JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2024
·
IF 4.5
Xue Zhang,Jiang Chen,Yuan Yin,Shijun Xiao,Rui Zhang,Haiyang Guo,Tong Yang,Tongyu Zhou,Siyan Zhang,Yang Yang,Caili Bi,Xiao-Jun Li
Targeted delivery of chemotherapeutic agents to the cancerous cells is of fundamental importance and the key step of the targeted delivery system design is to choice a specific receptor. Glypican-3 (GPC3) is a known cell membrane-associated oncofetal proteoglycan that is specifically up-regulated in the fast-growing hepatocarcinoma cells but rarely expressed in the normal healthy liver. Therefore, GPC3 may be a perfect targeting receptor for delivery treatment of hepatocellular carcinoma (HCC). In the present study, a GPC3 specific-targeting nanoliposomal drug delivery system was constructed with GPC3 targeting peptide (named as L5 peptide) modification and anticancer drug cantharidin encapsulation, which aims to realize cantharidin targeted treatment of liver cancer. In our study, nanoliposome specifically targeting GPC3 receptor was successfully constructed with particle size of 127.9 nm and a spherical shape. The targeted liposomes were stable under 4 °C or room temperature for almost 15 days. The drug release from L5-modified liposomes was controlled and delayed. Their targeted delivery properties were characterized by relatively more accumulation in the GPC3 highly expressed HepG2 cells than that of GPC3 lowly expressed Huh-7 cells. The competition results also indicated that the liposomes with L5 peptide modification could competitively bind to GPC3 receptor. Moreover, the liposomes showed colocalization with the lysosome after 3 h incubation. The L5-modified liposomal CTD had an augmented cell growth inhibition and tumor inhibition than that of the free CTD on HepG2 cells and GPC3 highly expressed tumor mice. Our study establishes a new strategy for improving HCC treatment and chemotherapeutic agent targeting delivery.
研究领域:
肿瘤学
·
药剂学
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DOI
高影响因子
Scientific Reports
·
2020
·Vol. 10
·期 1
·1-8
·
IF 3.998
Zhang Youyou,Liu Liang,Ren Liang
A rapid, sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination and quantification of cantharidin in rats liver and kidney. After grinding with methanol, the supernatant was determined by LC-MS/MS using an Thermo Accucore C18 column (100 mm×2.1 mm, 2.6 μm) with a gradient elution of 0.1% formic acid and 0.1% acetonitrile, and in the subsequent analysis using selected reaction monitoring mode, three ion transitions were monitored for analyte. The limit of detection (LOD) was 0.741 ng/ml and the limit of quantitation (LOQ) was 2.471 ng/ml. Good linearity (R 2 = 0.9998) was observed for the analyte over the linear range (5–400 ng/ml). The LC-MS/MS method was applied to the analysis of rats liver and kidney in different postmortem intervals (6 h, 12 h, 24 h, 48 h, 72 h and 168 h after death) after a single dose (4 mg/kg) of cantharidin administration by gavage. At 72 h after death, the cantharidin concentration in livers and kidneys were significantly higher than that in other postmortem intervals. Linear regression equations between postmortem interval and lg postmortem cantharidin concentration in rats liver and kidney were Y = 0.007455*X + 1.332(R 2 = 0.863) and Y = 0.002689*X + 1.433 (R 2 = 0.115) respectively. The animal experiment demonstrated LC-MS/MS method can be used to determine the postmortem cantharidin concentration in rats liver and kidney and the determination of cantharidin in the rats liver after death has potential value for postmortem interval estimation in cantharidin poisoning.
研究领域:
毒理学
·
分析化学
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法医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2026
·
IF 3.1
Hong Tang,Qing Rao,Ting Liu,Zixia Hu,Zhanhui Feng,Yu Chen,Yan He,Dongbing Cui,Ximei Li,Qing Zhang,Ying Peng,Weiwei Li,Jiang Zheng
Cantharidin (CTD) possesses potent anticancer activity, whereas its prominent hepatotoxicity severely limits its clinical application. Because the detailed molecular mechanisms responsible for CTD-triggered hepatotoxicity have not been fully elucidated, additional investigations are necessary to uncover its toxicological pathways. This study investigated the mechanism of CTD-triggered hepatotoxicity and the protective effects of exogenous glutathione (GSH) supplementation. In vitro results showed that CTD reduced the GSH/glutathione disulfide (GSSG) ratio and the activities of catalase (CAT) and glutathione peroxidase (GPX) in hepatocytes, induced a compensatory upregulation of superoxide dismutase (SOD), and promoted malondialdehyde (MDA) accumulation. Additionally, CTD downregulated glutamate-cysteine ligase modifier subunit (GCLM) expression, decreased mitochondrial membrane potential (MMP), suppressed B-cell lymphoma 2 (Bcl-2) expression, and upregulated Bcl-2-associated X protein (Bax), cysteine-dependent aspartate-directed protease (caspase-9), downstream caspase-3, and cytochrome c (Cyt c) levels, thereby triggering hepatocyte apoptosis, with no significant changes in cellular cysteine (Cys) content and glutamate-cysteine ligase catalytic subunit (GCLC) expression. In vivo experiments verified that CTD markedly decreased hepatic GSH and Cys levels and downregulated GCLC expression, whereas GCLM expression and hepatic Cyt c levels showed only a slight upward trend without statistical significance. Glutathione ethyl ester (GSH-OEt) pretreatment in vitro and GSH intervention in vivo effectively prevented CTD-caused oxidative damage. Collectively, CTD induces divergent expression patterns of glutamate-cysteine ligase (GCL) subunits in vitro and in vivo, disrupts GSH metabolic homeostasis, and provokes oxidative stress and mitochondrial dysfunction, ultimately leading to hepatocellular injury.
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DOI
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2020
·Vol. 40
·期 11
·1491-1497
·
IF 2.997
Youyou Zhang,Liang Liu,Liang Ren
The cardiotoxicity of cantharidin has been well characterized, but the understanding of the underlying mechanism(s) is incomplete. To more fully understand the differentially expressed genes (DEGs) in cantharidin-induced myocardial injury, Sprague-Dawley rats were exposed to cantharidin (1.34 mg/kg or 2.67 mg/kg) for 24 h and then the heart was sampled for pathologic changes analysis and RNA-sequencing-based transcriptomic profiling. In addition, serum troponin T (TN-T) levels were also tested using the enzyme-linked immunosorbent assay method. The results showed that cantharidin could cause myocardial damage and elevated serum TN-T levels. The genes with a fold change ≥2 were considered as DEGs and we found 38 DEGs that were mainly enriched in eight pathways revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The cellular component of gene ontology analysis showed that the DEGs were mostly enriched in the extracellular matrix. In conclusion, our present study demonstrated that cantharidin induces myocardial injury by multiple modulatory mechanisms, which provide new insights for further study of the pathophysiologic mechanism of cantharidin-induced myocardial injury.
研究领域:
药理学
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分子生物学
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毒理学
·
心脏病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED ENTOMOLOGY
·
2016
·Vol. 141
·期 5
·363-371
·
IF 1.517
J. B. Fan,S. van de Velde,W. B. Sun,H. Yu,Y. L. Zhang,D. Wang
The oriental armyworm, Mythimna separata Walker (Lepidoptera: Noctuidae), is a severe pest of graminaceous crops in Asia and Australia. In this study, we investigated the impacts of Cry2Ab, cantharidin and its analogues (cantharidin-23 and cantharidin-24) on M. separata growth, hydrolytic enzymes and detoxifying enzymes. Differences in weight gain and enzyme activities among all treatments were observed. Larval and pupal weight gain and hydrolytic enzyme activities declined when larvae were treated with Cry2Ab, cantharidin and its analogues, individually or in combination. The combination of Cry2Ab and cantharidin or cantharidin-24 had a markedly adverse effect on larval weight gain. Alkaline phosphatase and acid phosphatase were inhibited, whereas glutathione S-transferase was upregulated in all treatments with sublethal doses. The maximum reduction in alkaline phosphatase activity and increase in glutathione S-transferase activity occurred after the larvae were treated with a combination of Cry2Ab and cantharidin-24 over 48 h. The results suggest that the compositions of Cry2Ab, cantharidin and cantharidin-24 have a potential use in pest management.
研究领域:
昆虫学
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植物保护
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生物化学
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DOI
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Wenwen Jiao,Hao Li,Yingjie Wu,Qing Wen,Wenzhen Wang,Jia Tian,Yulong Ren,Jinyuan Ma,Danxiang Zhao,Junli Zhao,Yu Zhang,Guang Han
Hepatocellular carcinoma (HCC) is a challenging cancer to treat due to its high malignancy, strong invasiveness, and high risk of metastasis. Inhibiting lymphatic metastasis in the early stages is crucial for HCC therapy. Active targeted drug delivery systems, imbued with tumor and lymphatic targeting capability via ligand–receptor mediation, represent a promising therapeutic strategy. Cantharidin (CTD), the primary effective component of poisonous traditional Chinese medicine (PTCM) Mylabris, has unique therapeutic effects on HCC. However, its high toxicity limits its clinical application. In this study, based on the high expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in the peritumoral lymphatic vessels and glycyrrhetinic acid receptor (GA-R) in hepatocellular carcinoma cells, we developed CTD-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles modified with glycyrrhetinic acid (GA)–hyaluronic acid (HA) copolymers (GA-HA-PLGA/CTD NPs) through electrostatic interactions. This nanoparticle platform could preferentially accumulate cargo into the tumors and peritumoral lymphatic vessels, increasing drug accumulation in tumors and lymph nodes while decreasing drug accumulation in other organs, particularly the heart and kidney. As a result, it could enhance antitumor efficacy and inhibit lymphatic metastasis better than PLGA/CTD NPs while also reducing systemic toxicity. Furthermore, the variation of HA molecular weights and degrees of GA substitution could regulate the distribution of nanoparticles within tumors and lymph nodes. Overall, GA-HA-PLGA/CTD NPs exhibit promising potential as a therapeutic approach for HCC treatment and lymphatic metastasis inhibition, providing a potential strategy for the application of PTCMs in HCC treatment.
研究领域:
肿瘤学
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药学
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纳米技术
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分子生物学
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DOI
高影响因子
RSC Advances
·
2024
·Vol. 14
·期 39
·28753-28767
·
IF 3.9
Yu Hu,Tian Lan,Ji Li,Lingjun Li,Jizheng Song
Cantharidin (CTD) has been widely used to treat hepatocellular carcinoma (HCC) in clinical practice. However, the current CTD preparations may induce hepatic and renal damage due to their non-specific distribution. Therefore, redox-sensitive polymer Pluronic F127-disulfide bond-poly(D,L-lactide) (F127-SS-PDLA) and active targeting polymer F127-glycyrrhetinic acid (F127-GA) were synthesized to prepare mixed micelles (GA/F127-SS-PDLA/CTD) for effective delivery of CTD. Fourier transform infrared (FTIR) spectroscopy and 1H nuclear magnetic resonance (1H-NMR) spectroscopy were used to verify the successful synthesis of F127-SS-PDLA and F127-GA. During the preparation, this study was the first to screen the density of GA by cellular uptake assay. The results indicated that mixed micelles with 10% and 15% F127-GA (weight fraction) exhibited superior cellular uptake in comparison to micelles with 5% and 20% F127-GA. GA/F127-SS-PDLA/CTD micelles prepared by thin film hydration method demonstrated excellent drug loading capacity for CTD (16.12 ± 0.11%). The particle size and zeta potential of GA/F127-SS-PDLA/CTD micelles were 85.17 ± 1.24 nm and −11.71 ± 0.86 mV, respectively. Hemolysis and stability assay showed that the mixed micelles had good blood compatibility and could remain stable for 30 days at 4 °C. The redox-sensitivity of GA/F127-SS-PDLA/CTD micelles in vitro was verified under reducing conditions through dynamic light scattering (DLS) and an in vitro drug release experiment, which showed obvious particle size variation and rapid drug release ability. In cellular experiments, GA/F127-SS-PDLA/CTD micelles could induce superior cytotoxicity, apoptosis and intracellular reactive oxygen species (ROS) levels compared with free CTD, non-sensitive F127-PDLA/CTD micelles and redox-sensitive F127-SS-PDLA/CTD micelles. The cellular uptake ability of nile red-labeled GA/F127-SS-PDLA micelles, which was evaluated via fluorescent microscope and flow cytometry, indicated that the modification of GA significantly increased micelle uptake in HepG-2 cells. Consequently, GA/F127-SS-PDLA/CTD micelles could be considered as a satisfactory drug administration strategy in the treatment of HCC.
研究领域:
药学
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生物医学工程
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肿瘤学
·
材料科学
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产品关联
DOI
PubMed
高影响因子
REPRODUCTIVE TOXICOLOGY
·
2023
·
IF 3.3
Yuanyuan Xiao,Ruxia Liu,Wenchao Tang,Changfu Yang
Cantharidin (CTD) is a chemical constituent derived from Mylabris and has good antitumor effects, but its clinical use is restricted by its inherent toxicity. However, few researches have reported its reproductive toxicity and mechanisms. This study aims to assess CTD's toxicity on mouse testes and the protective effect of Astragalus polysaccharides (APS). Briefly, biochemical analysis, histopathology, transmission electron microscopy, immunohistochemistry, and Western blotting were used to evaluate the oxidative damage of mouse testicular tissue after exposure to CTD and treatment by APS. Our research suggests a dramatic decrease in testicular index and serum testosterone levels after CTD exposure. The testis showed obvious oxidative damage accompanied by an increase in mitochondrial autophagy, the Nfr2-Keap1 pathway was inhibited, and the blood–testis barrier was destroyed. Notably, these changes were significantly improved after APS treatment. The internal mechanisms of APS ameliorate CTD-induced testicular oxidative damage in mice may be closely connected to regulatory the Nrf2-Keap1 signaling pathway, restraining autophagy, and repairing the blood–testis barrier, providing theoretical support for further study on the reproductive toxicity mechanism of CTD and clinical treatments to ameliorate it.
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DOI
PubMed
高影响因子
DRUG DELIVERY
·
2026
·
IF 8
Wanting Jiang,Hao Zheng,Shengmei Wang,Rubing Xu,Xi Chen,Jing Yang,Xinhua Xia
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, yet conventional chemotherapy is limited by poor tumor specificity and severe toxicity. Cantharidin (CTD), a natural antitumor agent, is hindered by nephrotoxicity and hepatotoxicity. This study aimed to construct a dual-ligand-modified CTD-loaded solid lipid nanoparticle (GA-FA-CSLNs) using 18-glycyrrhetinic acid (GA) for hepatocyte targeting and folate-PEG3500-DSPE (FA) for long circulation, and to evaluate its antitumor efficacy, mechanism, and safety. GA-FA-CSLNs were prepared by emulsification-ultrasonication and optimized via Box-Behnken design. The nanoparticles were characterized. In vitro antitumor activity was assessed in Huh-7 cells using CCK-8, flow cytometry, and Western blotting. In vivo efficacy and safety were evaluated in Huh-7 tumor-bearing nude mice, and pharmacokinetics in SD rats. GA-FA-CSLNs exhibited favorable physicochemical properties. In vitro studies showed enhanced cellular uptake, the lowest IC50, and 43.2% apoptosis in Huh-7 cells. Mechanistically, GA-FA-CSLNs downregulated Eph receptor B4(EphB4) and Bcl-2, while upregulating caspase-3 and Bax. In vivo, the tumor inhibition rate reached 58.67%, superior to free CTD and sorafenib, with 100% 14-day survival and no significant abnormalities in serum biochemistry or histopathology. Pharmacokinetic analysis showed prolonged elimination half-life (2.54 h) and a 3.2-fold increase in area under the blood concentration-time curve versus unmodified CSLNs. GA-FA-CSLNs represent a promising actively targeted nanoplatform that enhances CTD antitumor efficacy against HCC via EphB4 pathway inhibition while reducing systemic toxicity, offering a potential strategy for targeted HCC therapy.
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Yang Tang,Qun Jiang,Rongli Chen,Siqi Wu,Yichang Luo,Xi Huang,Guofang Yu,Cui Shao
Recent advances in immune checkpoint inhibitors (ICIs), particularly those targeting PD-1/PD-L1, have transformed cancer treatment. However, their efficacy is often hampered by the immunosuppressive tumor microenvironment (TME). Here, we developed a cantharidin-loaded nanomedicine (CA@TPGS-AmP), composed of D-α-tocopheryl polyethylene glycol succinate (TPGS) and naturally derived amphiphilic peptides (AmP), designed to enhance PD-1 blockade via induction of immunogenic cell death (ICD). In vitro, CA@TPGS-AmP markedly improved the solubility of cantharidin and exhibited superior penetration in 3D tumor spheroids. It effectively triggered key ICD events, including calreticulin (CRT) surface exposure, ATP release, and HMGB1 translocation, thereby promoting dendritic cell (DC) maturation. In vivo, CA@TPGS-AmP significantly augmented the antitumor efficacy of PD-1 therapy in 4T1 orthotopic breast cancer and LLC lung cancer models. Mechanistically, the combination therapy remodeled the TME into an immunostimulatory state by increasing CD8+ T cell infiltration and activation, leading to enhanced tumor suppression compared to monotherapies. These findings support CA@TPGS-AmP as a promising adjunct to PD-1 blockade and highlight the potential of natural product-based nanomedicine in advancing cancer immunotherapy.
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DOI
PubMed
高影响因子
Biomaterials Science
·
2021
·Vol. 9
·期 23
·7862-7875
·
IF 6.843
Xiao Cheng,Ye Liu,Hao Zhou,Junke Leng,Xiaofeng Dai,Dong Wang,Kun Ma,Changhao Cui,Jijun Fu,Zhaoming Guo
The treatment efficiency of the Fenton reaction is expected to be greatly restricted due to problems such as inefficient delivery of Fenton catalysis, limited H2O2 concentration and uneven tumour tissue. Accurate photothermal therapy (PTT) could improve the efficiency of Fenton catalysis to some extent by raising the temperature. However, the heat shock response (HSR) of tumour cells caused by PTT and Fenton reaction would attenuate the treatment effect. In this study, we developed an iron ions-mediated Fenton reaction combined with a PTT treatment platform based on a metal–organic framework, i.e., PPy-CTD@MIL-100@MPCM nanoparticles (PCMM NPs), and further explored the inhibitory effect of PCMM NPs on the heat shock response (HSR). PCMM NPs could accumulate in tumour tissue via the coated macrophage cell membranes (MPCMs) to target inflammatory tissues. The photothermal effect of polypyrrole (PPy) accelerated the release of cantharidin (CTD) and iron ions loaded in the PCMM NPs. CTD, as an HSR inhibitor, could inhibit this response of tumour cells and improve the effect of PTT. Meanwhile, the heat generated during the PTT process could improve the efficiency of the Fenton reaction. This study suggested that PCMM NPs could serve as a combined treatment platform to enhance the Fenton reaction based on amplified photothermal therapy.
研究领域:
纳米技术
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癌症研究
·
治疗工程
·
材料科学
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DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2021
·
IF 3.963
Yifan Li,Hong Sun,Hassan Yasoob,Zhen Tian,Yue Li,Ruichi Li,Shengli Zheng,Jiyuan Liu,Yalin Zhang
Cantharidin (CTD) is a natural toxin with effective toxicity to lepidopteran pests. Nevertheless, little information is available on whether pests develop resistance to CTD. After being exposed to CTD (50 mg/L to 90 mg/L) or 10 generations, the resistance ratio of laboratory selected cantharidin-resistant Mythimna separata (Cantharidin-SEL) strain was only elevated 1.95-fold. Meanwhile, the developmental time for M. separata was prolonged (delayed1.65 in males and 1.84 days in females). The reported CTD target, the serine/threonine phosphatases (PSPs), have not been shown significant activity variation during the whole process of CTD-treatment. The activity of detoxification enzymes (cytochrome monooxygenase P450, glutathione-S-transferase (GST) and carboxylesterase) were affected by CTD selection, but this change was not mathematically significant. More importantly, no obvious cross-resistance with other commonly used insecticides was observed in the M. separata population treated with CTD for 10 generations (resistance ratios were all lower 2.5). Overall, M. separata is unlikely to produce target-site insensitivity resistance, metabolic resistance to CTD. Meanwhile, cantharidin-SEL is not prone to develop cross-resistance with other insecticides. These results indicate that CTD is a promising biogenetic lead compound which can be applied in the resistance management on M. separata .
研究领域:
昆虫学
·
害虫管理
·
毒理学
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产品关联
DOI
PubMed
高影响因子
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