possible Adjuvant Therapies to Counteract Breast and Prostate Cancer Progression to Bone Metastasis.

Bone metastasis is a serious and often lethal complication of particularly frequent carcinomas, such as breast and prostate cancers, which not only reduces survival but also worsens the patients' quality of life. Therefore, it is important to find new and/or additional therapeutic possibilities that can counteract the colonization of bone tissue. High adherence to the Mediterranean diet (MD) is effective in the prevention of cancer and improves cancer patients' health, thus, here, we considered its impact on bone metastasis. We highlighted some molecular events relevant for the development of

Calcium Signalling in Breast Cancer Associated Bone Pain.

Calcium (Ca2+) is involved as a signalling mediator in a broad variety of physiological processes. Some of the fastest responses in human body like neuronal action potential firing, to the slowest gene transcriptional regulation processes are controlled by pathways involving calcium signalling. Under pathological conditions these mechanisms are also involved in tumoral cells reprogramming, resulting in the altered expression of genes associated with cell proliferation, metastatisation and homing to the secondary metastatic site. On the other hand, calcium exerts a central function in nocicepti

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… Through nuclear pores cytosolic calcium can enter the nuclear space where it can regulate the activity of transcription factors acting therefore on genes expression. Adapted from [ 14 ]. …

Инженерная иммунологическая ниша направляет терапевтическое развитие в модели прогрессивного множественного склероза.

Первичный прогрессивный множественный склероз (MS) представляет собой аутоиммунное заболевание, вызывающее демиелионацию и имеющее лишь один класс лечения, одобренного УЛХ, — истощение клеток В. Новейшее лечение может возникнуть в результате более глубокого понимания взаимодействия между различными типами клеток в заболевших тканях на протяжении всего процесса развития. Первоначально мы описываем инженерную иммунологическую нишу (ИН) на основе биоматериалов как суррогатную для заболевших тканей функцию иммунных клеток и фенотипную динамику на протяжении хронической прогрессивной модели MS мыши

Bortezomib-Loaded Mesoporous Silica Nanoparticles Selectively Alter Metabolism and Induce Death in Multiple Myeloma Cells.

A mesoporous silica-based nanodevice bearing the antineoplastic drug bortezomib (BTZ), whose release is triggered in acidic environment and grafted with folic acid (FOL) as a targeting function (FOL-MSN-BTZ) was tested on folate receptor overexpressing (FR+) multiple myeloma (MM) cells and on FR negative (FR-) normal cells. FOL-MSN-BTZ efficacy studies were conducted by means of growth experiments, TEM, TUNEL assay and Western Blotting analysis (WB). Metabolic investigations were performed to assess cells metabolic response to MSNs treatments. FOL-MSN-BTZ exclusively killed FR+ MM cells, leadi

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy.

Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent treatment advancements have extended overall survival (OS), refractory MM has a poor prognosis, with a median OS of between 4 and 6 months. Nuclear export inhibition, specifically inhibition of CRM1/XPO1, is an emerging novel treatment modality that has shown promise in treatment-refractory MM. Initially discovered in yeast in 1983, early clinical applications were met with significant toxicities that limited their utility. The cr

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… The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep. 2012;2(2):207–215. doi: 10.1016/j.celrep.2012.07.007. 7. Zhou F, Qiu W, Yao R, Xiang J, Sun X, Liu S, et al. …

Melatonin: Facts, Extrapolations and Clinical Trials.

Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the (generally) positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated. Based on the assumption that melatonin is safe, high doses have been a

Dual Roles of NIX/BNIP3L in Tumors: Friend or Foe.

Cancer is one of the leading causes of disease-related death worldwide, and targeting key regulatory genes to induce programmed cell death in tumor cells has emerged as a crucial therapeutic strategy, following surgery, radiotherapy, and chemotherapy. As a mitochondrial outer membrane protein, NIX/BNIP3L can both mediate apoptosis to inhibit tumor cell growth and promote tumor cell survival by clearing intracellular reactive oxygen species (ROS) through mitophagy. Therefore, we summarize a brief overview of the structure and function of NIX/BNIP3L, as well as the mechanisms of NIX/BNIP3L gener

Invited Lectures : Overviews Purinergic signalling: past, present and future.

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FDA-Approved Drugs for Hematological Malignancies-The Last Decade Review.

Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug

Calcium Phosphate Ceramics Can Prevent Bisphosphonate-Related Osteonecrosis of the Jaw.

Bisphosphonate-associated osteonecrosis of the jaw (BRONJ), a post-surgical non-healing wound condition, is one of the most common side effects in patients treated with nitrogen-containing bisphosphonates. Its physiopathology has been related with suppression of bone turnover, of soft tissue healing and infection. Biphasic calcium phosphates (BCP) are used as a drug delivery vehicle and as a bone substitute in surgical wounds. Due to their capacity to adsorb zoledronate, it was hypothesized these compounds might have a protective effect on the soft tissues in BRONJ wounds. To address this hypo

Clinical Utility of Selinexor/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: A Review of Current Evidence and Patient Selection.

Multiple myeloma (MM) is one the most common hematological malignancies, and despite the survival prolongation offered by proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and anti-CD38 monoclonal antibodies, the need for novel agents is prominent. Selinexor is a first-in-class, oral, selective inhibitor of exportin-1 (XPO1), a vital protein for the exportation of more than 200 tumor suppressor proteins from the nucleus. Both in solid tumors and hematologic malignancies, selinexor-mediated inhibition of nucleus export seems to effectively lead to cancer cell death. Selinexor in combi

Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk.

In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of a

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… The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation . Cell Rep . 2012 ; 2 : 207 ‐ 215 . 22902403 10.1016/j.celrep.2012.07.007 PMC3463940 14 Jardin F , Pujals A , Pelletier L , et al. …

Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia.

The therapeutic landscape of acute myeloid leukaemia (AML) has evolved beyond the classic '7 + 3'/DA regimen, through the approval and incorporation of targeted treatments in both front-line and relapsed/refractory settings. Indeed, the use of selective BCL-2 antagonists (e.g. venetoclax) and FLT3 inhibitors (e.g. midostaurin, gilteritinib) which target specific molecular characteristics of leukaemic cells, has enhanced outcomes and survival rates. Arguably one of the most exciting advancements has been the clinical development of menin inhibitors for the treatment of patients harbouring speci

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… Lens Epithelium‐Derived Growth Factor Methyl‐Binding Domain Mixed Lineage Leukaemia protein 1 multiple myeloma Mixed Phenotype Acute Leukaemia Multiple Endocrine Neoplasia, type 1 Myeloid Ecotropic viral Integration Site 1 homologue newly diagnosed nucleophosmin 1 mutant nucleophosmin 1 Nuclear … Pore complex 214 (rearrangements) Nuclear Pore complex 98 (rearrangements) overall response rate Polymerase‐Associated Factor (1 complex) Plant Homeodomain patients relapsed/refractory Su(var)3–9, Enhancer‐of‐zeste, and Trithorax Super Elongation Complex Therapeutically Applicable Research …

T-Type Calcium Channels: A Mixed Blessing.

The role of T-type calcium channels is well established in excitable cells, where they preside over action potential generation, automaticity, and firing. They also contribute to intracellular calcium signaling, cell cycle progression, and cell fate; and, in this sense, they emerge as key regulators also in non-excitable cells. In particular, their expression may be considered a prognostic factor in cancer. Almost all cancer cells express T-type calcium channels to the point that it has been considered a pharmacological target; but, as the drugs used to reduce their expression are not complete

Dual targeting of protein translation and nuclear protein export results in enhanced antimyeloma effects.

Selinexor (KPT-330) is a small molecule inhibitor of XPO1, which mediates the transport of tumor suppressor proteins, oncogene messenger RNAs, and other proteins involved in governing cell growthfrom the cell nucleus to the cytoplasm. It is overexpressed in many cancer types. Because eukaryotic translation initiator factor 4E (eIF4E) plays a critical role in protein translation in cancer cells in multiple myeloma (MM), we evaluated the effectiveness of combined inhibition of protein translation and nuclear export in MM. Selinexor, an inhibitor of nuclear protein export, dose-dependently decrea