Pharmaceutics
·
2024
·Vol. 16
·期 9
·1174
·
IF 4.9
Siying Huang,Simeng Xiao,Xuehao Li,Ranran Tao,Zhangwei Yang,Ziwei Gao,Junjie Hu,Yan Meng,Guohua Zheng,Xinyan Chen
Considering that the precise delivery of Celastrol (Cst) into mitochondria to induce mitochondrial dysfunction may be a potential approach to improve the therapeutic outcomes of Cst on TNBC, a novel tumor mitochondria dual-targeted mixed-micelle nano-system was fabricated via self-synthesized triphenylphosphonium-modified cholesterol (TPP-Chol) and hyaluronic acid (HA)-modified cholesterol (HA-Chol). The Cst-loaded mixed micelles (Cst@HA/TPP-M) exhibited the characteristics of a small particle size, negative surface potential, high drug loading of up to 22.8%, and sustained drug release behavior. Compared to Cst-loaded micelles assembled only by TPP-Chol (Cst@TPP-M), Cst@HA/TPP-M decreased the hemolysis rate and upgraded the in vivo stability and safety. In addition, a series of cell experiments using the triple-negative breast cancer cell line MDA-MB-231 as a cell model proved that Cst@HA/TPP-M effectively increased the cellular uptake of the drug through CD44-receptors-mediated endocytosis, and the uptake amount was three times that of the free Cst group. The confocal results demonstrated successful endo-lysosomal escape and effective mitochondrial transport triggered by the charge converse of Cst@HA/TPP-M after HA degradation in endo-lysosomes. Compared to the free Cst group, Cst@HA/TPP-M significantly elevated the ROS levels, reduced the mitochondrial membrane potential, and promoted tumor cell apoptosis, showing a better induction effect on mitochondrial dysfunction. In vivo imaging and antitumor experiments based on MDA-MB-231-tumor-bearing nude mice showed that Cst@HA/TPP-M facilitated drug enrichment at the tumor site, attenuated drug systemic distribution, and polished up the antitumor efficacy of Cst compared with free Cst. In general, as a target drug delivery system, mixed micelles co-constructed by TPP-Chol and HA-Chol might provide a promising strategy to ameliorate the therapeutic outcomes of Cst on TNBC.
研究领域:
药学
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纳米技术
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肿瘤学
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生物医学工程
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药物递送系统
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Advanced Science
·
2026
·
IF 14.1
Jinrun Chen,Yuqin Wu,Bofei Xu,Jiabei Hou,Yijing Li,Yuhan Hu,Yutuo Zhu,Wenqiao Zhang,Shuqi Feng,Huanting Jin,Yuchen Cheng,Yuanyuan Jin,Jianhong Zhou,Xingyi Li
Activation of retina-specific CD4 + T cells capable of breaking through the blood-retinal barrier (BRB) was significantly associated with the onset and progression of autoimmune uveitis (AU). Antigen-presenting cells (APCs) orchestrate this process by presenting retinal antigens to naïve CD4 + T cells and driving their differentiation into autoreactive CD4 + T cells. Here, we report an intestinal APCs-targeted strategy for treating AU based on orally administered nanoCEL (diameter: 37.06 ± 0.12 nm), a pH-responsive nanomedicine exhibiting a great gastric acid stability and a pH-responsive drug release behavior. After oral administration, nanoCEL effectively penetrates the intestinal mucus barrier and targets APCs in the intestine. Using an experimental autoimmune uveitis rat model, oral administration of nanoCEL (2 mg/kg) exhibits a superior therapeutic efficacy than free CEL treatment by suppressing the antigen-presenting ability of APCs and impairing pathogenic T cell differentiation. Additionally, nanoCEL medication protects the BRB from the damage of pathogenic T cells by the reduction of the infiltration of peripheral immune cells and the activation of retinal glial cells. Compared to free CEL, oral administration of nanoCEL remarkably enhances drug bioavailability and improves biosafety without apparent systemic toxicity. Thus, the proposed APC-targeted nanodrug delivery system might be a promising strategy to treat AU.
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International Journal of Biological Sciences
·
2026
·Vol. 22
·期 13
·7427
·
IF 11.7
Hong Xu,Hongyu Chen,Fengling He,Xinlan Li,Wanxin Li,Qingqing Yang,Tingting Zhang,Jin Liu,Xiaoke Shi,Shilin Chen,Defang Li,Jun Lu
Aberrant activation of macrophages and their amplification of inflammatory responses constitute the core pathological basis driving the progression of acute lung injury (ALI). Celastrol (CE), despite its potent anti-inflammatory activity, suffers from poor aqueous solubility and substantial systemic toxicity, which severely limit its clinical translation. Capitalizing on the metabolic signature of pro-inflammatory M1 macrophages, specifically their high expression of glucose transporter 1 (GLUT1), we designed a glucose-modified CE prodrug that self-assembled into carrier-free nanoparticles CG NPs. With markedly improved solubility and systemic stability, CG NPs rapidly and persistently accumulated in the inflammatory lungs of LPS-induced ALI mice facilitated by GLUT1-mediated targeting and uptake by M1 macrophages. Compared with free CE, CG NPs exhibited enhanced overall therapeutic efficacy while significantly reducing hepatorenal toxicity. Mechanistic studies revealed that by targeting Drp1, CG NPs disrupt Drp1-MiD51 interaction, thus inhibiting excessive mitochondrial fission and ROS accumulation, which blocks NF-κB-mediated inflammatory signaling and M1-driven cytokine release. Molecular docking suggested that glucose conjugation may confer CG with a superior ability to regulate mitochondrial homeostasis over CE, potentially driven by its unique U-shaped conformation that inserts into Drp1 and forms a denser hydrogen-bond network, which could contribute to enhanced binding affinity. In summary, this study proposes a nanoprodrug strategy that combines precise targeting with mitochondrial protection, offering a promising therapeutic avenue for inflammatory diseases such as ALI.
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ADVANCED FUNCTIONAL MATERIALS
·
2026
·
IF 19
Hongyang Jiang,Xiaoyu Zhu,Weizhen Pan,Wenchao Xu,Hanlin Tao,Yiduo Jia,Yang Xun,Zhuo Liu,Jihong Liu,Zhiping Zhang,Songwei Tan
Kidney stones (KS) are a kind of common urological disease with high prevalence and recurrence rates, which is closely linked to oxidative stress in the renal microenvironment and ferroptosis of renal tubular epithelial cells. Clinical used citric acid drugs can only reduce stone formation while along with the concerns about their effectiveness and side effects. Therefore, developing effective drugs for KS has great clinical significance. Celastrol (Cel) is a potential therapeutic drug for KS. However, the narrow therapeutic window (LD50 of ≈3 mg kg −1 in mice) and poor targeting greatly limited its application. Through iterative optimization based on molecular docking and structure–activity relationship evaluation, this study designed “drug-excipient integration” cerium-doping glutathione carbon dots (Ce-CDs) for Cel targeting delivery. The Ce-CDs@Cel nanodrug showed obvious kidney accumulation and even KS targeting with good biosafety. Importantly, such system met three goals in a single stroke: erosion of stones directly, ferroptosis inhibition by up-regulating the expression of the Slc7a11/GPX4 pathway, and remodeling renal microenvironment by reducing the expression levels of stone-related molecules and reactive oxygen species. These synergistic effects significantly reduced the deposition of calcium oxalate crystals. Overall, the multi-functional Ce-CDs@Cel provide a pharmaceutical design strategy and new insights into the treatment of KS.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2026
·
IF 4
Liu Jie,Chen Jun,Zhang Lei,Xia Chunyong
Doxorubicin (DOX) efficacy in breast cancer is limited by dose-dependent cardiotoxicity and the development of multidrug resistance, while celastrol (Cel) suffers from poor solubility, low bioavailability and systemic toxicity. Their combination offers synergistic potential, but effective co-delivery remains challenging. We designed a protein-based nanoplatform via ferric ion-mediated biomimetic mineralization co-assembly of DOX, Cel, and human serum albumin (HSA) for enhanced antitumor therapy. HSA-Fe(III)-Cel-DOX nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug loading and encapsulation efficiencies were determined by high-performance liquid chromatography (HPLC). In vitro drug release was evaluated with or without glutathione (GSH). Cytotoxicity against 4T1 murine breast cancer cells was assessed by CCK-8 assay. The optimized HSA-Fe(III)-Cel-DOX NPs (8 mM Fe 3 ⁺) exhibited uniform spherical morphology with an average diameter of approximately 64.6 nm and narrow size distribution (PDI = 0.103). The nanoparticles demonstrated exceptionally high drug encapsulation efficiencies (96.7 ± 1.9% for DOX and 94.5 ± 1.4% for Cel) and drug loading capacities (19.7 ± 0.5% for DOX and 17.3 ± 0.4% for Cel). The formulation exhibited excellent colloidal stability over 28 days of storage. In vitro release studies revealed remarkable GSH-responsive behavior, with cumulative release reaching 77.0 ± 3.3% for DOX and 64.0 ± 2.9% for Cel at 12 h under reducing conditions, while negligible release (< 5%) under non-reducing conditions was observed in the absence of GSH. Cytotoxicity assays demonstrated that HSA-Fe(III)-Cel-DOX NPs exerted significantly enhanced antitumor effect against 4T1 cells compared to free DOX or free Cel alone. At an equivalent DOX concentration of 0.5 μg/mL, the nanoparticles reduced cell viability to 29.2 ± 1.2%, substantially lower than free DOX (89.7 ± 2.0%) or free Cel (100.4 ± 2.2%). We successfully constructed a ferric ion-mediated biomimetic nanoplatform via co-assembly of DOX, Cel, and HSA. This nanoplatform offers facile preparation, excellent stability, GSH-responsive drug release, and significantly enhanced in vitro cytotoxicity, representing a promising strategy for synergistic breast cancer therapy.
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Acta Pharmaceutica Sinica B
·
2021
·
IF 11.614
Long Xi,Zibei Lin,Fen Qiu,Shaokui Chen,Ping Li,Xin Chen,Zhenping Wang,Ying Zheng
Psoriasis is an autoimmune skin disease in which dendritic cells (DCs) trigger the progression of psoriasis by complex interactions with keratinocytes and other immune cells. In the present study, we aimed to load celastrol, an anti-inflammatory ingredient isolated from Chinese herbs, on mannosylated liposomes to enhance DC uptake as well as to induce DC tolerance in an imiquimod-induced psoriasis-like mouse model. Mannose was grafted onto liposomes to target mannose receptors on DCs. The results demonstrated that compared with unmodified liposomes, DCs preferred to take up more fluorescence-labeled mannosylated liposomes. After loading celastrol into mannose-modified liposomes, they effectively inhibited the expression of maturation markers, including CD80, CD86 and MHC-II, on DCs both in vitro and in vivo . Additionally, after intradermal injection with a microneedle, celastrol-loaded mannose-modified liposomes (CEL-MAN-LPs) achieved a superior therapeutic effect compared with free drug and celastrol-loaded unmodified liposomes in the psoriasis mouse model in terms of the psoriasis area and severity index, histology evaluation, spleen weight, and expression of inflammatory cytokines. In conclusion, our results clearly revealed that CEL-MAN-LPs was an effective formulation for psoriasis treatment and suggested that this treatment has the potential to be applied to other inflammatory diseases triggered by activated DCs.
研究领域:
皮肤科
·
免疫学
·
药学
·
纳米技术
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IBRO Neuroscience Reports
·
2024
·
IF 2
Min Wei,Yi Liu,Dongsheng Li,Xingdong Wang,Xiaodong Wang,Yuping Li,Zhengcun Yan,Hengzhu Zhang
Background Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage. Methods We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH). Results Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites. Conclusions Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.
研究领域:
神经科学
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药理学
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分子生物学
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FREE RADICAL BIOLOGY AND MEDICINE
·
2021
·
IF 7.376
Xiulin Yang,An Chen,Qingchun Liang,Qianqian Dong,Mingwei Fu,Xiaoyu Liu,Siyi Wang,Yining Li,Yuanzhi Ye,Zirong Lan,Jing-Song Ou,Lihe Lu,Jianyun Yan
Vascular calcification is very commonly observed in patients with chronic kidney disease (CKD), but there is no efficient therapy available. Oxidative stress plays critical roles in the progression of vascular calcification. Celastrol (Cel), a natural constituent derived from Chinese herbals, exhibits anti-oxidative stress activity. Here, we investigated the effect of celastrol on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings and CKD rats. Alizarin red staining and gene expression analysis showed that Cel dose-dependently inhibited rat VSMC calcification and osteogenic differentiation. Similarly, ex vivo study revealed that Cel inhibited calcification of rat and human arterial rings. In addition, micro-computed tomography, alizarin red staining and calcium content analysis confirmed that Cel inhibited aortic calcification in CKD rats. Interestingly, Cel treatment increased the mRNA and protein levels of heme oxygenase-1 (HMOX-1), and reduced the levels of reactive oxygen species (ROS) in VSMCs. Furthermore, both pharmacological inhibition of HMOX-1 and knockdown of HMOX-1 by siRNA independently counteracted the inhibitory effect of Cel on vascular calcification. Moreover, knockdown of HMOX-1 prevented Cel treatment-mediated reduction in ROS levels. Finally, Cel treatment reduced Vitamin D3-induced aortic calcification in mice and this effect was blocked by HMOX-1 inhibitor ZnPP9. Collectively, our results suggest that up-regulation of HMOX-1 is required for the inhibitory effect of Cel on vascular calcification. Modulation of HMOX-1 may provide a novel strategy for the treatment of vascular calcification in CKD.
研究领域:
肾病学
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药理学
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分子生物学
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心血管疾病
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JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2024
·
IF 3.6
Shanjiang Chen,Jianjian Yang,Fuli Liu
Celastrol (CEL) belongs to the group of non-steroidal immunosuppressants with the potential to improve cardiac hypertrophy (CH). However, the poor biocompatibility and low bioavailability of CEL limit its in vivo application. This study was aimed to develop a targeted drug delivery system that can efficiently and safely deliver CEL to target tissues, providing a research basis for the application of CEL in CH therapy. A novel ROS-sensitive drug-loaded nanomicelle, dodecanoic acid (DA)-phenylboronic acid pinacol ester-dextran polymer encapsulating CEL (DBD@CEL), was synthesized using chemical synthesis. Then, the morphology, particle size, drug-loaded content, and ROS-responsive release behavior of DBD@CEL were studied. Pharmacokinetics and biocompatibility were evaluated using healthy mice. Finally, the ability and mechanism of DBD@CEL in improving CH in vivo were investigated using a mouse CH model. DBD@CEL was successfully prepared with a drug loading of 18.9%. It exhibited excellent stability with an average particle size of 110.0 ± 1.7 nm. Within 48 h, DBD@CEL released only 19.4% in the absence of H2O2, while in the presence of 1 mM H2O2, the release rate increased to 71.5%. Biocompatibility studies indicated that DBD@CEL did not cause blood cell hemolysis, had no impact on normal organs, and did not result in abnormal blood biochemical indicators, demonstrating excellent biocompatibility. In vivo studies revealed that DBD@CEL regulated the activation of NF-κB signaling, inhibits pyroptosis and oxidative stress, and thereby ameliorates CH. The ROS-responsive DBD@CEL nanodrug delivery system enhances the therapeutic activity of CEL for CH, providing a promising drug delivery system for the clinical treatment of CH.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Congjian He,Jiahui Zhou,Xixi Wu,Yujin Zhou,Siya Wang,Bo Liu,Ting Luo,Ying Chen,Jia Yuan,Di Wang,Chen Zhang,Jinfeng Shi
Low concentrations or limited residence times in tumor tissues, making celastrol (Cel) difficult to exert significant therapeutic effects. Thus, we developed Zein/hyaluronic acid core-shell nanoparticles (Cel/Zein@HA NPs) for active targeted delivery of Cel via CD44 receptor over-expression on cancer cells, which may strengthen the therapeutic efficacy of Cel and improve delivery targeting. Cel-loaded Zein nanoparticles (core), are elegantly enveloped by a hydrophilic HA coating that forms the shell, resulting in significantly improved encapsulation efficiency and ensured good stability. The cellular uptake of Cel/Zein@HA NPs in HepG2 cells was 1.57-fold higher than nontargeting Cel/Zein NPs. Near-infrared fluorescence imaging confirmed the accumulation of Cel/Zein@HA NPs in H22 liver cancer tumors in mice, resulting in effective antitumor effects and good biosafety. Besides, in vitro and in vivo experiments showed that compared with Cel/Zein NPs, Cel/Zein@HA NPs had more efficient inhibitory effect on tumor proliferation and lower systemic toxicity. Further studies revealed that Cel/Zein@HA NPs induced apoptosis in hepatocellular carcinoma cells by modulating Bax and Bcl-2 expression, while also inhibiting tumor angiogenesis by decreasing CD31 and VEGF levels. Overall, this study presents a promising strategy for enhancing targeted liver cancer therapy through the utilization of biopolymer nanoparticle-based nano-pharmaceuticals that facilitate CD44-mediated cellular uptake.
研究领域:
药学
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纳米技术
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癌症研究
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生物医学工程
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
·
IF 8.5
Xiaoying Wang,Hua Zhang,Chongxian Li,Lanlan Cai,Longxin Lin,Yu Lin,Wei Xu
Hyaluronic acid derivatives have broad prospects in the in vivo targeted delivery of insoluble antitumor drugs. In this study, rhein-selenocystamine-hyaluronic acid (RSeHA) polymeric micelles (PMs) were designed and developed to load celastrol (Cela) to solve its poor water solubility, low bioavailability, and severe toxicity for breast cancer treatment. Cela-loaded RSeHA PMs (Cela/RSeHA PMs) with a particle size of 159.61 ± 8.33 nm and drug-loading capacity of 36.57 ± 1.66 % showed excellent redox dual-responsiveness for drug rapid-release in tumors. Cela/RSeHA PMs can be taken up by the MCF-7 and 4T1 cells, exhibiting a good killing effect on these cells in a time- and concentration-dependent manner. Pharmacokinetic results showed that Cela/RSeHA PMs significantly enhanced the bioavailability and prolonged the circulation time of Cela in vivo . The PMs enhanced Cela's distribution in the tumor, improving its tumor-targeting ability. The pharmacodynamic results in 4 T1 tumor-bearing mice showed that Cela/RSeHA PMs could inhibit the growth of tumors, with a tumor inhibition rate of 59.45 ± 12.64 %, and significantly decrease serum CA15–3 level, displaying a good anti-breast cancer effect without organ damage. In summary, RSeHA PMs are expected for tumor-targeting and redox dual-responsive delivery of water-insoluble anti-breast cancer drugs.
研究领域:
药学
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纳米技术
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肿瘤学
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高分子化学
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生物医学工程
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BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2018
·Vol. 41
·期 8
·1243-1250
·
IF 1.694
Yunpeng Qi,Renping Wang,Liang Zhao,Lei Lv,Fan Zhou,Tian Zhang,Feng Lu,Hongli Yan,Gengli Duan
Celastrol is well known for its anti-cancer effects, yet its specific mechanisms against colon cancer are still not fully elucidated. In this study, cytotoxic effect of celastrol against HCT116 colon cancer cells was investigated based on cell viability assay and flow cytometry assay, and the possible mechanism was explored using a strategy combining metabolic profiling and targeted metabolite analysis based on ultra performance liquid chromatography (UPLC)/MS. Celastrol was found to inhibit the growth of colon cancer cells and induce apoptosis. Metabolomics analysis revealed characteristic changes in metabolic profiles of the colon cancer cells, revealing altered levels of amino acids, carnitine, and lipid markers. Most interestingly, with the assistance of targeted metabolite analysis, tryptophan (Trp) level was significantly increased whereas kynurenine (Kyn) level was decreased in colon cancer cells after celastrol treatment, together with markedly declined Kyn/Trp ratios. Western blot analysis revealed that expression of indoleamine 2,3-dioxygenase (IDO), the enzyme catalyzing Trp to generate Kyn, was dramatically inhibited in colon cancer cells after celastrol treatment, with a dose-dependent manner. These results suggest that suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against HCT116 colon cancer cells. This study provided scientific basis for further development of celastrol on treating colon cancer.
研究领域:
肿瘤学
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药理学
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代谢组学
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细胞生物学
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高影响因子
危险品化学品经营许可证（带存储）