Materials Today Bio
·
2025
·
IF 10.2
Jiaxing Wang,Jingru Cui,Yujie Chen,Huijie Zhou,Xiaofang Li,Xiangxiang Wu,Rongyi Zhou,Huahui Zeng
Triptolide (TP), derived from the herb Tripterygium wilfordii, has a highly potent antitumor effect, but its poor water solubility and high toxicity hinder its clinical use. Here, a novel triptolide prodrug (TP-PEG-SS) was synthesized by conjugating TP and stachydrine (SS) with polyethylene glycol (PEG), which endowed TP with high water solubility, the capability to target tumor mitochondria, significant antitumor efficacy and low toxicity. Subsequently, TP-PEG-SS was self-assembled with ginsenoside Rg3 and lecithin to form nanovesicles (NVs). The NVs exhibited double-targeted performance for actively targeting tumor mitochondria via electrostatic interaction and entering M2 macrophage via glucose transporter GLUT-1, thereby greatly inhibiting the tumor cell growth by triggering apoptosis of tumor and polarization of M1 macrophage. In Pan02 tumor-bearing mice, the NVs were selectively accumulated in the tumor regions and improved the immunosuppressive tumor microenvironment, thereby exerting a more potent synergistic antitumor effect of both Rg3 and TP, as well as less systemic toxicity than free TP. Consequently, the NVs is a promising antitumor nanovesicle with double-targeted capability, which may enhance the clinical applicability of TP.
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PubMed
高影响因子
Applied Materials Today
·
2024
·
IF 7.2
Huahui Zeng,Man Li,Zhirong Wang,Tianqi Wang,Zhenqiang Zhang,Xiangxiang Wu
M1 macrophages play a crucial role in the development of rheumatoid arthritis (RA), which can produce various inflammation cytokines, and reactive oxygen species (ROS). Disulfide bonds as reduction-responsive linkages have been extensively employed in the drug delivery systems. However, disulfide bonds are rarely reported in the development of the oxidation-responsive drug carriers. Herein, we designed and synthetized novel oxidation-responsive drug carriers based on disulfide bonds, and further developed nanoparticles (FA-TP@NPs) by self-assembly for the RA treatment. FA-TP@NPs was decorated with folic acid and loaded with triptolide (TP), a potent anti-inflammation Chinese medicine, to target and enter M1 macrophages through the folate receptor on the cytomembrane for simultaneous repolarization of the M2 macrophage and elimination of the M1 macrophage. As expected, FA-TP@NPs exhibited an oxidation-responsive TP release via disulfide-bond oxidation and ester-bond hydrolysis in the presence of intracellular ROS, which accumulated preferentially in inflamed joints. FA-TP@NPs exerted a potent anti-arthritic effect with high biosafety in CIA mice, as evidenced by repolarizing M2 macrophages, inducing M1 macrophage apoptosis, and reducing TNF-α, IL-6, and IL-1β expression. This work shows that FA-TP@NPs give a deep insight into disulfide bond-based oxidation-responsive drug delivery systems, and provide a potential platform for RA treatment.
研究领域:
药学
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免疫学
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纳米医学
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高影响因子
ACS Applied Materials & Interfaces
·
2024
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IF 8.3
Yuanyuan Wen,Kaiming Li,Mengnan Ni,Hui Jiang,Haisi Wu,Qinqi Yu,Jinyu Li,Xiaolin Li,Jifu Wei,Wei Wu,Huae Xu
Recently, paclitaxel (PTX) was reported to increase intracellular lipid reactive oxygen species (ROS) levels, triggering cancer cell ferroptosis. Based on this, some efforts had been made to improve PTX treatment for non-small-cell lung cancer (NSCLC). Our previous studies demonstrated that triptolide (TPL) could improve the antitumor effect of PTX. Nevertheless, the poor solubility and side effects often limit the application of chemotherapy drugs. In this paper, we constructed a novel nanodrug delivery system (NDDS) chemosynthesis by PEGylated generation 3 (G3) dendritic polylysine coloaded with PTX and TPL (PTX-TPL-PEG-PLL, PTPP), which was endowed with the ability of tumor targeting and favorable solubility. In addition, we demonstrated that TPL could induce ROS generation by regulating the NF-κB signaling pathway to enhance the ferroptosis-induced effect of PTX. Besides, ferroptosis induced by PTPP could improve chemoresistance through inhibiting the level of P-gp, GPX4, and SLC7A11. Furthermore, we determined that ferroptosis may strengthen the immune response by increasing the expression of CD8+ T cells and IFN-γ+ cells while decreasing Treg cells. In general, PTPP may be a potential system for NSCLC treatment.
研究领域:
肿瘤学
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药理学
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纳米技术
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免疫学
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PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-16
·
IF 3.8
Li Siyao,Chen Quanlong,Zhang Yanglin,Wang Di,Hu Huiling,Li Jingjing,Zhang Chen,Zhang Jinming
Triptolide (TP), a major active component of the herb Tripterygium wilfordii Hook F, has been shown excellent pharmacological effects on rheumatoid arthritis. However, TP is prone to causing severe organ toxicity, which limits its clinical application. In recent years, microneedle technology has provided a new option for the treatment of arthritis due to its advantages of efficient local transdermal drug delivery. In this study, we constructed a microneedle platform to deliver TP locally to the joints, thereby enhancing TP penetration and reducing systemic toxicity. Additionally, we investigated whether acupoint drug delivery can produce a synergistic effect of needles and drugs. First, TP was loaded into microneedles using polyvinylpyrrolidone and hyaluronic acid as matrix materials. Next, we established a rat adjuvant-induced arthritis (AIA) model to evaluate the therapeutic effect of TP-loaded microneedles. The experiments showed that TP-loaded microneedles alleviated the AIA rats’ inflammatory response, joint swelling, and bone erosion. However, there was no significant difference in the therapeutic effect observed in the acupoint and non-acupoint administration groups. In conclusion, TP-loaded microneedles have the advantages of safety, convenience, and high efficacy over conventional administration routes, laying a foundation for the transdermal drug delivery system-based treatment of rheumatoid arthritis.
研究领域:
药学
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生物医学工程
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中医
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风湿病学
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PubMed
高影响因子
Journal of Biomedical Research
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2021
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IF 0
Siwan Wang,Hui Jiang,Jia Wang,Haisi Wu,Ting Wu,Mengnan Ni,Qianqian Zhao,You Ji,Ziting Zhang,Chunming Tang,Huae Xu
As a well-known anticancer drug, paclitaxel (PTX), a first-line chemotherapeutic agent, remains unsatisfactory for gastric cancer therapy. It is reported that triptolide (TPL) could enhance the anti-gastric cancer effect of PTX. Considering the poor solubility of both drugs, we developed a red blood cell membrane-biomimetic nanosystem, an emerging tool in drug delivery, to co-load paclitaxel and triptolide (red blood cell membrane coated PTX and TPL co-loaded poly(lactic- co -glycolic acid) [PLGA] nanoparticles, RP(P/T)). The successful preparation was confirmed in terms of particle size, morphology, and surface markers assays. This biomimetic system could prolong circulation and escape immune surveillance. And these properties were verified by stability, in vitro drug release, and cellular uptake assays. Moreover, the MTT and colony formation assays demonstrated the superior anti-proliferation effect of the RP(P/T) to free drugs. The enhanced antitumor effects of RP(P/T) on migration and invasion were also evaluated by wound-healing and transwell assays. Overall, the bionic co-delivery nanoplatform with improved efficacy in vitro is a promising therapy for gastric cancer.
研究领域:
药学
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肿瘤学
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纳米技术
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药物递送系统
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PubMed
Frontiers in Pharmacology
·
2022
·
IF 5.988
Chenxi Li,Rui Liu,Yurong Song,Youwen Chen,Dongjie Zhu,Liuchunyang Yu,Qingcai Huang,Zhengjia Zhang,Zeyu Xue,Zhenglai Hua,Cheng Lu,Aiping Lu,Yuanyan Liu
Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by synovial inflammation in multiple joints. Triptolide (TP) is a disease-modifying anti-rheumatic drug (DMARD) highly effective in patients with RA and has anti-inflammatory properties. However, its clinical application has been limited owing to practical disadvantages. In the present study, hyaluronic acid (HA) hydrogel-loaded RGD-attached gold nanoparticles (AuNPs) containing TP were synthesized to alleviate the toxicity and increase therapeutic specificity. The hydrogels can be applied for targeted photothermal-chemo treatment and in vivo imaging of RA. Hydrogel systems with tyramine-modified HA (TA-HA) conjugates have been applied to artificial tissue models as surrogates of cartilage to investigate drug transport and release properties. After degradation of HA chains, heat was locally generated at the inflammation region site due to near-infrared resonance (NIR) irradiation of AuNPs, and TP was released from nanoparticles, delivering heat and drug to the inflamed joints simultaneously. RA can be penetrated with NIR light. Intraarticular administration of the hydrogels containing low dosage of TP with NIR irradiation improved the inflamed conditions in mice with collagen-induced arthritis (CIA). Additionally, in vitro experiments were applied to deeply verify the antirheumatic mechanisms of TP-PLGA-Au@RGD/HA hydrogels. TP-PLGA-Au@RGD/HA hydrogel treatment significantly reduced the migratory and invasive capacities of RA fibroblast-like synoviocytes (RA-FLS) in vitro , through the decrease of phosphorylation of mTOR and its substrates, p70S6K1, thus inhibiting the mTOR pathway.
研究领域:
药学
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纳米技术
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生物医学工程
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风湿病学
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PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 2
·553
·
IF 4.6
Meng Yang,Jianxia Meng,Lu Han,Xiaoyan Yu,Zhimin Fan,Yongfang Yuan
Compared with traditional oral and injection administration, the transdermal administration of traditional Chinese medicine has distinctive characteristics and advantages, which can avoid the “first pass effect” of the liver and the destruction of the gastrointestinal tract, maintain a stable blood concentration, and prolong drug action time. However, the basic theory and technology research in transdermal drug delivery are relatively limited at present, especially regarding research on new carriers of transdermal drug delivery and pharmacokinetic studies of the skin, which has become a bottleneck of transdermal drug delivery development. Triptolide is one of the main active components ofTripterygium wilfordii, which displays activities against mouse models of polycystic kidney disease and pancreatic cancer but its physical properties and severe toxicity limit its therapeutic potential. Due to the previously mentioned advantages of transdermal administration, in this study, we performed a detail analysis of the pharmacokinetics of a new transdermal triptolide delivery system. Triptolide nanoemulsion gels were prepared and served as new delivery systems, and the ex vivo characteristics were described. The metabolic characteristics of the different triptolide transdermal drug delivery formulations were investigated via skin–blood synchronous microdialysis combined with LC/MS. A multiscale modeling framework, molecular dynamics and finite element modeling were adopted to simulate the transport process of triptolide in the skin and to explore the pharmacokinetics and mathematical patterns. This study shows that the three−layer model can be used for transdermal drug delivery system drug diffusion research. Therefore, it is profitable for transdermal drug delivery system design and the optimization of the dosage form. Based on the drug concentration of the in vivo microdialysis measurement technology, the diffusion coefficient of drugs in the skin can be more accurately measured, and the numerical results can be verified. Therefore, the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery systems. This research will provide a new technology and method for the study of the pharmacokinetics of traditional Chinese medicine transdermal drug delivery. It has important theoretical and practical significance in clarifying the metabolic transformation of percutaneous drug absorption and screening for appropriate drugs and dosage forms of transdermal drug delivery.Keywords:triptolide;transdermal drug delivery;nanoemulsion gel;multiscale mathematical modeling;synchronous microdialysis
研究领域:
药剂学
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药物代谢动力学
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中药学
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生物医学工程
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PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Xinli Qiu,Lihua Qiang,Yiru Wang,Bingxi Li,Zehui Lei,Jing Wang
Background Staphylococcus aureus (SA) remains a global health threat due to its increasing drug resistance and intracellular persistence, which compromise the conventional antibiotic efficacy. Host-directed therapy (HDT) has emerged as a promising alternative by modulating host immunity. With multi-targeting and immunomodulatory properties, traditional Chinese medicine (TCM) monomers represent ideal candidates for HDT. However, their ability to promote host immunity-mediated SA clearance remains largely unexplored. Methods Forty-one TCM monomers potentially regulating host apoptosis, a core mechanism of the host innate immune defense against intracellular pathogens, were screened to identify a compound that promotes the clearance of intracellular SA and methicillin-resistant SA (MRSA). The mechanism was investigated in infected macrophages using transcriptomics, proteomics, molecular dynamics simulations, and biochemical assays. The physiological function of the TCM monomer was examined in infected mice through lung pathology and multi-omics analysis, including transcriptomics, proteomics, metagenomics, and metabolomics. Results Triptolide was identified as a potent facilitator of host immunity-mediated intracellular clearance of SA and MRSA, without exerting direct bactericidal effects. Mechanistically, triptolide directly binds to the X-linked inhibitor of apoptosis protein (XIAP), disrupting its interaction with caspases to relieve their inhibition and thereby induce apoptosis. Furthermore, in murine infection models, triptolide treatment reduced bacterial loads, alleviated inflammation, and induced macrophage apoptosis in lungs, concurrently maintaining microbiota homeostasis and improving metabolic function. Conclusion This study establishes a proof of concept for triptolide as a HDT candidate against SA and MRSA infections, which not only enhances host apoptosis-mediated pathogen clearance but also maintains host microbiota and metabolic homeostasis.
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PubMed
高影响因子
Nanomedicine
·
2026
·
IF 4.6
Yingchao Gao,Ning Zhang,Jun-Fei Zhang,Zhengqi Fei
Objective This study aimed to develop chitosan-based nanoparticles (ChNPs) for Triptolide (TPL) delivery to mitigate intervertebral disc degeneration (IDD).Methods TPL-magnesium (Mg) ChNPs were prepared by mixing TPL, magnesium sulfate, and chitosan under controlled stirring, followed by nanoparticle characterization. An in vitro IDD model was established by stimulating nucleus pulposus cells (NPCs) with IL-1β. The therapeutic effect and biosafety of TPL-Mg ChNPs was assessed using cell counting kit-8. In an in vivo IDD rat model, pathology of intervertebral discs was evaluated via micro-computed tomography and histological staining. Western blotting, immunofluorescence, and immunohistochemistry were used to assess MAPK signaling, mitophagy activity, and extracellular matrix (ECM) programs.Results TPL inhibited the proliferation of IL-1β-induced NPCs. TPL was complexed with Mg2+, and further coated with chitosan via electrostatic adsorption to obtain TPL-Mg ChNPs. TPL-Mg ChNPs exhibited physical stability and biosafety, and could control drug release. TPL-Mg ChNPs were internalized by damaged NPCs within 4 hours and inhibited reactive oxygen species release. In vitro, TPL-Mg ChNPs protected NPCs and maintained ECM metabolic balance. In vivo, TPL-Mg ChNPs significantly improved IDD pathology in rats by inhibiting MAPK signaling and activating mitophagy.Conclusion TPL-Mg ChNPs ameliorate IDD progression by inhibiting the MAPK pathway and activating mitophagy.
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高影响因子
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2015
·Vol. 29
·期 11
·533-543
·
IF 1.925
Xiaoyan Liu,Yanqiu Liu,Mengchun Cheng,Hongbin Xiao
ABSRACT The present study was undertaken to investigate the metabolic responses of human liver cells HL-7702 on chemicals purified from traditional Chinese medicine: emodin, triptolide, and aristolochic acid. Cytotoxicity tests demonstrated a dose-dependent toxic effect of emodin, triptolide, and aristolochic acid on HL7702 cells for 48 h. Emodin (14 μM), aristolochic acid (12 μg/mL), or triptolide (18 nM) was individually administrated to HL7702 and cell samples were collected after 48 h for metabolites extraction and analysis. Pattern recognition analysis reflected the significant difference in metabolic profiles between chemical-treated groups and the control group. Finally, eight metabolites including N 1 -acetylspermidine, Glu Gly, N -undecanoylglycine, C 16 sphinganine, sphinganine, glutathione, l -palmitoylcarnitine, and elaidic carnitine were detected as potential common biomarkers. Three pathways including sphinganine metabolism, fatty acid oxidation, and oxidative stress were identified. Our findings indicated that metabolomics would be an efficient approach to understand the molecular mechanism of hepatotoxicity induced by chemicals.
研究领域:
药理学
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毒理学
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代谢组学
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细胞生物学
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PubMed
高影响因子
Frontiers in Oncology
·
2022
·
IF 5.738
Di Kang,Yan Liu,Yi Song,Bingqian Fang,Qichun Zhang,Lihong Hu
Triptolide exhibits superior and broad-spectrum antitumor activity. However, the narrow safety window caused by the toxicity of triptolide limits its clinical applications. Although several characterized targets for triptolide are reported, the association between triptolide and its targets in cancer therapy is not fully understood. Here, we show that acute myeloid leukemia (AML) cell lines are sensitive to triptolide by constructing an in vitro cell and in vivo xenograft models. Meanwhile, the triptolide-induced hepatotoxicity increases with increasing dosages within the xenograft models. Additionally, the expression levels of WSTF-RPB1 are strongly associated with the sensitivity to triptolide in hematological cancer cells and can be downregulated in a dose and time-dependent manner. Finally, we show that optimizing dosing regimens can achieve the same pharmaceutical effect and reduce toxicity. In summary, this study aims to search for triptolide-sensitive cell lines as well as the underlying molecular mechanisms in order to broaden the safety window of triptolide; thus, increasing its clinical utility.
研究领域:
肿瘤学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NANOPARTICLE RESEARCH
·
2024
·Vol. 26
·期 4
·1-18
·
IF 2.1
Lu Zhimeng,Yan Kun,Liu Chunlei,Wang Jiapeng,Yu Guiping,Zhang Hao
Tripterygium wilfordii Hook F, a traditional medicine in China has bioactive but toxic triptolide (TP, a diterpenoid triepoxide) as its main active constituents. The applications of TP are hampered by its prominent toxicity and low solubility in water. In this study, a safe pH-sensitive material [methoxy polyethylene glycol (mPEG)- adipic dihydrazide (ADH)] was synthesized and loaded with TP to form pH-sensitive polymeric micelles, thereby improving the safety and solubility of TP, as well as providing a theoretical basis for the wide application of TP. The mPEG-ADH/TP micelles were characterized by a series of indicators [namely entrapment efficiency (EE), critical micellar concentration (CMC), electrokinetic potential, stability, polydispersed index (PDI), and particle size]. Also, we ascertained the in vitro release of TP from mPEG-ADH/TP micelles along with pharmacokinetic investigations in vivo. Besides, we evaluated the cytotoxicity of mPEG-ADH/TP micelles against A549 cells, HCT116 cells, and HaCat cells and further conducted in vivo toxicity studies in rats. The TP-loaded mPEG-ADH micelles had smaller sized particles (48.3 nm), excellent PDI (0.142), stable property and higher EE (89.87%). Importantly, the TP in the mPEG-ADH/TP micelles was almost completely released at acidic pH (pH 5.0), while the drug was released slowly and sparingly at physiological pH (pH 7.4). The results suggest the release of TP from mPEG-ADH/TP micelles was sensitive to pH, which could facilitate targeting of the drug into intra-cellularly low pH endosomes and lysosomes as well as enhance cytotoxicity in cancer tissues. Moreover, mPEG-ADH/TP micelles exhibited excellent proliferation inhibition on tumor cells. In addition, the liver injury of rats in the 1 mg/kg dose of mPEG-ADH/TP micelles group was significantly reduced by Hematoxylin–eosin (HE) staining. Taken together, mPEG-ADH/TP micelles could act as a promising alternative to enhance the efficacy of oncologic treatments.
研究领域:
药理学
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肿瘤学
·
药物递送系统
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高影响因子
危险品化学品经营许可证（带存储）