Anti-Cancer Research Progress of Triptolide: Mechanisms of Action, Structural Modifications, Nanodelivery Systems and Clinical Challenges.

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REVIEW
Anti-Cancer Research Progress of Triptolide:
Mechanisms of Action, Structural Modifications,
Nanodelivery Systems and Clinical Challenges
Zhong-Xin Li1,2,*, Lanlan Zang
3,4,*, Yan-Qing Li1, Mi Zhang2, Dan-Meng Zhao2, Xiu-Yuan Han1, Ji-Feng Zhao1,
Chuan-Hua Ding1, Wen-Shan Liu1,3,4
1Department of Pharmacy, Clinical Research Center, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, 261041, People’s
Republic of China; 2School of Pharmacy, Shandong Second Medical University, Weifang, Shandong, 261053, People’s Republic of China;
3Pharmaceutical Laboratory, Department of Pharmacy, Linyi People’s Hospital, Shandong Second Medical University, Linyi, Shandong, 276000, People’s
Republic of China; 4State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, Jiangsu, 210000, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Wen-Shan Liu; Chuan-Hua Ding, Email liuwenshan@sdsmu.edu.cn; dchh422@163.com
Abstract: Triptolide is a bioactive diterpenoid lactone from traditional Chinese medicine with notable anti-tumor, immunosuppres -
sive, and anti-inflammatory properties. However, its clinical utility is hampered by poor solubility, a narrow therapeutic index, and
multi-organ toxicity. In response, extensive efforts have been made to improve its efficacy and safety profile. This review critically
examines recent progress in Triptolide research, covering its mechanisms of action, derivative design, drug delivery systems, and
cancer-specific applications. It also evaluates its clinical potential against pancreatic, breast, and ovarian cancers, addresses ongoing
challenges, and suggests future research paths to accelerate clinical translation. This article presents a narrative review summarizing
the research progress on the pharmacological activities, structural modifications, and nanodelivery systems of Triptolide. Literature
searches were conducted in PubMed and Web of Science using keywords including “Triptolide”, “pharmacological activity”,
“structural modification”, and “nanodelivery”, combined with Boolean operators. The search timeframe was from database inception
to March 2026. Inclusion criteria were: original research articles related to the pharmacological activities, structural modifications or
nanodelivery systems of Triptolide, peer-reviewed journal articles published in English or Chinese. Exclusion criteria were: duplicate
publications, conference abstracts, dissertations, and preprints, articles irrelevant to the topic. Study selection was performed
independently by two reviewers, with disagreements resolved through discussion or consultation with a third reviewer. A total of
158 articles were included in this review.
Keywords: triptolide, anticancer activity, structure-activity relationship, analogs of triptolide, nano/micro-formulation
Introduction
Cancer is one of the major challenges to human health and survival, and it is also a serious issue that modern medicine urgently
needs to overcome.1 In recent years, with the in-depth study of natural medicines, their anti-tumor activity has gradually
attracted widespread attention. Numerous studies have shown that natural active ingredients can significantly inhibit tumor
cell proliferation, promote apoptosis, and even reverse drug resistance by intervening in multiple signaling pathways,
demonstrating good therapeutic potential.2–4 In this context, a series of drugs derived from natural products have been
successfully developed and applied in clinical practice, such as paclitaxel extracted from Taxus chinensis,5 vincristine from
Changchun flowers,6 and topotecan derived from camptothecin.7 These agents have become essential first-line treatments in
various solid tumor chemotherapy regimens, significantly improving patient survival and prognosis.
Tripterygium wilfordii Hook. f., known as “Leigongteng” in Chinese, a perennial vine belonging to the Celastraceae
family, has been used in traditional Chinese medicine for over two hundred years to treat rheumatoid arthritis, psoriasis,
and other autoimmune diseases. 8 Triptolide is the main active ingredient of the natural medicine T. wilfordii, which was
Drug Design, Development and Therapy 2026:20 601715 1
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Drug Design, Development and Therapy
Open Access Full T ext Article
https://doi.org/10.2147/DDDT.S601715
Received: 9 February 2026
Accepted: 7 May 2026
Published: 25 May 2026
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/
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first isolated in 1972 and has shown significant anti-leukemia effects. 9 Given its strong anti-inflammatory, immunosup -
pressive, and broad-spectrum anti-tumor effects, Triptolide has attracted steadily rising research interest since that
time.10,11 At present, Triptolide has demonstrated significant inhibitory effects on at least 60 tumor cell lines, 12 including
breast, pancreatic, ovarian, and lung cancers, among other malignancies. Compared with other traditional chemotherapy
drugs, Triptolide has the following characteristics: t demonstrates potent broad-spectrum anti-tumor activity in animal
models. Its antitumor activity is independent of the tumor suppressor p53, as it remains effective against p53-deficient
tumor cells. 13 It is effective against tumor cells with high multidrug resistance protein 1 (MRP1) expression and can
reverse tumor drug resistance. 14,15 It exhibits more potent antitumor activity than conventional chemotherapeutic agents
and demonstrates significant efficacy at low concentrations. 12
However, the clinical application of Triptolide is severely constrained by its inherent defects, including significant
hepatorenal toxicity and irreversible reproductive toxicity. 16–23 It also has a narrow therapeutic window, poor water
solubility (only 17 μg/mL), which complicates the development of injectable formulations. 24 In addition, Triptolide
exhibits poor stability, the epoxide ring and hydroxyl groups in its structure are prone to hydrolysis or oxidation under
physiological conditions,25 leading to reduced in vivo activity. To address these challenges, efforts have been made on
multiple fronts, including mechanistic studies, structural modification, and the development of novel delivery systems, to
facilitate the clinical translation of Triptolide. At present, the mechanism of action of Triptolide has been gradually
elucidated, and the synthesis of its structurally modified derivatives has also been further developed. Meanwhile, the
emergence of novel drug delivery systems has provided promising solutions to many of Triptolide’s disadvantages.
This review summarizes and analyzes the mechanism of action, structure-activity relationship, and the latest
developments in cellular and animal research aimed at minimizing or overcoming the limitations of Triptolide in clinical
applications. It discusses useful strategies, including the development of structural derivatives and nano/micro delivery
systems. For researchers interested in designing novel anti-tumor drugs based on Triptolide, addressing the drawbacks of
the parent compound, and exploring various approaches to its modification, this review serves as a valuable resource.
Molecular Mechanisms and Signal Pathway Regulation
The key signaling pathway proteins of Triptolide are shown in ( Figure 1) and ( Table 1).
Induce Apoptosis
Transcriptional Inhibition
Global transcriptional inhibition is the primary mechanism of action of Triptolide. XPB is the DNA helicase subunit of
the transcription factor IIH (TFIIH) complex, which regulates transcription initiation by RNA polymerase II (Pol II) and
is essential for nucleotide excision repair (NER). 26 Triptolide irreversibly inhibits the ATPase activity of XPB through
covalent binding, which subsequently triggers phosphorylation and ubiquitination of the largest subunit of RNA
polymerase II, Rpb1, ultimately leading to its degradation. 27,28 This cascade of events results in global suppression of
both gene transcription and NER, with short-lived oncoproteins (such as c-Myc) and cyclins being particularly affected.29
Mitochondrial Apoptosis
Mitochondria are central regulators of apoptosis. Following the translocation of Bax to the mitochondria, the release of
cytochrome c (Cyto c) triggers a key step in the mitochondrial apoptosis pathway: the formation of the apoptosome. 30
P53 is a downstream effector of PI3K, and Bax/Bcl-2 are directly regulated by p53. Triptolide inhibits the ubiquitination
and degradation of p53, thereby upregulating Bax and downregulating Bcl-2/Mcl-1. This induces a pro-apoptotic shift
and leads to loss of mitochondrial membrane potential. Consequently, Cyto c is released, which activates the Caspase
cascade, thereby finalizing the apoptotic process. 31–40 For example, in MDA-MB-231 breast cancer cells, Triptolide
treatment increased Caspase-3 expression by 4-fold and induced characteristic apoptotic morphology, including cell
shrinkage, chromatin condensation, and nuclear fragmentation. 41
Triptolide promotes apoptosis not only by directly activating caspase pathways but also by indirectly relieving their
suppression by other factors. This dual mechanism is evidenced in two distinct models. In a study on cisplatin-resistant
ovarian cancer SKOV3/DDP cells, Triptolide induced apoptosis by significantly increasing Smac protein expression and
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reducing levels of anti-apoptotic proteins, including Survivin, VEGF, and MMP-2, thereby relieving the inhibition on
Caspase-3.42 In another context, Triptolide was shown to trigger the proteasomal ubiquitination and degradation of
EBNA1, which consequently eliminates its inhibitory effect on the Caspase-9 pathway. 43
Heat Shock Protein Pathway
Heat shock protein (HSP) plays an anti-apoptotic role in malignant cells. For instance, HSP70 inhibits apoptosis by
stabilizing unfolded proteins and lysosomes, reducing cytoplasmic Ca 2+ levels, and facilitating the repair of damaged
proteins.44 Research indicates that Triptolide downregulates HSP70 expression in tumor cells. 45 For example, in MKN28
and MKN45 gastric cancer cell lines, Triptolide induces apoptosis by inhibiting the transcription factor Sp1, thereby
downregulating pro-survival proteins such as HSP70 and HSF1. 46
Furthermore, HSP90 client proteins include key regulators of cell proliferation and survival, such as receptor tyrosine
kinases, metastable/mutant signaling proteins, transcription factors and cell cycle regulators. 47 Inhibition of HSP90 can
therefore concurrently destabilize multiple oncoproteins across numerous signaling pathways. 47 This is demonstrated in
HeLa cells, where Triptolide triggers cell cycle arrest and apoptosis via an HSP90β-dependent pathway. 48
TNF-Related Apoptosis-Inducing Ligand Pathway
TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a potent cytokine that induces apoptosis by binding to death
receptors (DRs). Triptolide directly acts on DR5, thereby activating the Caspase-8 mediated apoptotic signaling cascade
and inducing cell apoptosis. 48,49 Supporting this mechanism, a study on pancreatic cancer MIA PaCa-2 cells reported
a 6-fold increase in DR5 expression following Triptolide treatment compared to untreated cell. 50
Figure 1 The signaling pathway proteins of Triptolide.
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Fas Pathway
The Fas signaling pathway is central to the physiological regulation of apoptosis and is implicated in the pathogenesis of
various malignancies and immune diseases. Triptolide directly targets the Fas receptor, activating the Fas-associated
death domain (FADD)/Caspase-8 cascade. This leads to the proteolytic cleavage of proCaspase-8 into its active form,
Caspase-8, thereby initiating apoptosis. 49 A study in HepaRG cells demonstrated that Triptolide upregulates the protein
expression levels of both Fas and Caspase-8 in a dose-dependent manner. 36
Cuproptosis Pathway
Cuproptosis is a form of copper-dependent cell death. Triptolide can inhibit cancer by disrupting copper homeostasis and
inducing cuproptosis. Compared with other diterpenoids that act on microtubules (eg., paclitaxel) or ion channels (eg.,
ginkgolides), Triptolide achieves precise and efficient disruption of cellular copper homeostasis not through ordinary
chemical chelation or non-specific stress, but by targeting specific copper efflux proteins. The mechanism involves down-
regulating X-linked inhibitor of apoptosis protein (XIAP), thereby stabilizing copper metabolism MURR1 domain-contain-
ing protein 1 (COMMD1). The accumulated COMMD1 subsequently inhibits the copper transporters ATP7A/B, impairing
copper efflux. This leads to intracellular copper accumulation and ultimately triggers apoptosis in cancer cells.51
NF-κB Pathway
NF-κB is constitutively activated in various cancers, where it drives tumor progression through multiple mechanisms,
including the upregulation of anti-apoptotic genes and VEGF, as well as the induction of epithelial-mesenchymal
transition (EMT). 47,52 Triptolide inhibits NF-κB by blocking p65 phosphorylation. 53 For instance, in glioma studies,
T able 1 The Potential Mechanisms of Triptolide in Exerting Its Anticancer Effects
Signaling
Pathway
T arget Cancer T ype Cancer Cell Lines
PI3K/Akt PI3K↓, p-Akt↓, Akt↓, ERK↓, GSK3β↓, RPL23↑,
MDM2↓,
p53↑, VEGF↓
Breast cancer,
ovarian cancer,
nasopharyngeal carcinoma,
NSCLC
MCF-7,
C666-1,
MDA-MB-468,
SKOV3/DDP
Apoptotic pathway Bax↑, Bcl-2↓
Caspase-3/7↑,
Caspase-8↑,
Caspase-9↑
Thyroid cancer,
ovarian cancer,
pancreatic cancer,
hepatocellular carcinoma,
NSCLC,
burkitt lymphoma
MDA-MB-231,
SKOV3/DDP ,
Pan02,
HepG2,
A549, H460,
Raji, NAMALWA and Daudi
HSP HSP70/HSF1↓,
HSP90↓
Gastric cancer MKN28 and MKN45
TRAIL DR5↑,
Caspase-8↑
Pancreatic cancer MIA PaCa-2
Fas Fas↑, ProCaspase-8↑, Caspase-8↑ Liver cancer HepaRG
XPB TFIIH↓ Prostate cancer
renal cancer,
lung cancer,
PC3,
SK RC-52,
H460 and H1975
Cuproptosis XIAP↓, COMMD1↑, ATP7A/B↓ Cervical cancer HeLa and SiHa
NF-κB P65 nuclear translocation inhibition Glioma,
human multiple myeloma
U251,
MM.1R
EMT E-cadherin↑, Vimentin↓, Snail↓ Glioma,
ovarian cancer,
NSCLC
U87 and U251,
SK-OV-3,
NCI-H1299 and NCI-H460,
A2780/DPP
PTHrP-RANK RANKL↓ Breast cancer MDA-MB-231
Notes: ↓: molecular-level decrease. ↑: molecular-level increase.
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Triptolide has been shown to induce apoptosis. This effect is mediated through the suppression of the NF-κB pathway,
thereby activating oxidative stress. 54
Arrest the Cell Cycle
The phosphatidylinositol 3-kinase (PI3K)/Akt signaling axis is a crucial pathway through which Triptolide exerts its
inhibitory effects on tumor cells. 35,55–57
Tumor suppressor genes are crucial regulators of the cell cycle and apoptosis, and their suppression or loss often
triggers dysregulated proliferation in tumor cells. Phosphatase and tensin homolog (PTEN) and p53 are well-known
tumor suppressors, located upstream and downstream of the PI3K pathway, respectively. Most cancers harbor mutations
in PTEN or p53 related genes, which significantly reduce the expression of these tumor suppressors. 58,59
PTEN functions upstream of the PI3K pathway. In leukemia studies, treatment with Triptolide significantly enhanced
both the expression and activity of PTEN, an effect attributed to the suppression of miR-190. miR-190a-3p can bind to
and inactivate PTEN. Triptolide downregulates arsenite-resistance protein 2 (Ars2), which disrupts the Ars2-CBP80
/CBP20-Drosha complex interaction. This disruption inhibits the processing of primary miR-190a-3p (pri-miR-190a-3p)
into its mature form. Consequently, the downregulation of miR-190a-3p upregulates its target gene, PTEN, ultimately
leading to cell cycle arrest at the G1 phase. 60 Similarly, in non-small cell lung cancer (NSCLC), Triptolide targets and
inhibits miR-21, thereby alleviating its suppression of PTEN. The increased PTEN protein levels contribute to inhibition
of NSCLC cell proliferation and promotion of apoptosis. 61
P53 acts as a downstream effector of the PI3K pathway. The activity of p53 is primarily regulated by its inhibitor,
mousedouble minute 2 (MDM2). 62 Triptolide activates the RPL23–MDM2–p53 pathway: under ribosomal stress,
ribosomal protein L23 (RPL23) is released and binds to MDM2, competitively inhibiting MDM2-mediated ubiquitina -
tion and degradation of p53, thereby stabilizing it. Additionally, Triptolide downregulates Akt expression and impairs the
ubiquitination-promoting function of Akt-enhanced MDM2, further contributing to p53 stabilization. The stabilized p53
is then activated and exerts two key functions: it upregulates pro-apoptotic factors such as PUMA and Caspases-3/9
while downregulating the anti-apoptotic protein Bcl-2, thereby inducing apoptosis; it also upregulates the cell cycle
inhibitor p21, inducing cell cycle arrest at the G2/M phase.63 In MCF-7 and MDA-MB-468 breast cancer cells, Triptolide
has been shown to reduce MDM2 levels in a dose-dependent manner. 64
Furthermore, Triptolide has been demonstrated to modulate key pathways, including PI3K/Akt/mTOR, p38, mitogen-
activated protein kinase (MAPK) and Foxo3a, promoting protective autophagy and apoptosis, which ultimately
diminishes cancer cell viability. 65 In terms of inhibiting metastasis, Triptolide inhibits the proliferation, migration, and
angiogenesis of endothelial cells. This is achieved by blocking the activation of the PI3K/Akt/mTOR signaling pathway
and downregulating the expression of vascular endothelial growth factor (VEGF) and its associated markers CD31 and
CD105.66,67
Inhibit Cell Metastasis
EMT Pathway
Triptolide attenuates EMT, inducing a characteristic shift toward an epithelial phenotype via E-cadherin upregulation and
downregulation of Vimentin and Snail, a shift that curbs the metastatic potential of tumor cells. 42,68–72
Parathyroid Hormone-Related Protein-RANK Pathway
Bone metastases are the most common skeletal events in advanced breast cancer and represent a major clinical challenge,
as they severely compromise patient quality of life and survival. 73 To address this complication, Triptolide acts primarily
via two mechanisms: by inhibiting the stimulation of osteoclast differentiation by tumor-secreted factors (eg., TNF-α and
IL-6), and by directly binding to parathyroid hormone-related protein (PTHrP). This binding blocks the PTHrP-RANKL
axis, thereby suppressing the cancer-induced overproduction of RANKL by osteoblasts. This dual action disrupts the
vicious “tumor–bone destruction” cycle, positioning Triptolide as a promising candidate drug for treating bone
metastases.
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T oxicity of Triptolide
The toxicity of Triptolide is a major bottleneck for its clinical translation, characterized by multi-organ/system damage and
a narrow therapeutic window. Acute toxicity data show that in mice, the LD50 values for intravenous and intraperitoneal
administration are approximately 0.8 and 0.9 mg/kg,74,75 respectively, while the oral LD50 in rats is about 1.19 mg/kg.
Triptolide can cause multi-organ toxicity, and nearly all major organ systems are its targets. Cardiotoxicity is
manifested as elevated cardiac enzymes, electrocardiogram abnormalities (eg., ST-segment changes, peaked T waves),
bradycardia, and myocardial tissue damage.20 Hepatorenal toxicity is one of the major dose-limiting toxicities, leading to
hepatocyte injury, apoptosis, and impairment of liver and kidney function. 20 Reproductive toxicity is also a concern for
Triptolide. In males, it can cause spermatogenesis disorders, epididymal dysfunction, and infertility. 76 In females, it can
affect ovarian function, leading to menstrual disorders and even amenorrhea. 77 In addition, Triptolide can also cause
digestive system toxicity, immune system toxicity (eg., spleen injury), ototoxicity, and hematologic toxicity (eg., bone
marrow suppression).74,78
The toxicity of Triptolide results from the interaction of multiple factors and multiple pathways. The core molecular
mechanism of its toxicity stems from its non-selective inhibition of the XPB subunit of TFIIH, leading to RNA
polymerase II dysfunction and global transcriptional inhibition, which in turn triggers various cell death pathways. 26
Furthermore, Triptolide induces massive production of reactive oxygen species (ROS) and directly impairs mitochondrial
function, which is one of the core mechanisms underlying hepatotoxicity and other organ injuries. 79 At the same time,
Triptolide can induce multiple forms of programmed cell death, including apoptosis, autophagy, necroptosis, pyroptosis,
ferroptosis, and cuproptosis, and these death pathways play different roles in the toxicity of distinct organs. 80
To address its high toxicity, current mitigation strategies mainly include structural modification (eg., the water-soluble
prodrug Minnelide) and the development of novel nano-delivery systems.
Drug Structure and Derivatives
Structure-Activity Relationship of Triptolide
Triptolide possesses a unique abietane-type diterpenoid skeleton with three six-membered rings (A, B, C rings) and one
five-membered lactone ring (D ring), forming a “6-6-6-5” fused ring system ( Figure 2). Based on decades of structural
modification studies, the structure-activity relationship of Triptolide has been gradually clarified, providing clear
Figure 2 Structure activity relationship of Triptolide.
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guidance for the design of low-toxicity and high-activity derivatives. We have preliminarily summarized the structure-
activity relationship of Triptolide ( Figure 2).81–85
A ring: The substitution of C-2 position will reduce its biological activity while increasing its toxicity. The substituent
introduced at the C-2 position hinders the normal oxidative metabolism of this site by cytochrome P450 enzymes in the
liver, leading to increased systemic exposure and half-life. At the same time, the introduced substituent also interferes
with the binding of the C-18 carbonyl group to the target, thereby reducing activity. Introducing appropriate functional
groups, such as hydroxyl, at the C-5 position can significantly reduce toxicity while retaining its immunosuppressive and
anticancer activity.
B ring: The epoxy group of Triptolide is closely related to its activity. Opening the C-7 and C-8 epoxy groups will
significantly reduce the biological activity of Triptolide.
C ring: The structural modifications of Triptolide mainly focus on the C-ring. The C-14 β-OH is an important
modification site, its β-orientation is essential for maintaining potent anticancer activity. Oxidation of this hydroxyl to
a ketone, or its acetylation, substantially reduces both anti-inflammatory and immunosuppressive activities. Therefore,
modifications at this site are primarily esterifications, often involving the attachment of water-soluble groups to improve
solubility, or conjugation with targeted macromolecules to achieve tumor cell targeting. When the hydroxyl group at
C-14 is substituted with a fluorine atom, the resulting compound also exhibits strong anticancer activity. The α-epoxide
group at C-12 and C-13 is a crucial component of Triptolide bioactivity and represents another major site for structural
modification. Introduction of a hydroxyl group at C-12 results in compounds with significant anti-inflammatory activity
only, whereas the introduction of a chlorine atom can significantly reduce toxicity. When the epoxide ring between C-12
and C-13 is opened, the compound loses both its anticancer and immunosuppressive activities, retaining only its anti-
inflammatory effects.
D ring: The lactone ring of Triptolide D-ring is an essential structure for its biological activity, any structural
modification that breaks or opens this ring will result in a complete loss of anti-inflammatory, immunosuppressive, and
antitumor effects. Only when the lactone ring is retained can the derivative maintain the ability to covalently bind to
target proteins.
Guided by the above structure-activity relationship, Triptolide derivatives can be designed to achieve lower toxicity,
higher efficacy, and a wider therapeutic window, thereby enhancing their translational potential.
Research on the Structural Modification of Triptolide
The severe toxicity and unfavorable pharmacokinetic profile of Triptolide remain major limitations to its clinical
application.25 Structural modification represents a direct and effective strategy to enhance its safety. By altering specific
functional groups, for instance, through the introduction of large polar substituents or tumor-targeting motifs into the
molecule (Figure 3), it is possible to significantly reduce toxicity while retaining biological activity and improving tumor
cell targeting ( Table 2).
Esterification of C-14-OH Groups
It is well established that the β-orientation of the C-14-OH is essential for maintaining the potent anticancer activity of
Triptolide. Guided by this principle, structural modifications have long focused predominantly on the C-14-OH
group.83,85 Researchers have synthesized a series of bioactive derivatives through the chemical modification of
Triptolide (Figure 4).
PG490-88 (also known as F60008), a water-soluble prodrug of Triptolide, was once a highly promising derivative. In
cellular and animal models, it demonstrated enhanced biological activity over Triptolide alongside significantly reduced
liver and kidney toxicity, and as a monotherapy, it could induce the regression of lung and colon carcinoma xenografts. 86
Despite advancing to Phase I clinical trials, the outcomes were unsatisfactory. In plasma, PG490-88 is converted into
Triptolide by plasma esterases. However, it remains unclear which esterases are responsible for this conversion, and due
to interpatient variability in plasma esterase activity, the extent of conversion is unpredictable, with conversion rates
differing by up to 3-fold among individuals. Moreover, the conversion process is slow and incomplete. This unpredict -
able and uncontrollable pharmacokinetic profile was implicated in two patient deaths during the trials, 87 leading to their
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subsequent suspension. Therefore, in subsequent studies, pharmacogenomics can be used to elucidate the specific
conversion process, thereby enabling the design of prodrugs that are safer, more controllable, and exhibit less inter -
individual variability.
G-2 is a Triptolide prodrug designed with gamma-hydroxybutyric acid as a linker to conjugate glucose via glycosidic
bonds. This structure avoids the release of the toxic intermediate F60008, which was implicated in previous clinical
fatalities,87 while significantly improving aqueous solubility and stability, remaining undegraded in human serum for up
to 72 hours. G-2 also exhibits enhanced selectivity toward cancer cells, showing significantly lower IC 50 values in
malignant cell lines (PC3, MDA-MB-231) than in normal cells (ranging from 2.52 to 6.88 μg/mL). 88 Furthermore, owing
to the hypoxic microenvironment common in rapidly metabolizing tumors, 89 and because hypoxia upregulates the
expression of GLUT-1 on the surface of cancer cells, 90 G-2 demonstrated a 5-fold increase in potency against PC3
cells under 1% O 2, whereas the efficacy of doxorubicin decreased. In a prostate cancer model, G-2 showed markedly
improved therapeutic properties: the maximum tolerated dose in mice increased from 0.2 mg/kg (for the parent drug) to
1 mg/kg, and its antitumor effect persisted longer after treatment cessation. 88
Similarly, Liu et al developed a series of six Triptolide-glucose conjugates as positional isomers, targeting glucose
transporter 1 (Glut-1). Among them, TG2, formed by conjugating Triptolide to the C-2-OH position of d-glucose,
demonstrated the most potent cytotoxicity against tumor cells and the lowest toxicity toward non-tumor cells, achieving
a therapeutic index 5.7 times higher than that of Triptolide. Moreover, in vivo studies confirmed that TG2 possesses
superior antitumor efficacy compared to the parent compound. Notably, even when achieving a tumor inhibition rate
exceeding 90%, no adverse reactions were observed. 91
“Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment”. 92
TAMs can engulf substantial amounts of nanomaterial and transport nanocarriers into hypoxic tumor regions, thereby
promoting drug accumulation at the target site. 93,94 Leveraging this mechanism, Liaw et al designed a fourth-generation
hydroxyl-terminated PAMAM dendrimer (G4-OH) delivery system for Triptolide targeting toward TAMs. In this system,
the C-14-β-OH group of Triptolide was esterified with azido-PEG6-acid. The resulting product was then conjugated to an
alkyne-modified dendrimer (D-hexyne) via CuAAC click chemistry to form D-Trip conjugates. The resulting D-Trip
Figure 3 Representative modified drugs at various sites of Triptolide.
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exhibited a 500-fold increase in water solubility compared to free Triptolide. Its small particle size and near-neutral zeta
potential facilitated blood-brain barrier penetration and renal clearance. D-Trip remained stable at physiological pH but
sustained a prolonged release under simulated tumor microenvironment conditions. Notably, the IC 50 of D-Trip on IFN-
γ-activated microglia (a TAM model) was 88.1 μg/mL, significantly lower than that of free Triptolide. In an orthotopic
glioblastoma mouse model, D-Trip (0.5 mg/kg/day) reduced tumor burden to 12% of total brain mass, significantly lower
than free drug (20%) and control (35%), while markedly alleviating free Triptolide-induced toxicities such as injection
site inflammation, hepatic necrosis/steatosis, and myocardial fibrosis. 95
CX-23 is a water-soluble prodrug carboxylated at the C-14-OH group of Triptolide, representing the first anti-
hepatocarcinoma prodrug candidate designed for activation by NAD(P)H quinone oxidoreductase 1 (NQO1). Compared
T able 2 The Effect of Structural Modification with Triptolide
Drug Purpose Modification Result
PG490-88 Improve water solubility Water solubility: >30 mg/mL.
G-2 Enhance selectivity towards tumor cells IC50 in cell lines:
Primary cells from 2.52 μg/mL to 6.88 μg/mL,
cancer cell lines from 0.164 μg/mL to 4.1 μg/mL.
TG-2 Improve water solubility and enhance selectivity
towards tumor cells
log P (pH 7.4):
Triptolide −0.021 ± 0.03, TG-2 −0.347 ± 0.04.
IC50 in cell lines:
NCI-H1975 1.5 μg/mL, HUVEC 5.52 μg/mL.
D-Trip Improve water solubility Water solubility:
Triptolide 0.017 mg/mL, D-Trip 50 mg/mL.
IC50 in cell lines:
BV2 88.1 μg/mL, vs Triptolide 140.3 μg/mL.
CX23 Reduce toxic side effects and improve targeting IC50 in cell lines:
HEPG2 32.2 μg/mL, normal hepatocytes 320 μg/mL.
A549 25 μg/mL, A549/DDP 4.74 μg/mL, BEAS-2B over 75.9 μg/mL.
Cet-TPL Targeting EGFR overexpressing cancer cells IC50 in cell lines:
A549 and H1299 2.5 μg/mL.
H520 > 100 μg/mL.
Y -TR1 Reduce toxic side effects and target CD26+cancer
cells
IC50 in cell lines:
Triptolide: STO clone12 (CD26+) and MSTO wt (CD26-) 3.6 μg/mL.
Y -TR1: MSTO clone12 (CD26+) 15μg/mL, MSTO wt (CD26-) 35 μg/mL.
LD50 in vivo:
Triptolide 0.83 mg/kg body weight, Y -TR1 932.5 mg/kg.
Minnelide Improve water solubility Water solubility:
80 mg/mL.
AS-TP Improve water solubility and targeting Water solubility:
Triptolide 17 μg/mL, AS-TP more than 3533 μg/mL.
IC50 in cell line:
MCF-10A about 0.42 μg/mL.
MDA-MB-231 0.162 μg/mL, MDA-MB-468 0.188 μg/mL, 4T1 0.195 μg/mL.
LLDT -288 Reduce toxicity IC50 in cell line:
Cancer cells, range from 6.56 μg/mL to 55.5 μg/mL.
HFF and HL-7702 cells, range from 316 μg/mL to 497 μg/mL.
CK21 Reduce toxicity IC50 in cell line:
AsPC-1 and Panc-1, CK21 similar as Triptolide.
Human fibroblast, CK21 more than 296 μg/mL.
LLDT -8 Reduce toxicity LD50 in vivo:
Triptolide 0.86 mg/kg.
LLDT -8 9.3 mg/kg (i.p.) and 6.8 mg/kg (P .O.),
no lethality at 4.1 mg/kg.
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with normal tissues, NQO1 overexpression is observed across a spectrum of cancers, including those of the breast, colon,
cervix, lung, and pancreas, 96–100 making it a useful enzyme for tumor-specific drug activation. CX-23 significantly
reduced toxicity toward normal cells, particularly nephrotoxicity, while retaining the potent antitumor activity of
Triptolide.101 It remained inactive in vitro and required enzymatic reduction by NQO1 within tumor cells. In the
presence of NAD(P)H, NQO1 converted CX-23 into the active metabolite Triptolide and the byproduct CX-21.
Furthermore, CX-23 exhibited excellent stability in human plasma and liver microsomes, demonstrating resistance to
hydrolysis by carboxylesterases and metabolism by CYP450 enzyme systems. 101
In a HepG2 xenograft nude mouse model, intraperitoneal administration of CX-23 at a molar dose equivalent to that
of Triptolide exhibited comparable antitumor efficacy. Furthermore, the CX-23 group showed significantly reduced
creatinine and blood urea nitrogen levels compared to the Triptolide group, indicating effective mitigation of renal
toxicity.102 These results suggest that CX-23 could represent a safer and more effective therapeutic candidate.
Antibody-drug conjugates (ADCs) consist of tumor-targeting monoclonal antibodies which are linked to cytotoxic
payloads via specifically designed chemical linkers. 103 These three components work in concert to selectively deliver
potent cytotoxic agents into tumor cells, where the drug is released intracellularly to exert its effect. 104 Compared to
traditional drug delivery methods, ADCs have multiple advantages. The monoclonal antibody specifically recognizes
antigens on the tumor cell surface, thereby enabling precise drug enrichment in tumor tissues and significantly reducing
off-target toxicity.105 Furthermore, conjugation to a large, hydrophilic antibody limits the antigen independent uptake of
the cytotoxic payload into antigen negative cells, which helps to widen the therapeutic window. 106
Cet-TPL is an ADC formed by conjugating the C-14-OH group of Triptolide to the anti-EGFR monoclonal antibody
Cetuximab (Cet) (Figure 5). It achieves precise targeting by binding of Cet to EGFR, which is highly expressed on cancer
cells, thereby triggering receptor-mediated endocytosis. Cet-TPL significantly inhibited the proliferation of EGFR
overexpressing cells, such as A549 and H1299 lung cancer cells and UM-SCC6 head and neck cancer cells, with an
IC50 as low as 2.5 μg/mL. It remained effective against models with resistance to either Cet or TPL monotherapy, yet
Figure 4 Prodrugs include PG490-88, G-1, G-2, TG-2, and CX-23. ADCs include Cet-TPL and Y -TRI. D-TRIP is a dendrimer conjugate.
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showed no inhibition toward EGFR negative cells (H520) or normal lung fibroblasts (MRC-5). In an A549 transplant
tumor mouse model, Cet-TPL completely inhibited the growth of EGFR overexpressing tumors, exhibiting stronger
efficacy than either Triptolide or Cetuximab alone, at effective doses of 25–50 mg/kg. Cet-TPL significantly reduced
toxicity and expanded the treatment window. 107
ADC Y-TRI is composed of the humanized anti-CD26 monoclonal antibody YS110 covalently linked to a Triptolide
derivative (TR-1) via a heteroduplex linker (Figure 6). CD26, a target overexpressed in various malignant tumors such as
mesothelioma and leukemia, is associated with tumor growth.108 Y-TRI conferred potent and selective anti-tumor activity
against CD26-positive cells both in vitro and in vivo, without significant toxicity. It exhibited dose-dependent cytotoxi -
city in CD26-positive mesothelioma and leukemia cell lines, with an IC 50 of approximately 15–30 μg/mL, but showed
minimal toxicity in CD26-negative lines. Y-TRI demonstrated significantly greater efficacy than the unconjugated YS110
antibody.109
Figure 5 Synthesis pathway of Cet-TPL.
Figure 6 Synthesis pathway of Y -TR1.
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Although EGFR and CD26 are highly expressed in various tumors, both also have basal expression levels in normal
tissues, which constitutes a major risk of on-target, off-tumor toxicity for ADCs or targeted delivery systems. 110 EGFR is
normally expressed in the skin, gastrointestinal tract, liver, and renal tubular epithelium, and can lead to rash, diarrhea, oral
mucositis, and liver/kidney injury. Studies have shown that while EGFR-targeting ADCs demonstrate efficacy, they also
induce severe infusion reactions and ocular toxicities, indicating a narrow therapeutic window.111 CD26 is highly expressed in
renal tubules, intestinal epithelium, activated lymphocytes, and vascular endothelium, potentially causing renal tubular injury,
lymphopenia, and gastrointestinal inflammation.110 Even when normal tissue expression levels are low, high payload toxicity,
linker instability, non-specific uptake by normal cells (eg., endocytosis mediated by FcγRs, FcRn, and C-type lectin receptors),
and high organ exposure (eg., kidney, liver) can amplify off-target toxicity.112 To address these risks, when designing EGFR/
CD26-targeting ADCs, one can employ bispecific ADCs, low-toxicity payloads, or prodrug-type payloads to reduce off-target
risk. Additionally, histopathological examination of skin, kidney, and intestinal tissues should be included in toxicological
assessments, and a low-dose, multi-dose regimen should be prioritized.
Etherification of C-14-OH Groups
Minnelide, the disodium salt of 14-O-phosphonomethyl Triptolide, is a water-soluble prodrug of Triptolide. The
introduction of a highly electronegative and hydrophilic phosphonate group at the C-14 position drastically enhances
its aqueous solubility to 61 mg/mL, compared to only 17 μg/mL for the parent compound. 113 Minnelide itself is inactive
in vitro and must be converted into active Triptolide in vivo by alkaline phosphatase. As the most advanced Triptolide
derivative in clinical development, Minnelide has progressed to a Phase I trial for gastrointestinal cancers 114,115 and
a Phase II trial for pancreatic cancer. 116
AS-TP is a conjugate in which the oligonucleotide aptamer AS1411 is linked to a C-14-OH modified Triptolide via an acid-
labile acetal bond. By exploiting its ability to bind nucleolin and be internalized by tumor cells, the aptamer AS1411 enables the
targeted delivery of Triptolide.117 This pH-sensitive aptamer-drug conjugate is primarily internalized via the macropinocytosis
pathway and enriched in lysosomes. In the acidic environment of triple-negative breast cancer (TNBC) lysosomes, the acetal
bond is cleaved, releasing active Triptolide. In vitro, AS-TP demonstrated the most potent cytotoxicity (lowest IC50) against
a panel of breast cancer cell lines, while exhibiting minimal toxicity in normal breast cells (MCF-10A). In vivo, the accumulation
of AS-TP in TNBC xenografts was 11-fold higher than that in the control group and was sustained for over 24 hours. AS-TP
achieved a superior tumor growth inhibition (TGI) value of 83.7%, significantly surpassing the 63% TGI of the clinical
benchmark drug Eribulin. Furthermore, at therapeutic doses, AS-TP caused no significant weight loss or organ damage.118
Modification of C-14 Carbon
LLDT-288 is a C-14-modified derivative of Triptolide with broad spectrum and potent antitumor activity. The compound
showed nanomolar-range IC 50 values against multiple tumor cell lines (eg., A549, U251, SK-OV-3, MCF-7), accom -
panied by low cytotoxicity in normal cells. In a PC3 xenograft mouse model, orally administered LLDT-288 demon -
strated promising therapeutic efficacy along with significantly reduced systemic toxicity. 119
Modification of D Ring C-19 Carbon
CK21 represents an innovative structural derivative distinct from conventional C-14 modifications. It features a C–C
double bond introduced at the C-19 position of the D-ring, forming (E)-19-[(1’-benzoyloxy-1’-phenyl)-methylene]-
Triptolide. CK21 retained potent anticancer activity comparable to Triptolide in human pancreatic cancer cells (AsPC-1,
Panc-1) and in four types of patient derived pancreatic tumor organoids, while exhibiting minimal toxicity toward normal
human fibroblasts, with effects only observed at concentrations ≥ 296 μg/mL. 120 Mechanistically, CK21 inhibited
pancreatic cancer cells by suppressing X-box binding protein (XBP) ATPase activity and downregulating the NF-κB
pathway. This promoted ROS production and initiated mitochondria-mediated apoptosis. In vivo, daily administration of
CK21 (3 mg/kg) potently reduced the volume of subcutaneous AsPC-1 and Panc-1 tumors; complete tumor regression
was observed in up to 70% of cases. In an orthotopic transplantation model, CK21 not only markedly reduced primary
tumor volume but also suppressed metastatic progression. Moreover, CK21 remained effective against large established
tumors (~900 mm 3) and demonstrated promising efficacy as a monotherapy in gemcitabine-resistant tumors.
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Compared with Triptolide, CK21 exhibits significantly reduced toxicity and side effects, but an obvious gender-based
difference in toxicity is observed, with female rats showing higher sensitivity: the MTD in female rats is only half that in
male rats. 120 This is related to gender differences in the expression of the rat CYP450 enzyme system. Triptolide is
primarily metabolized by the cytochrome P450 3A system.121 CYP3A2 displays clear sexual dimorphism in rats: it is the
major CYP3A isoform in male rats but is almost undetectable in female rats. 122 In humans, Triptolide is mainly
metabolized by CYP3A4,121 and interindividual variability in CYP3A4 is very significant. Moreover, CYP3A4 metabolic
activity is generally higher in females than in males. 123 Therefore, when Triptolide and its derivatives are used clinically,
the dosage should be adjusted according to individual patient conditions. At the same time, attention should also be paid
to potential drug-drug interactions during combination therapy.
Hydroxylation of C-5-H
(5R)-5-hydroxyTriptolide (LLDT-8) is a structural analog of Triptolide hydroxylated at the C-5 position and is currently in
Phase I/II clinical trials. 124,125 It exhibited superior drug-like properties, including higher solubility, and most notably,
markedly reduced toxicity. The in vitro cytotoxicity of LLDT-8 was 122-fold lower, and it’s in vivo acute toxicity was 10-
fold lower than those of Triptolide.126 Although the research on LLDT-8 mainly focuses on anti-inflammatory and immuno-
suppressive activities,127,128 its anti-tumor efficacy is also significant. In vitro studies demonstrated that LLDT-8 potently
inhibited the growth of various human and mouse cancer cell lines (P-388, HL-60, A-549, MKN-28, and MCF-7), with IC50
values in the nanomolar range.124 These findings indicate that LLDT-8 is a highly promising anticancer drug candidate.
Nano/Micron T echnology Encapsulation of Triptolide
The advent of nanotechnology and the design of nano-/microscale drug carriers have greatly improved the targeting precision
of therapeutic agents. These systems offer multiple advantages, including enhanced targeting capability, improved intracel-
lular delivery to overcome drug resistance, and sustained or controlled drug release. 129–133 To address the poor solubility,
instability, and toxicity of Triptolide, multiple delivery systems (eg., liposomes, polymeric micelles, nanoparticles, micro-
emulsions, and inorganic materials) have been utilized. These carriers improve its pharmacokinetic profile, thus reducing
adverse effects (Figure 7). Selected studies on these Triptolide delivery systems are listed in Table 3.
Figure 7 Seven Triptolide nano drug delivery systems that have been developed to date and their advantages.
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T able 3 Comparison of the Characteristics of Various Triptolide Nano Delivery Systems
Name Carrier
Classification
Composition Materials Preparation
Method
Parameters Cell
Lines
Cancer
Related
Characteristic Effect
TPL-LA-lip Liposomes Triptolide-LA, EPCS, DSPE-
PEG2K
Thin film hydration
method
Size: 96.88
±0.52 nm,
EE: 98.18%
Panc 02 Pancreatic
cancer
reduce systemic toxicity. LD50: 25.13 mg/kg, 15.7 times that of
free Triptolide (0.83 mg/kg).
FA+TPP-TPL-Lips Liposomes Soy lecithin, cholesterol,
FA-PEG3400-DSPE,
TriptolideP-PEG2000-TK-
DSPE, Triptolide
Thin film
dispersion method
Size: 99.28 ±
5.7 nm,
EE: 74.37%
Huh-7 Liver
cancer
Enhance tumor cell uptake and inhibit
migration.
Migration rate 10%, fluorescence
imaging showed enrichment at the
tumor site, TGI: 79.37%.
TPL/NPs Nanoparticle HA,VE, BACy, HDD,
4-amino-1-butanol,
Triptolide
Nanoprecipitation
method
Size: 191 nm,
EE: 94.93%,
DL: 8.63%
MDA-
MB-
231,
MCF-7,
4T1
Breast
cancer
PH/redox dual responsive drug release. In a simulated tumor
microenvironment, the drug release
reached 85.32% over 24 hours, TGI:
84.76%.
THE NPs Nanoparticle Triptolide, HSP Chemical coupling Size: 85 nm,
DL: 91.99%
BCa
5637
Bladder
cancer
High drug loading capacity, improve the
blood circulation.
AUC: 14.69 μg/L·h, T1/2: 4.9h, TGI:
79.6%.
C16-N/DIR Nanogel C16-GNNQQNYKD-OH,
Triptolide
Physical
encapsulation
Size: 11 nm,
DL: 1.19%
Bel-
7402/
Luc
Liver
cancer
Abdominal cavity drug storage, long-
acting sustained release and liver
targeting.
Intraperitoneal retention time: >13
days, TGI: 99.7%.
C60-SMEDDS/Triptolide Microemulsion DSPE-PEG-C60, MCT,
Cremophor EL, PEG 400
Physical
encapsulation
Size: 50 ±
0.19 nm, DL:
2%
BEL-
7402,
HepG2
Liver
cancer
Targeted protection of normal cells
while retaining antitumor activity.
Apoptosis rate: in L02 cell, C60-
SMEDDS/TP 20.8%, Triptolide 50.5%.
TPL-TFBF Metal
nanoparticles
TA, Fe3+, BSA-FA,
Triptolide
Physical
encapsulation
Size: 100 nm,
EE: 89.4%,
DL: 36.2%
B16F10 Melanoma Targeted delivery, synchronously
inducing ferroptosis and pyroptosis
through nano MOFs, amplifying ICD
effect.
ROS intensity was 4-fold higher than
Triptolide, TGI: 65.58%.
TPL/
siHIF-1α@Zr-MOF@CM
Metal
nanoparticles
Benzoic acid,
ZrOCl2·8H2O, H2TCPP ,
siHIF-1α
Physical
encapsulation
Size: 198.8
nm,
DL:20.56%
Kyse-30 Esophageal
cancer
Nanoparticles with cancer cell
membrane coating technology, exhibiting
homologous recognition and homing
properties.
IC50: 50 μg/mL, at pH 5.5, the drug
release reached 70% over 36 hours.
Apoptotic rate: 56%.
Na2GA-TPL Nanomicelles Na2GA, Triptolide Ball milling Size: 176 nm HepG2,
MCF-7
Breast
cancer,
liver cancer
Oral formulations enhance solubility and
bioavailability.
Water solubility: 2.3 mg/mL, AUC:
257 μg/L·h, T1/2: 3.213h, IC50: HepG2
0.006 μg/mL, TGI 64.48%.
Ce6-pTP-CsA Adipocyte CsA, Ce6, pTP Physical
encapsulation
12.9 ±
4.1 μm, DL:
25.85 μg/106
cells
A375M-
1
Melanoma Using tumor cells to actively recruit
adipocytes for targeted drug delivery.
A375-M1 exhibited time-dependent
uptake, BEAS-2B almost no uptake.
invasion inhibition rate: 88.83%.
cRGD-Exo-TPL Nanoparticle cRGD, Exo, Triptolide Physical
encapsulation
Size: 157.34
± 6.21 nm,
DL: 10.76%
A375 Melanoma Targeted delivery of extracellular
vesicles, extended half-life, high
biocompatibility.
The uptake of cRGD-Exo/TP was 1.98
times that of Exo/TP (at 12 hours),
invasion inhibition rate: 78.93%, T 1/2:
27.14h, TGI: 65.73%.
TPL-siRC@tHyNPs. Nanoparticle 1,2-Dioleoyl-sn-glycero
-3-phosphoethanolamine,
DR5-Exo, siRNA
Freeze-thaw Size: 150nm,
EE: 80.07%,
DL: 7.77%
A375M Melanoma Targeted delivery of extracellular
vesicles, extended half-life, Significantly
inhibit lung metastasis.
IC50: 50ng/mL (Triptolide
concentration), T1/2: 5.08h, apoptotic
rate: 80.34 ± 3.57%,TGI: 91%.
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Liposome
Chen et al esterified the C-14-OH group of Triptolide with tetradecanoic acid to generate a highly lipophilic prodrug, TPL-LA,
which was subsequently encapsulated into liposomes to form TPL-LA-lip (Figure 8A). Utilizing the enhanced permeability
Figure 8 The Synthetic route, structural morphology, and encapsulation type of TPL-LA-lips ( A), FA+TPP-TP-lips (B), TPL-NPs (C) and THE NPs ( D).
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and retention (EPR) effect, this formulation accumulated in tumor tissue and was hydrolyzed there by carboxylesterase,
thereby releasing active Triptolide. In a pancreatic cancer mouse model, TPL-LA-lip (at a Triptolide equivalent dose of
0.59 mg/kg) achieved a significantly higher tumor inhibition rate than either free Triptolide or the clinical derivative
Minnelide, and prolonged mouse survival. Moreover, the LD 50 of TPL-LA-lip was 15.7 times that of free Triptolide,
indicating a substantially improved safety profile.134
Zhou et al constructed a novel, dual-targeting nano-liposome, FA+TPP-TPL-Lips ( Figure 8B). The system utilized
folic acid (FA) to recognize folate receptors on hepatocellular carcinoma cells (Huh-7), while the triphenylphosphine ion
(TPP) facilitated accumulation within mitochondria driven by the mitochondrial membrane potential. In therapeutic
studies, FA+TPP-TPL-Lips achieved a tumor inhibition rate of 79.37%, a marked improvement over the 11.79% rate
observed with free Triptolide. This was corroborated by the lowest PCNA proliferation index and the highest TUNEL
apoptosis index. Furthermore, the formulation did not cause significant weight loss or pathological damage to major
organs in mice, indicating a favorable safety profile. 135 Collectively, FA+TPP-TPL-Lips significantly reduce toxicity to
normal hepatocytes and enhance tumor selectivity.
Nanoparticle
CD44 is overexpressed in numerous tumor cells, 136 and hyaluronic acid (HA) is recognized as its primary ligand. 137
Upon binding to CD44, HA can activate signaling pathways involved in tumor progression, including those regulating
the cytoskeleton and matrix metalloproteinases (MMPs). 138 Shi et al developed novel multifunctional nanoparticles
(TPL/NPs) (Figure 8C) featuring a hyaluronic acid vitamin E succinate (HA-VE) shell for CD44-mediated endocytosis
and a poly-β-aminoester (PBAEss) core that enables pH/redox dual-responsive drug release. Under simulated tumor
microenvironment conditions, TPL/NPs significantly lowered the IC 50 against MDA-MB-231 cells (4.96–9.5 μg/mL)
compared to free Triptolide (28.02–31.94 μg/mL), induced higher apoptosis rates, and arrested the cell cycle at the G0/
G1 phase. In vivo, TPL/NPs (0.4 mg/kg) strongly suppressed tumor growth and reduced lung metastatic nodules by
89.99%, outperforming free Triptolide (55.38%). Moreover, TPL/NPs demonstrated a favorable toxicological profile and
were well-tolerated, showing no signs of significant hepatorenal toxicity. 139
Li et al used a special method to construct a nano drug delivery system containing Triptolide. Two natural products
targeting EGFR and its downstream PI3K/AKT pathway, Triptolide and Hesperidin (HSP), were coupled using a succinic
acid linker. This formed an amphiphilic T-H-EGFR targeting prodrug (THE), which self-assembled into nanoparticles
THE NPs ( Figure 8D ). This prodrug-based design results in an exceptionally high drug-loading capacity. THE NPs
accumulated in tumors via the EPR effect and subsequently released the active drugs in the acidic lysosomal environ -
ment. Pharmacokinetic studies revealed that THE NPs significantly prolonged the blood circulation of the hydrophobic
Triptolide, which exhibited an area under the curve (AUC) 8.96 times greater and a half-life 5.4 times longer than those
of free Triptolide. In a xenograft bladder cancer model, the THE NPs group maintained the smallest tumor volume and,
in acute toxicity assays, showed no significant adverse effects compared to the control. 57 This work pioneers a new
prodrug-based nanocarrier strategy, offering a fresh paradigm for future drug delivery research.
Polymeric Micelle
Zhao et al developed a long-acting sustained release hydrogel, termed C16-N/DIR ( Figure 9A ), via a co-assembly
strategy. The gel provided sustained drug release over 14 days without any sudden release. After intraperitoneal
administration, C16-N/DIR was retained in the abdominal cavity for more than 13 days and exhibited high, stable
accumulation in the liver, thereby significantly reducing cardiac, pulmonary, and renal exposure. Treatment with C16-N/
DIR resulted in a substantial tumor inhibition rate and significantly prolonged median survival. 140
Microemulsion
DSPE-PEG-C60, a fullerene derivative with antioxidant activity, was incorporated into a self-microemulsifying drug delivery
system (SMEDDS) by Xu et al to alleviate Triptolide-induced mitochondrial dysfunction and associated ROS accumulation in
normal cells.38,141 The resulting C60-SMEDDS/Triptolide system conferred selective protection to normal cells (L02, GES-1)
against Triptolide’s cytotoxicity in vitro, primarily through the potent antioxidant activity of the C 60 derivative, which
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scavenged ROS and preserved mitochondrial function. Importantly, the system did not compromise Triptolide’s cytotoxic
efficacy against tumor cells (BEL-7402, HepG2). This work provided a promising strategy for developing safer and more
effective Triptolide formulations. However, as the study is currently confined to in vitro models, further animal experiments
are required to validate it’s in vivo safety and toxicity reduction mechanism.142
Metal Organic Framework (MOF) Nanosystems
TPL-TFBF is a multifunctional nano drug delivery system based on MOFs developed by Wang et al. The MOF was
formed by coordinating tannic acid (TA) with Fe3+, loaded with the antitumor drug Triptolide, and surface modified with
folic acid (FA) functionalized bovine serum albumin (BSA) to enable active targeting. TPL-TFBF synchronously induced
ferroptosis and pyroptosis, thereby amplifying immunogenic cell death (ICD) and promoting tumor cell apoptosis. In
a melanoma model, TPL-TFBF achieved a tumor inhibition rate comparable to that of the positive control, while in
a lung metastasis model, it nearly completely suppressed metastatic spread. 143 This system opens new avenues for tumor
immunotherapy based on the modulation of cell death pathways.
In the study by Liu et al, an esophageal cancer cell membrane-coated Zr-MOF nanosystem TPL/siHIF-1α@Zr-MOF@CM
was developed for co-loading a photosensitizer, the chemotherapeutic drug Triptolide, and HIF-1α siRNA. The nanosystem
Figure 9 The Synthetic route, structural morphology, and encapsulation type of C16-N/DIR ( A), Ce6-pTP-CsA (B) and TPL-siRC@Lip ( C).
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exhibited pH-sensitive drug release and homologous targeting ability. Under 660 nm laser irradiation, Zr-MOF generated
abundant ROS, while TPL further enhanced ROS production, and siHIF-1α knocked down HIF-1α expression to alleviate
tumor hypoxia, thereby overcoming the hypoxia-induced limitation of photodynamic therapy. In vitro and in vivo experiments
demonstrated that the nanosystem combined with laser irradiation significantly inhibited esophageal cancer cell proliferation,
induced apoptosis, and effectively suppressed tumor growth in a xenograft mouse model, accompanied by downregulation of
Ki67 and HIF-1α without obvious toxicity. 144 By amplifying ROS generation and reversing hypoxia, this nanoplatform
provides a new strategy for photodynamic combination therapy of esophageal cancer.
Other Nanosystems
Zhu et al synthesized a drug-loaded solid dispersion of Triptolide using Na 2GA (Na2GA-TPL) to enhance its solubility
and therapeutic efficacy. The formulation significantly enhanced both the solubility and oral bioavailability of Triptolide
compared to the free drug. Consequently, it exhibited greater potency, as indicated by significantly lower IC 50 values in
cancer cells such as MCF-7 and HepG2. In a HepG2 liver cancer mouse model, Na 2GA-TPL achieved a tumor inhibition
rate of 64.48% and markedly reduced hepatotoxicity. 145 These results suggest that the Na 2GA-based solid dispersion is
a promising candidate for an oral Triptolide formulation.
Lung metastasis is one of the most common metastatic patterns in patients with advanced melanoma, accounting for
a mortality rate of up to 70% in affected patients.146 However, current treatment methods, including chemotherapy, targeted
therapy, and immunotherapy, often have limited efficacy.147 To address this challenge, Li et al developed a biomimetic drug
delivery system (Ce6-pTP-CsA) that leverages the ability of tumor cells to recruit and break down adipocytes for energy. The
system was constructed by encapsulating pre-packaged drugs, such as cetuximab palmitate (pTP) and the photosensitizer Ce6,
into cryo-shocked adipocytes (CsA) to enhance tumor targeting (Figure 9B). Ce6-pTP-CsA altered the systemic distribution of
Triptolide, showing minimal accumulation in the heart and spleen and significantly reduced concentrations in the liver and
kidneys. Pharmacokinetic analysis revealed that its half-life was approximately 18 times longer, and the AUC value increased
4-fold compared to the free drug, which indicated a substantially prolonged duration of action. In treated models, Ce6-pTP-CsA
resulted in the smallest tumor area and showed no significant difference in organ damage compared to the control group.148
Extracellular vesicles function as natural nanocarriers for the targeted delivery of anticancer drugs, genes, and
miRNAs to tumor cells. 108 Building on this concept, Gu et al constructed a targeted delivery system, cRGD-Exo-TPL.
They first isolated exosomes from human umbilical cord mesenchymal stem cells (hUCMSCs), then modified them with
the cyclic peptide cRGD for targeted delivery. The cRGD-Exo-TPL system achieved enhanced tumor targeting and
exhibited a 2.11-fold higher accumulation at the tumor site compared to the non-targeted Exo-TPL group. Its circulation
half-life was also significantly prolonged to 27.14 hours. In in vivo studies, cRGD-Exo-TPL achieved a tumor inhibition
rate of 65.73%, surpassing the 44.76% rate of free Triptolide, and extended the survival period to 44.5 days. Importantly,
it avoided the weight loss and liver/kidney damage associated with free Triptolide. 149 This work establishes a key
paradigm for developing targeted nanomedicines based on extracellular vesicles.
Similarly, Gu et al developed a targeted biomimetic drug delivery system termed TPL-siRC@tHyNPs. The system was
constructed by co-encapsulating Triptolide, CYP3A4 siRNA, and DR5 Exo into liposomal carriers (TPL-siRC@Lip).
These liposomes subsequently fuse with cell membranes to facilitate targeted drug delivery to tumor cells via DR5 receptor
recognition ( Figure 9C ). In vivo experiments demonstrated that TPL-siRC@tHyNPs specifically accumulated in lung
tissue, effectively inhibiting the growth of pulmonary metastatic melanoma (PMM) while showing negligible systemic
toxicity in tumor-bearing mice.150
Discussion and Future Perspectives
Triptolide is one of the most promising chemotherapeutic agents today, demonstrating great potential in the treatment of
autoimmune diseases and cancer. Through mechanistic studies, structural modifications, and advanced delivery systems,
considerable progress has been made in reducing its toxicity and improving its pharmacokinetic profile, leading to
a series of Triptolide derivatives and delivery platforms with clinical potential. However, despite advances in preclinical
and clinical research, the development of Triptolide-based drugs still faces major challenges. Its poor physicochemical
properties and efficacy-toxicity homology remain major obstacles to formulation development.
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Structural modification is one of the core approaches to improving the druggability of Triptolide, aiming to increase
solubility, reduce toxicity, and enhance targeting while retaining pharmacological activity. The prodrug strategy is
a current research hotspot, advanced mainly through three technical routes: esterification, targeted group conjugation,
and stimuli-responsive design. Numerous Triptolide derivatives designed via these three routes have been reported, yet
none have been approved for clinical use. Key obstacles include: the efficiency of prodrug conversion is influenced by
interindividual metabolic differences (eg., CYP3A4 activity), insufficient drug loading capacity of targeted delivery
systems, and a lack of long-term toxicity data. Therefore, future research on structural modification should focus on
developing novel prodrug platforms that combine high drug loading, precise release, and low off-target effects, while
also strengthening systematic evaluation of pharmacokinetics and toxicokinetics.
The introduction of nanotechnology offers a systematic solution to overcome the bottlenecks of Triptolide, such as
poor water solubility, high toxicity, and rapid metabolism. Compared with free Triptolide, nanoformulations can
significantly increase drug concentration at the lesion site through passive targeting (EPR effect) and active targeting
(ligand modification), while reducing exposure to normal tissues. However, the targeting efficiency of most delivery
systems (eg., ADCs or ligand-modified nanoparticles) remains limited, typically only 10-20%, which restricts therapeutic
efficacy. Improving targeting efficiency through novel ligand design or optimization of delivery systems remains a key
challenge. Future research on nano-delivery systems should focus on optimizing drug loading capacity and biomimetic
membrane coating technologies, achieving multimodality imaging-guided precision drug delivery, and scaling up and
standardizing nanoformulation manufacturing processes to facilitate clinical translation.
The clinical translation of Triptolide is the ultimate goal of the entire research chain. Currently, the most promising
Triptolide derivative, Minnelide, has entered clinical trials. Minnelide is a water-soluble prodrug of Triptolide that has
completed Phase I clinical trials and is now undergoing Phase II trials to evaluate its efficacy in patients with pancreatic
cancer. In 2025, a Phase I dose-escalation trial of Minnelide was also initiated in patients with relapsed/refractory acute
myeloid leukemia (AML) to determine the maximum tolerated dose and the recommended Phase II dose. Future clinical
translation research should focus on advancing subsequent clinical trials of Minnelide and novel derivatives, developing
biomarker-based patient stratification strategies for personalized therapy, and pursuing clinical filing and evaluation of
nano-delivery systems.
Conclusion
As a natural diterpenoid epoxide with broad-spectrum bioactivity, Triptolide shows significant therapeutic potential for
autoimmune diseases and cancers. Substantial progress has been made in enhancing its safety and pharmacokinetic
profile through structural modification, prodrug design, and advanced delivery systems, leading to several promising
candidates. Despite persistent challenges in mitigating toxicity, overcoming resistance, and achieving clinical translation,
ongoing scientific and technological advances are poised to enable Triptolide-based therapies for refractory diseases.
Future efforts should focus on elucidating its mechanisms of action, refining derivative designs, and accelerating clinical
development to provide patients with safer and more effective treatment option.
Data Sharing Statement
Data will be made available on request.
Acknowledgments
This work was supported by the Natural Science Foundation of Shandong Province of China (ZR2024LMB021), the
Open Project of State Key Laboratory of Neurology and Oncology Drug Development (SKLSIM-F-2024113), Research
Project of Weifang Municipal Health Commission (WFWSJK-2024-072), the Medical Science Research Fund of Beijing
Medical and Health Public Welfare Foundation (BU1-M24001), and Linyi People’s Hospital Science and Technology
Innovation Team (LYSRMYY-KCTD-005).
Disclosure
The authors report no conflicts of interest in this work.
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