Combination therapy using Cel-CSO/Taxol NPs for reversing drug resistance in breast cancer through inhibiting PI3K/AKT/NF-κB/HIF-1α pathway.

IF 5.7 3区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Drug Delivery and Translational Research Pub Date : 2025-03-01 Epub Date: 2024-06-26 DOI:10.1007/s13346-024-01653-3

Huahui Zeng, Xiaohu Zeng, Can Wang, Guoqiang Wang, Qikang Tian, Junwei Zhao, Lingzhou Zhao, Ruiqin Li, Ying Luo, Haotian Peng, Zhenqiang Zhang, Xiaofang Li, Xiangxiang Wu

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Abstract

The resistance of malignant tumors to multiple drugs is a significant obstacle in cancer treatment and prognosis. Accordingly, we synthesized a celastrol (Cel) prodrug (Cel-CSO) by conjugating chitosan oligosaccharides (CSO) to Cel for reversing Taxol resistance in chemotherapy, followed by self-assembly with Taxol into a novel nanoplatform of Cel-CSO/Taxol nanoparticles (termed NPs). NPs showed a suitable size (about 153 nm), excellent stability and prolonged release of Cel and Taxol in a manner that depended on both pH and time. NPs effectively inhibited the overexpression of multidrug resistance-related protein P-gp, hypoxia inducible factor-1α (HIF-1α), and triggered the MCF-7/Taxol cell apoptosis through inhibiting the PI3K/AKT/NF-κB/HIF-1α pathway. In tumor-bearing mice, NPs exhibited significant curative effects in inducing apoptosis of MCF-7/Taxol tumors which showed a low expression level of P-gp, microtubule-related proteins TUBB3 and Tau. The results indicated that NPs may be a promising strategy to overcome drug resistance caused by P-gp, which improve the antitumor effects in drug-resistant breast cancer.

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利用 Cel-CSO/Taxol NPs 通过抑制 PI3K/AKT/NF-κB/HIF-1α 通路逆转乳腺癌耐药性的联合疗法。

恶性肿瘤对多种药物的耐药性是癌症治疗和预后的一大障碍。因此，我们将壳聚糖寡糖（CSO）与 Cel 结合，合成了一种 Celastrol（Cel）原药（Cel-CSO），用于逆转 Taxol 在化疗中的耐药性，然后与 Taxol 自组装成一种新型的 Cel-CSO/Taxol 纳米颗粒（称为 NPs）。NPs 具有合适的尺寸（约 153 nm）、出色的稳定性以及 Cel 和 Taxol 的长期释放，释放方式取决于 pH 值和时间。NPs 通过抑制 PI3K/AKT/NF-κB/HIF-1α 通路，有效抑制了多药耐药性相关蛋白 P-gp 和缺氧诱导因子-1α（HIF-1α）的过度表达，并引发 MCF-7/Taxol 细胞凋亡。在肿瘤小鼠中，NPs在诱导MCF-7/Taxol肿瘤细胞凋亡方面表现出显著的疗效，而这些肿瘤的P-gp、微管相关蛋白TUBB3和Tau的表达水平较低。结果表明，NPs可能是克服P-gp引起的耐药性的一种有前途的策略，它能提高耐药乳腺癌的抗肿瘤效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Delivery and Translational Research MEDICINE, RESEARCH & EXPERIMENTALPHARMACOL-PHARMACOLOGY & PHARMACY

CiteScore

11.70

自引率

1.90%

发文量

160

期刊介绍： The journal provides a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. Rationally developed, effective delivery systems can potentially affect clinical outcome in different disease conditions. Research focused on the following areas of translational drug delivery research will be considered for publication in the journal. Designing and developing novel drug delivery systems, with a focus on their application to disease conditions; Preclinical and clinical data related to drug delivery systems; Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes Short-term and long-term biocompatibility of drug delivery systems, host response; Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering; Image-guided drug therapy, Nanomedicine; Devices for drug delivery and drug/device combination products. In addition to original full-length papers, communications, and reviews, the journal includes editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of the Controlled Release Society.