JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Yuwen Song,Tingting Xu,Hao Li,Jing Liu,Shumin Cao,Yichen Yang,Nianlu Li,Peiwen Lv,Min Han,Haohan Sun,Guangfu Dang,Jianxin Li,Hao Sun,Tao Xin,Huitang Xia,CanWei Zhang
Corneal neovascularization (CoNV) is a leading cause of visual impairment worldwide. However, CoNV remains challenging to cure clinically because of the limitations of current drugs. New and more effective therapeutic formulations for CoNV treatment are therefore urgently needed. Antisense oligonucleotide drugs hold great promise for the treatment of neovascular diseases, and ionizable cationic lipid nanoparticles (icLNPs) have shown excellent performance for nucleic acid delivery, with high encapsulation, good cellular uptake, and effective endosomal escape. In the present study, we identified integrin β1 ( Itgb1 ) as a key gene involved in angiogenesis and revealed the significant upregulation of Flt1 in vascular endothelial cells and pericytes in CoNV using single-cell sequencing. Itgb1 knockdown significantly inhibited the proliferation and migration of vascular endothelial cells and CoNV in mice. Based on these findings, we developed Itgb1 -small interfering RNA (siRNA)-loaded icLNPs, and conjugated anti-Flt1 peptide to their surface to improve CoNV targeting. Furthermore, because lipid nanoparticles reportedly trigger immune responses by upregulating pro-inflammatory cytokine expression, which may promote neovascularization, we modified triptolide (a compound with anti-inflammatory properties) into the icLNPs. The triptolide-modified, anti-Flt1 peptide-conjugated, and Itgb1 -siRNA-loaded icLNPs ( Itgb1 -siRNA@TPL) effectively inhibited the proliferation and migration of vascular endothelial cells in vitro and CoNV in mice after eye drop administration. These effects occurred via downregulation of the PI3K/AKT and NF-κB signaling pathways. Finally, the biosafety of Itgb1 -siRNA@TPL was tested, and the results revealed that it was not toxic to the cornea or major organs and had no impact on corneal epithelial healing. In conclusion, Itgb1 -siRNA@TPL represent a novel, noninvasive, and effective approach for the treatment of CoNV.
研究领域:
医学
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分子生物学
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药剂学
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PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2020
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IF 7.097
Yaoyao Luo,Jingjing Li,Yichen Hu,Fei Gao,George Pak-Heng Leung,Funeng Geng,Chaomei Fu,Jinming Zhang
The clinical application of triptolide (TPL) in tumor therapy has been greatly limited by its toxicity and inefficient delivery. Herein, a localized and sustained-release thermo-sensitive hydrogel was developed for the intra-tumor administration of TPL. Based on the amphiphilic structure of poly ( N -isopropylacrylamide -co- acrylic acid)- g -F68 copolymer, it was able to form nano-micelles to efficiently encapsulate TPL, and then turn into a hydrogel at 37 °C. [email protected] exhibited a sustained drug release profile in vitro and a stronger anticancer effect caused by “two strikes”. The “first strike” was its enhanced cytotoxicity compared to free TPL, due to the enhanced pro-apoptosis effect observed in both MDA-MB-231 and MCF-7 cells caused by the regulation of endogenous mitochondrial pathways. Furthermore, [email protected] exhibited a “second-strike” through its anti-angiogenesis capabilities mediated through VEGFR-2 signaling inhibition. As expected, after intra-tumoral injection at a 0.45 mg/kg TPL-equivalent dose three times over 14 days in 4T1 tumor-bearing mice, [email protected] led to lower systemic toxicity and higher antitumor efficacy compared to multiple injections of TPL. In this regard, these findings indicate that this injectable thermo-responsive hydrogel carries great potential for TPL as a safe and effective cancer therapy.
研究领域:
药学
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肿瘤学
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材料科学
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生物医学工程
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 3
·1252
·
IF 6.208
Jing Yang,Xujiao Tang,Xue Ke,Yutong Dai,Jinsong Shi
Triptolide (TP), the main active ingredient ofTripterygium wilfordii Hook.f., displays potent anti-inflammatory, antioxidant, and antiproliferative activities. In the present study, the effect of TP on acute pancreatitis and the underlying mechanisms of the disease were investigated using a caerulein-induced animal model of acute pancreatitis (AP) and an in vitro cell model. In vivo, pretreatment with TP notably ameliorated pancreatic damage, shown as the improvement in serum amylase and lipase levels and pancreatic morphology. Meanwhile, TP modulated the infiltration of neutrophils and macrophages (Ly6G staining and CD68 staining) and decreased the levels of proinflammatory factors (TNF-α and IL-6) through inhibiting the transactivation of nuclear factor-κB (NF-κB) in caerulein-treated mice. Furthermore, TP reverted changes in oxidative stress markers, including pancreatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), in acute pancreatitis mice. Additionally, TP pretreatment inhibited intracellular reactive oxygen species (ROS) levels via upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes expression (HO-1, SOD1, GPx1 and NQO1) in vitro. Taken together, our data suggest that TP exert protection against pancreatic inflammation and tissue damage by inhibiting NF-κB transactivation, modulating immune cell responses and activating the Nrf2-mediated antioxidative system, thereby alleviating acute pancreatitis.Keywords:acute pancreatitis;triptolide;inflammatory responses;oxidative stress
研究领域:
药理学
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免疫学
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分子生物学
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PubMed
高影响因子
International Journal of Nanomedicine
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2023
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IF 8
Ayimukedisi Yalikong,Xu-Quan Li,Ping-Hong Zhou,Zhi-Peng Qi,Bing Li,Shi-Lun Cai,Yun-Shi Zhong
Background Colon cancer (CRC) was a malignant tumor and there were about 25% of patients with tumor metastasis at diagnosis stage. Chemotherapeutic agents for metastatic CRC patients were with great side effects and the clinical treatment results of advanced CRC were still not satisfactory. Human epidermal growth factor receptor 2 (HER2) is overexpressed in some CRC patients and is an effective target for CRC patient treatment. Anti-HER2 therapy had a beneficial role in the treatment of HER2-positive metastatic CRC with fewer side effects. CRC patients with BRAF mutations were resistant to HER2 antibodies treatment. Therefore, there was an urgent need to develop new therapeutic agents.Methods HER2 targeted nanoparticles (TPLNP) drug delivery system loading triptolide (TPL) were prepared and identified. The effects of TPLNP and free TPL on cell viability, targeting and cell cycle progression on HT29 (BRAF mutation) with HER2 overexpression, were evaluated by Cell Counting Kit-8 (CCK8), Fluorescence Activating Cell Sorter (FACS) and immunofluorescence methods, respectively. The anti-tumor efficacies of TPLNP were evaluated in subcutaneous xenograft model of colon cancer and the survival rate, tumor volume, liver and kidney indexes of tumor-bearing mice were measured.Results TPLNP was small in nanosize (73.4±5.2nm) with narrow size distribution (PDI=0.15±0.02) and favorable zeta potential (pH=9.6, zeta potential: −57.3±6.69mV; pH=7.0, zeta potential: −28.7±5.1mV; pH=5.6, zeta potential: −21.1±4.73mV). Comparing with free TPL treatment group, TPLNP developed stranger colon cancer-killing efficiency in a dose- and time-dependent manner detected with CCK8 method; achieved good in vitro colon cancer targeting detected with flow cytometry and immunofluorescence experiments; enhanced more HT29-HER2 apoptosis and induced more cell cycle arrested in G1-S phase detected with FACS in vitro. As for in vivo antitumor response, TPLNP remarkably inhibited the growth of colon cancer in the colon cancer xenograft model, significantly improved the survival rate and did not exhibit significant liver and kidney toxicity in contrast with free TPL in vivo.Conclusion TPLNP was effectively against colon cancer with HER2 overexpression and BRAF mutation in pre-clinical models. In summary, the TPLNP appeared to be a promising treatment option for CRC in clinical application based on improved efficacy and the favorable safety profile.
研究领域:
肿瘤学
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药理学
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分子生物学
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PubMed
高影响因子
RENAL FAILURE
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2023
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IF 3
Chenlei Lv,Tianyang Cheng,Bingbing Zhang,Ke Sun,Keda Lu
Objectives: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte injury in DN.Methods: DN mouse models were established by feeding with a high-fat diet and injecting with streptozocin and MPC5 podocyte injury models were induced by high-glucose (HG), followed by TP treatment. Fasting blood glucose and renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), blood urea nitrogen (BUN), and kidney/body weight ratio of mice were examined. H&E and TUNEL staining were performed for evaluating pathological changes and apoptosis in renal tissue. The podocyte markers, reactive oxygen species (ROS), oxidative stress (OS), serum inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, and pyroptosis were detected by Western blotting and corresponding kits. MPC5 cell viability and pyroptosis were evaluated by MTT and Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify the regulation of TP on Nrf2.Results: TP improved renal function and histopathological injury of DN mice, alleviated podocytes injury, reduced OS and ROS by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, and weakened pyroptosis by inhibiting the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. In vitro experiments further verified the inhibition of TP on OS and pyroptosis by mediating the Nrf2/HO-1 and NLRP3 inflammasome pathways. Inhibition of Nrf2 reversed the protective effect of TP on MPC5 cells.Conclusions: Overall, TP alleviated podocyte injury in DN by inhibiting OS and pyroptosis via Nrf2/ROS/NLRP3 axis.
研究领域:
药理学
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肾病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
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2025
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IF 12.5
Han-Jian Hu,Zhenming Tian,Zeng-Lin Li,Chun Cheung Chan,Hongyan Zhang,Shipeng Tang,Yu Chen,Zhaoyin Chen,Tian Hu,Bin Liu,Gang-Biao Jiang
The inflammatory microenvironment and irregular lesion cavities following spinal cord injury (SCI) severely hinder neural regeneration. This study developed a copper-based supramolecular hydrogel (COCu/TP-g-COS) loaded with triptolide-grafted chitosan oligosaccharide (TP-g-COS) via a dynamic covalent crosslinking strategy for synergistic anti-inflammatory effects and SCI repair. The hydrogel, based on dynamic schiff base bonds between carboxymethyl chitosan (CMCS) and aldehyde-chitosan (OCS), as well as Cu 2+ coordination crosslinking, exhibits injectability, self-healing capability, and microenvironment responsiveness, enabling precise filling of irregular lesion cavities and sustained drug release. In vitro experiments demonstrated that COCu/TP-g-COS achieves pH-dependent staged release of TP, accompanied by continuous Cu 2+ release, which significantly suppresses inflammatory responses and promotes neural differentiation. In vivo experiments confirmed that COCu/TP-g-COS synergistically inhibits inflammation through TP and Cu 2+ , elevating the BBB score to 11 (0) in rats (vs. 3 (0.75) in the SCI group). Histological analysis revealed that the hydrogel significantly promoted axon regeneration and inhibited glial scar formation. Overall, this study provides a multifunctional therapeutic strategy integrating anti-inflammatory regulation and neural regeneration for SCI repair.
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高影响因子
Frontiers in Pharmacology
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2026
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IF 5.4
Quancheng Yang,Siqi Chen,Mengjia Sun,Xuejia Zhai,Yi Lv
Introduction Metabolic reprogramming is a central driver of malignant progression in non-small cell lung cancer (NSCLC). However, conventional targeted therapies face significant limitations due to drug resistance and narrow therapeutic windows. Triptolide, a natural tricyclic diterpenoid derived from Tripterygium wilfordii, exhibits potent antitumor activity, yet its precise mechanisms for modulating metabolic reprogramming in NSCLC remain elusive. Methods Using NSCLC cell models, we assessed TPL effects on proliferation, migration, and mitochondrial function via CCK-8, Transwell, ROS, and MMP assays. In vivo efficacy was evaluated in xenograft models. Untargeted metabolomics identified metabolic alterations, while DARTS proteomics screened for potential TPL-interacting proteins. Results TPL significantly inhibited NSCLC cell proliferation and induced metabolic alterations characterized by glycolytic suppression (HK2 downregulation) and concurrent disruption of mitochondrial oxidative phosphorylation (OXPHOS)-associated proteins. Metabolomics revealed systemic metabolic shifts, with pyruvate metabolism and glutathione pathways being most significantly altered. Mechanistically, multi-omics analysis identified PDHX as a key node within a broader metabolic network disrupted by TPL, associated with glycolytic suppression ( via HK2 degradation) and mitochondrial dysfunction. Conclusion These findings suggest that TPL exerts antitumor effects in NSCLC by disrupting both glycolysis and mitochondrial function, with PDHX identified as a candidate mediator. Further studies are warranted to explore its therapeutic potential.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2019
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IF 3.17
Jihang Dai,Yu Sun,Duoyun Chen,Yaxin Zhang,Lianqi Yan,Xiaolei Li,Jingcheng Wang
Fibroblasts excessive proliferation was considered as a decisive reason for epidural fibrosis , which was known as a serious complication of lumbar laminectomy. As a traditional Chinese medicine , triptolide (TP) was used to be proved effective in preventing several fibrosis scar formation diseases. However, little is known about the effect of TP on preventing epidural fibrosis and its possible mechanism. Here, we performed in vitro and in vivo experiments to detect the possible mechanism of TP in preventing epidural fibrosis. In vitro, the effect of TP on impacting fibroblasts proliferation activities was detected by CCK-8, cell cycle assay and EdU incorporation assay. Also, the expressions of cell proliferation protein markers and the expressions of p-PI3K, p-AKT, p-mTOR were detect by Western blot . Besides, the effect of TP on inducing fibroblast apoptosis and autophagy was tested by Western blots, flow cytometry, TUNEL staining , Transmission electron microscope (TEM) analysis and LC3 immunofluorescent staining. The results suggested that TP could suppress the activation of PI3K/AKT/mTOR signaling pathway. Meanwhile, TP could inhibit fibroblast proliferation and induce fibroblast apoptosis as well as autophagy, which was known as two cellular self-destructions. Furthermore, we speculated the possible molecular pathway, through which that TP could inhibit fibroblast proliferation, induce fibroblast apoptosis and autophagy. We used PI3-kinase activator (740Y-P) to activate the PI3K/AKT/mTOR signaling. Activation of PI3K/AKT/mTOR signaling pathway increase the proliferation of fibroblasts and suppressed the autophagy and apoptosis induced by TP. In vivo, we built epidural fibrosis models in rats and locally applied TP of various concentrations. Hematoxylin–eosin (HE) and Masson's trichrome were used to detect the effect of TP on reducing epidural fibrosis. And the results showed that TP could significantly reduce the surgery-induced epidural fibrosis. In conclusion, the results above shown that TP could reduce epidural fibrosis formation, and the potential mechanism might through inhibiting fibroblast proliferation and stimulating apoptosis and autophagy via suppressing PI3K/AKT/mTOR signaling pathway. It might provide a novel thought for reducing surgery-induced epidural fibrosis.
研究领域:
药理学
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神经外科
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细胞生物学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Yaning Ge,Xin Zhu,Zhengxian Zhang,Huanhuan Zhu,Tianqi Wang,Jingru Cui,Huahui Zeng,Xiangxiang Wu,Zhenqiang Zhang
Triptolide (TP) is a promising anti-tumor candidate derived from the herb Tripterygium wilfordii , but its poor water solubility and multi-organ toxicity limit its application. Here, we developed novel nanoparticles (TP-SP@NPs) modified with dextran sulfate and RGD peptide for double-targeted delivery of TP to both tumor cells and pro-tumor macrophages in pancreatic cancer treatment. TP-SP@NPs exhibited suitable particle size (about 98 nm), good stability and controlled release performance. TP-SP@NPs showed high cellular uptake in Pan02 cells and M2 macrophages through α v β 3 integrin-RGD interaction and SR-A-DS interaction, effectively inhibiting tumor growth by triggering apoptosis of these cells. In Pan02 tumor-bearing mice, TP-SP@NPs specifically accumulated at the tumor site and efficiently decreased the number of M2 macrophages, thereby exerting better curative effect on pancreatic cancer and lower systemic toxicity as compared with TP. As a result, TP-SP@NPs had achieved selective anti-tumor effect, good biosafety and great promise in clinical application.
研究领域:
药学
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肿瘤学
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纳米医学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Pei Qiao,Shuang Chen,Mengqing Zhao,Zhiran Ju,Junxiang Chen,Wenhao Xu,Lichan Mao
Triptolide (TP) is a bioactive compound with anti-inflammatory, antitumor, and immunomodulatory effects. Its application, however, is limited due to poor aqueous solubility, low bioavailability, and organ toxicity. Based on the classical compatibility theory of Tripterygium and Polygonatum for toxicity reduction in traditional Chinese medicine, and the super-self-assembly behavior observed in the decoctions of these two herbs, a novel nano-delivery system (TP-PSP) was designed with Polygonatum Sibiricum Polysaccharide (PSP) as the carrier. TP-PSP achieved 6-fold enhancements in solubility and 3-fold enhancements in membrane permeability. The bioavailability of TP-PSP increased by 6.8/5.9-fold in AUC 0-t /AUC 0-∞ , significantly reducing gastrointestinal toxicity by shortening intestinal retention. In the diabetic nephropathy (DN) mouse model, TP-PSP achieved better therapeutic effects by enabling kidney-targeted delivery. TP-PSP reduced serum creatinine and urea nitrogen by 38.7% and 42.5%, respectively. It also alleviated TP-induced renal, cardiac, and hepatic toxicity. Physical characterization and molecular dynamic simulations revealed that TP and PSP form stable supramolecular aggregates via hydrogen bonding. TP-PSP activated the Nrf2/SLC7A11/GPX4 pathway, enhancing antioxidant defenses and suppressing lipid peroxidation/ferroptosis. This study not only reports a clinically viable TP delivery strategy but also highlights the application potential of traditional Chinese medicine principles in developing advanced nanomedicine with better effects but lower toxicity. Significance This work presents a significant advancement beyond classical Chinese medical principles to overcome the major clinical limitations of triptolide (TP), a potent yet therapeutically challenging compound. Guided by the “Sovereign-Minister-Assistant-Envoy” principle and systematic, detailed prescription research, we identified Polygonatum Sibiricum Polysaccharide (PSP) as a promising carrier to enhance the solubility and reduce the toxicity of TP. We developed an engineered nano-delivery system (TP-PSP) with improvements in TP's solubility, dissolution rate, and bioavailability while simultaneously reducing its systemic organ toxicity. The system demonstrates kidney-targeted delivery and a significant reduction in key nephropathy markers, revealing strong therapeutic potential for diabetic kidney disease. Furthermore, our integrated experimental and molecular dynamics approach elucidates the fundamental self-assembly mechanism between TP and PSP, which is driven by hydrogen bonding. Notably, we identified Nrf2 pathway activation and ferroptosis inhibition as a novel protective mechanism against TP-induced nephrotoxicity, effectively expanding its therapeutic window for clinical translation. This study successfully bridges traditional medicine wisdom with modern nanotechnology, addressing critical pharmacological and environmental challenges in drug development. Beyond the specific application of TP, this work validates a scientific principle from Chinese medicine for guiding the design of nanomedicine, offering a generalizable template for reformulating other potent but toxic herbal compounds.
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高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2021
·Vol. 35
·期 7
·e5093
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IF 1.902
Wei Wu,Rui Cheng,Zhenzhou Jiang,Luyong Zhang,Xin Huang
A rapid and specific UPLC–MS/MS method with a total run time of 3.5 min was developed for the determination of pravastatin, fexofenadine, rosuvastatin, and methotrexate in rat primary hepatocytes. After protein precipitation with 70% acetonitrile (containing 30% H 2 O), these four analytes were separated under gradient conditions with a mobile phase consisting of 0.03% acetic acid (v/v) and methanol at a flow rate of 0.50 mL/min. The linearity, recovery, matrix effect, accuracy, precision, and stability of the method were well validated. We evaluated drug–drug interactions based on these four compounds in freshly suspended hepatocytes. The hepatic uptake of pravastatin, fexofenadine, rosuvastatin, and methotrexate at 4°C was significantly lower than that at 37°C, and the hepatocytes were saturable with increased substrate concentration and culture time, suggesting that the rat primary hepatocyte model was successfully established. Triptolide showed a significant inhibitory effect on the hepatic uptake of these four compounds. In conclusion, this method was successfully employed for the quantification of pravastatin, fexofenadine, rosuvastatin, and methotrexate and was used to verify the rat primary hepatocyte model for Oatp1, Oatp2, Oatp4, and Oat2 transporter studies. Then, we applied this model to explore the effect of triptolide on these four transporters.
研究领域:
药理学
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分析化学
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肝脏病学
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PubMed
高影响因子
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