DRUG DELIVERY
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2023
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IF 6
Simeng Xiao,Siying Huang,Xiaojing Yang,Yujie Lei,Mingxiang Chang,Junjie Hu,Yan Meng,Guohua Zheng,Xinyan Chen
In order to precisely deliver celastrol into mitochondria of tumor cells, improve antitumor efficacy of celastrol and overcome its troublesome problems in clinical application, a novel multistage-targeted celastrol delivery system (C-TL/HA) was developed via electrostatic binding of hyaluronic acid (HA) to celastrol-loaded cationic liposomes composed of natural soybean phosphatidylcholine and cholesterol modified with mitochondrial targeting molecular TPP. Study results in this article showed that C-TL/HA successfully transported celastrol into mitochondria, effectively activated apoptosis of mitochondrial pathway, exerted higher tumor inhibition efficiency and lower toxic side effects compared with free celastrol. More importantly, HA coating not only enabled this delivery system to have good stability and safety in vivo, but also increased drug uptake and facilitated tumor targeting through recognizing CD44 receptors rich on the surface of tumor cells. Conclusively, this HA-coated mitochondrial targeting liposomes may provide a prospect for the clinical application of celastrol in tumor therapy.
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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药物递送系统
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DOI
PubMed
高影响因子
Journal of Natural Medicines
·
2023
·
IF 3.3
Zou Gang,Yu Ruihong,Zhao Dezhang,Duan Zhaohui,Guo Shimin,Wang Tingting,Ma Limei,Yuan Zhiyi,Yu Chao
Abstract The impact of hypertension on tissue and organ damage is mediated through its influence on the structure and function of blood vessels. This study aimed to examine the potential of celastrol, a bioactive compound derived from Tripterygium wilfordii Hook F , in mitigating hypertension-induced energy metabolism disorder and enhancing blood perfusion and vasodilation. In order to investigate this phenomenon, we conducted in vivo experiments on renovascular hypertensive rats, employing indirect calorimetry to measure energy metabolism and laser speckle contrast imaging to evaluate hemodynamics. In vitro, we assessed the vasodilatory effects of celastrol on the basilar artery and superior mesenteric artery of rats using the Multi Wires Myograph System. Furthermore, we conducted preliminary investigations to elucidate the underlying mechanism . Moreover, administration of celastrol at doses of 1 and 2 mg/kg yielded a notable enhancement in blood flow ranging from 6 to 31% across different cerebral and mesenteric vessels in hypertensive rats. Furthermore, celastrol demonstrated a concentration-dependent (1 × 10 –7 to 1 × 10 –5 M) arterial dilation, independent of endothelial function. This vasodilatory effect could potentially be attributed to the inhibition of Ca 2+ channels on vascular smooth muscle cells induced by celastrol. These findings imply that celastrol has the potential to ameliorate hemodynamics through vasodilation, thereby alleviating energy metabolism dysfunctions in hypertensive rats. Consequently, celastrol may hold promise as a novel therapeutic agent for the treatment of hypertension. Graphical abstract
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PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2026
·
IF 11.9
Yudi Lu,Mei Zhou,Xunfa Zhang,Weijun Huang,Fan Li,NingLi Zhang,Nannan Lu,Chenggui Wu,Zhihui Feng,Shuangying Gui,Zhenbao Li
Chemotherapeutic paclitaxel (PTX) formulations are widely used in clinical cancer treatment; however, they are also associated with concomitant programmed death-ligand (PD-L1) upregulation and an immunosuppressive microenvironment. Herein, we rationally designed carrier-free, reduction-sensitive PTX dimer self-assembling nanoprodrugs (diPC NPs), composed of a glutathione (GSH)-responsive PTX dimer prodrug (diPTX) and the PD-L1 downregulator celastrol (Cel) for combinational chemoimmunotherapy. Following intravenous administration, the diPC NPs exhibited prolonged blood circulation and preferential tumour accumulation by exploiting the enhanced permeability and retention effect. Subsequently, the elevated GSH levels in tumour cells cleaved the disulfide bonds, triggering the rapid release of PTX and Cel. The released PTX elicited potent cytotoxic effects and induced immunogenic cell death (ICD), whereas the released Cel synergistically enhanced ICD and downregulated PD-L1 expression in tumour cells. Together, these effects resulted in remarkable antitumor efficacy with exhibited a favorable safety profile within the therapeutic window in both Lewis lung carcinoma cells and B16F10 tumour-bearing mice. Our findings highlight a promising strategy for highly efficient combination chemoimmunotherapy. KEY WORDS: Carrier-free; Reduction-responsive self-assembling; Paclitaxel dimer; Nanoprodrug; Celastrol; Chemoimmunotherapy.
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高影响因子
Materials Today Bio
·
2026
·
IF 11
Liming Yang,Yunfei Zhao,Jianguo Luo,Mengjiao Deng,Fangliang Wang,Gang Zou,Jun Chen,Yunyu He,Xuelan Gan,Yumei Dai,Yuminghang Chen,Chao Yu
The development of effective oral therapies for nonalcoholic steatohepatitis (NASH) remains a critical unmet need in clinical practice. Celastrol (CEL), a potent natural compound, is a promising candidate for NASH due to its lipid-modulating, anti-inflammatory properties, and antioxidative properties. However, its clinical translation is severely hindered by poor oral bioavailability and a narrow therapeutic window stemming from significant toxicity. To overcome these limitations, we present the design and fabrication of novel, carrier-free CEL nanoparticles stabilized through natural polysaccharide self-assembly. This innovative formulation strategy is aimed at substantially enhancing the oral bioavailability of CEL, thereby augmenting its therapeutic efficacy in NASH while mitigating associated adverse effects. In this study, we developed a polysaccharide-CEL supramolecular depot comprising 42 distinct nanoassemblies for oral delivery in NASH, identifying chondroitin sulfate (CS) as the optimal polysaccharide adjuvant. The resulting CS/CNA formulation markedly improved oral absorption, with a 3.12-fold increase in observed systemic exposure based on AUC (0-t) compared with free CEL. Inhibitor-based mechanistic studies suggested that CS/CNA transport across intestinal epithelial cells may involve multiple endocytosis pathways and partial lysosomal escape. In a murine model of NASH, CS/CNA demonstrated potent therapeutic efficacy by modulating hepatic inflammation and reducing lipid accumulation. Critically, the nanoassembly exhibited a favorable safety profile, mitigating the toxicity associated with free CEL. By enhancing therapeutic efficacy while reducing adverse effects, this strategy effectively widens the therapeutic window for celastrol. This work establishes CS/CNA as a promising oral therapeutic candidate and provides a robust platform for advancing the clinical potential of CEL for NASH management.
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PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Jun Tang,Yimeng Yang,Zihan He,Chuting Wang,Ziwei Gao,Yan Meng,Xinyan Chen,Qi Wang,Guohua Zheng,Junjie Hu,Cong Chang
Intrahepatic cholangiocarcinoma (ICC) is a rare malignant tumor with limited treatment options. Celastrol (Cela) shows potential treatment for ICC, but its clinical use is hindered by poor water solubility and toxic side effects. To address these challenges and enhance its anti-tumor efficacy, we developed hyaluronic acid (HA)-coated triphenylphosphine complex-modified liposomes (HCTL) for accurate delivery of Cela to tumor cell mitochondria.HCTL enhances Cela's water solubility and demonstrates a high rate of encapsulation, stability, and sustained drug release behavior. Moreover, HCTL exhibits outstanding anti-ICC efficacy by efficiently inducing apoptosis in ICC cells via the mitochondrial pathway due to its precise targeting capabilities. In an in-situ ICC mouse model activated by hydrodynamic transfection of AKT and Yap, HCTL downregulates tumor-associated proliferative indices, attenuates the severity of liver injury and modulates the tumor microenvironment. Importantly, HCTL overcomes systemic toxicity associated with Cela. To sum up, HCTL is a potentially effective drug delivery system for ICC treatment.
研究领域:
药学
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肿瘤学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
PEDIATRIC RESEARCH
·
2024
·
IF 3.1
Hu Yingying,Nan Yan,Lin Hongzhou,Zhao Qianlei,Chen Tingting,Tao Xiaoyue,Ding Bingqing,Lu Liying,Chen Shangqin,Zhu Jianghu,Guo Xiaoling,Lin Zhenlang
Background Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear. Methods Here, we established both in vitro and in vivo models of HI brain damage using CoCl 2 -treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models. Results Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA. Conclusions We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE. Impact
We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries.
Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.
研究领域:
神经科学
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药理学
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儿科
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分子生物学
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DOI
PubMed
高影响因子
ACS Omega
·
2024
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IF 3.7
Chenxin Xu,Yinghua Chen,Zhuoen Zhou,Ying Yan,Wenying Fu,Peng Zou,Daoyong Ni
Lung cancer is one of the leading causes of death. Celastrol is a natural product that has shown anticancer activity but has not yet been applied in clinical settings due to its narrow therapeutic window. In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol. At the same time, celastrol upregulated the expression of cytoprotective transcription factor Nrf2 and its downstream proteins, which are effective in preventing the oxidative damage caused by ROS accumulation. Notably, we found that the overexpression of Nrf2 enhances the tolerance of lung cancer cells to celastrol and that lung cancer cells H460 with a Keap1 mutation are insensitive to celastrol. This indicates that the increase in Nrf2 contributes to the survival of lung cancer cells. Thus, we brought in an Nrf2 inhibitor ML385 to suppress the activation of Nrf2. We found that when ML385 and celastrol were added together the survival rates of lung cancer cells decreased more and the detected ROS level became much higher compared to treatment with celastrol alone. We also discovered that ML385 suppressed the expression of HO-1 and GCLC, which amplified celastrol-induced ATF4/CHOP-dependent endoplasmic reticulum stress (ER stress). Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Chemistry
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2020
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IF 3.693
Niu Weina,Wang Jianguo,Wang Qinyao,Shen Jianjun
Ovarian cancer is a gynecological cancer from which it is difficult to be completely cured. It is common to use regimens as an effective treatment for ovarian cancer, but these inevitably bring serious side effects. New treatment strategies and special drugs are needed to improve the prognosis of patients. Celastrol is a natural product, isolated from traditional medicine, that has been proven to be curative for inflammation and cancers. However, the non-targeting and low solubility of celastrol limit its clinical application. We prepared celastrol-loaded nanoparticles for the efficient treatment of ovarian cancer via oxidative stress amplification. In this work, a tumor-targeted, ROS-sensitive nanoparticle was designed, synthesized, and assembled into a drug delivery system that used celastrol. Folic acid (FA) groups on the surface of nanoparticles guide them to actively target the surface of the tumor cell membrane. Thioketal (TK) bonds in nanoparticles can be oxidized and broken into -SH within the ROS level of tumor tissues, which causes the breaking of the PEG hydrophilic shell layer of nanoparticles and promotes the release of celastrol. The released celastrol further stimulated the production of ROS and amplified the intracellular ROS level to promote the apoptosis of tumor cells, thus achieving a therapeutic effect on the celastrol treated ovarian cancer.
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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天然产物化学
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产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
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2022
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IF 10.723
Xue Zhang,Xueya Xu,Xiaoying Wang,Yajuan Lin,Yaling Zheng,Wen Xu,Jian Liu,Wei Xu
A glycyrrhetinic acid-modified carboxymethyl chitosan-thioketal-rhein (GCTR) conjugate was designed and synthesized for the in vivo delivery of celastrol (Cela). Cela was encapsulated into polymeric micelles (PMs) formed by GCTR conjugates self-assembly in water to form Cela/GCTR PMs with high drug loading capacity and small particle size. Cela/GCTR PMs had a sustained-release characteristic in the blood environment and a rapid-release feature in the tumor microenvironment. Cela/GCTR PMs had a significant proliferation inhibitory effect on HepG2 and BEL-7402 cells, but a negligible impact on L-02 cells at low concentrations. Cela/GCTR PMs possessed reactive oxygen species (ROS)-responsive properties in vitro and in cells, could improve the bioavailability of Cela, and exert remarkable hepatoma-targeting properties. Cela/GCTR PMs could also effectively inhibit tumor growth with no apparent damage to different organs. In summary, GCTR PMs with good ROS-responsive and hepatoma-targeting properties are expected to be possible delivery carriers for hydrophobic antineoplastic drugs for hepatocellular carcinoma therapy.
研究领域:
药学
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生物医学工程
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肿瘤学
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材料科学
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产品关联
DOI
PubMed
高影响因子
Drug Delivery and Translational Research
·
2023
·Vol. 14
·期 2
·555-570
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IF 5.4
Huang Jian,Wang Zhengji,Chen Zihe,Huang Chunxin,Wang Ying,Li Xing,Lv Weiyang,Qi Guiqiang,Liu Huilin
Celastrol (CST) has positive pharmacological effects on various cancers, but clinical application is limited because of poor water solubility and systemic toxicity. Ferric oxide (Fe 3 O 4 ) has a large specific surface area and can be functionalized by inorganic modification to form complex magnetic drug delivery systems. Herein, Fe 3 O 4 was surface-modified with citric acid and polyethylene glycol (PEG) (via) the Mitsunobu reaction and then covalently bound to CST. Finally, magnetic microbubbles (MMBs) containing perfluoropropane (C 3 F 8 ) and Fe 3 O 4 -PEG 2K -CST particles were constructed with poly(lactic-co-glycolic acid) (PLGA) as the shell membrane. In vitro studies showed that ultrasound-mediated MMBs exhibited improved inhibition of VX2 cell proliferation compared to inhibition achieved using MMBs without ultrasound mediation, blank MMBs, or free CST. In ultrasound mode, MMBs have favorable imaging properties. After the application of a high mechanical index, MMBs collapse through the cavitation effect, releasing their internal Fe 3 O 4 -PEG 2K -CST. The CST is then delivered to the tumor microenvironment under acidic conditions. In magnetic resonance imaging T2 mode, a specific hypointense signal was observed in the tumor area compared with that before treatment, whereas no significant change occurred in the signal intensity of the surrounding organs. After treatment, pathological examination of tumor-bearing rabbit tissues showed that iron elements accumulated in several apoptosis cells in the tumor area, with no apparent abnormalities found in other areas. Thus, ultrasound-mediated MMBs could significantly improve the drug uptake of solid tumors and inhibit tumor growth with favorable biological safety. Graphical Abstract
研究领域:
药理学
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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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医学影像
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Ruisi Zhou,Yanting You,Zhiqiang Zha,Jie Chen,Yanchun Li,Xiaohu Chen,Xiaomei Chen,Xuefeng Jiang,Jinxiang Chen,Hiu Yee Kwan,Xiaoshan Zhao,Liping Huang,Yanyan Liu
Ovarian cancer (OC) stands as the second most prominent factor leading to cancer-related fatalities, characterized by a notably low five-year survival rate. The insidious onset of OC combined with its resistance to chemotherapy poses significant challenges in terms of treatment, emphasizing the utmost importance of developing innovative therapeutic agents. Despite its remarkable anti-tumor efficacy, celastrol (CEL) faces challenges regarding its clinical utilization in OC due to its restricted water solubility and notable side effects. In this study, celastrol (CEL) was encapsulated into Zeolitic imidazolate framework-8(ZIF-8) nanoparticle and grafted with biotin-conjugated polyethylene glycol (CEL@ZIF-8@PEG-BIO). Comprehensive comparisons of the physicochemical properties and anticancer activities of CEL and CEL@ZIF-8@PEG-BIO were conducted. Our findings revealed that CEL@ZIF-8@PEG-BIO exhibited favorable characteristics, including hydrodynamic diameters of 234.5 nm, excellent water solubility, high drug loading (31.60% ± 2.85), encapsulation efficiency (60.52% ± 2.79), and minimal side effects. Furthermore, CEL@ZIF-8@PEG-BIO can release chemicals in response to an acidic micro-environment, which is more likely a tumor micro-environment. In vitro, studies showed that CEL@ZIF-8@BIO inhibited cell proliferation, led to mitochondrial membrane potential (MMP) decline, and generated reactive oxygen species in OC cells. Both in vitro and in vivo experiments indicated that CEL@ZIF-8@PEG-BIO enhanced anti-tumor activity against OC via up-regulated apoptosis-promoting biomarkers and rendered cancer cell apoptosis via the P38/JNK MAPK signaling pathway. In conclusion, we have successfully developed a novel drug delivery system (CEL@ZIF-8@PEG-BIO), resulting in significant improvements in both water solubility and anti-tumor efficacy thereby providing valuable insights for future clinical drug development.
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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癌症治疗
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DOI
PubMed
高影响因子
Journal of Environmental Chemical Engineering
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2023
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IF 7.7
Juzhao Liu,Qiang Yuan,Guoyin Kai,Yujie Fu,Qi Cui
In this study, the porous cellulose microsphere carrier based on traditional Chinese medicine waste was successfully used to prepare a molecularly imprinted polymer (SPCC-CSL-MIPs) with specific selectivity for celastrol. Fourier transform infrared spectroscopy , scanning electron microscope , thermogravimetry , X-ray diffraction and binding experiments were performed to investigate and analyze the structure and adsorption performance of SPCC-CSL-MIPs. The experimental results showed that the SPCC-CSL-MIPs possessed a high adsorption capacity of 14.38 mg/g and a good imprinting factor of 2.36. Furthermore, the SPCC-CSL-MIPs could maintain a stable adsorption performance of 77.98% after 5 cycles. The above results indicated that the prepared SPCC-CSL-MIPs can be employed as an excellent adsorbent for ready and efficient celastrol enrichment and separation, and the content of celastrol in T. wilfordii extract was vastly increased from 0.46% to 3.87%, which proved that SPCC-CSL-MIPs exhibited the excellent ability of specific targeted enrichment and separation of celastrol from the complex matrix.
研究领域:
材料科学
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生物医学工程
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中药学
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DOI
高影响因子
危险品化学品经营许可证（带存储）