用于增强抗肿瘤疗法的 Celastrol 衍生物/DOX 共组装纳米药物。

Jiangtao Su, Xue Chen, Fan Ye, Chuchu Liu, Jiahao Liang, Xuejun Zhang, Xiaoxia Guo
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引用次数: 0

摘要

背景:多药耐药性(MDR)是临床化疗面临的主要挑战。联合用药可有效逆转多药耐药性:本研究将多柔比星(Doxorubicin,DOX)封装到由两亲性聚乙二醇化-聚(α-硫辛酸)-甲酰胺类似物塞拉斯托(mPEG-PαLA-CEN)原药聚合物形成的纳米颗粒中。CEN 通过形成酯键与聚(α-硫辛酸)支链相连。通过静电作用,DOX 被物理性地截留在纳米颗粒内。这两种药物可在低 pH 值和高 GSH 值条件下同时释放,从而克服 DOX 的抗药性:方法:通过 1H NMR、FT-IR 光谱、UV-Vis 光谱、DLS 和 TEM 确认了 mPEG-PαLA-CEN-DOX NPs 的化学结构。采用高效液相色谱法测量了载药含量、药效和药物释放。采用 MTT 法检测细胞毒性:结果:发现 CEN/DOX 负载纳米粒子呈球形,直径约为 229.7 nm。这种纳米粒子具有很高的生物相容性,在肿瘤微环境的低 pH 值和高 GSH 值条件下可释放 92% 的 DOX 和 71.8% 的 CEN。与游离 DOX 相比,mPEG-PαLA-CEN-DOX NPs 在体外对 MCF-7 和 MCF-7/ADR 肿瘤细胞株的药效均有所提高。与游离 DOX 相比,mPEG-PαLA-CEN-DOX NPs 对 MCF-7/ADR 细胞株的 IC50 从 46.10 μM 降至 8.36 μM:总之,本研究表明,PEG化聚(α-硫辛酸)-CEN共聚物不仅可用作生物相容性好、刺激响应性强的抗癌药物纳米载体,还可用作克服多药耐药性的化敏剂,这为CEN/DOX纳米药物的临床应用提供了理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Celastrol Derivative/DOX Co-Assembled Nanodrug for Enhanced Antitumor Therapy.

Background: Multidrug resistance (MDR) is a key challenge in clinical chemotherapy. The combination of drugs can effectively reverse multi-drug resistance.

Objective: In this study, doxorubicin (DOX) was capsulated into nanoparticles formed by an amphiphilic PEGylated-poly (α-lipoic acid)-methanamide analogue of celastrol (mPEG-PαLA-CEN) prodrug polymer. CEN was linked to the branched chain of poly (α-lipoic acid) by forming ester bonds. DOX was physically trapped inside the nanoparticles via electrostatic interaction. Both drugs can be simultaneously released in response to low pH and high GSH in order to overcome DOX resistance.

Methods: The chemical structure of the mPEG-PαLA-CEN-DOX NPs was confirmed through 1H NMR, FT-IR spectroscopy, UV-Vis spectrum, DLS, and TEM. Drug-loading content, efficacy, and drug release were measured using HPLC. Cell toxicity was examined using an MTT assay.

Results: CEN/DOX-loaded nanoparticles were found to have spherical shapes with diameters of around 229.7 nm. The NPs exhibited high biocompatibility and released 92% DOX and 71.8% CEN in response to low pH and high GSH of tumor microenvironments. As dual drug-loaded nanoparticles, the efficacy of mPEG-PαLA-CEN-DOX NPs against tumor cell lines in vitro was enhanced for both MCF-7 and MCF-7/ADR compared to free DOX. Compared to free DOX, the IC50 of mPEG-PαLA-CEN-DOX NPs reduced from 46.10 μM to 8.36 μM for the MCF-7/ADR cell line.

Conclusion: In conclusion, this study demonstrated that PEGylated poly (α-lipoic acid)-CEN copolymers can be used not only as biocompatible, stimulation-responsive anticancer drug nanocarriers but also as chemosensitizers to overcome multidrug resistance, which provide a theoretical base for clinical application of CEN/DOX nanodrug.

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