基于mPEG-β-环糊精和喜树碱前药的还原敏感自组装胶束作为药物释放载体

doi:10.5246/jcps.2021.12.081

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (12): 941-955.DOI: 10.5246/jcps.2021.12.081

• 【研究论文】 • 下一篇

基于mPEG-β-环糊精和喜树碱前药的还原敏感自组装胶束作为药物释放载体

陆益奔¹^,³, 张苗³, 郑永军¹, 侯昕宇³, 贺牧野¹^,³, 楼开炎¹^,³, 高峰¹^,²^,³^,^*()

1. 华东理工大学上海功能性材料化学重点实验室, 上海 200237
2. 华东理工大学上海新药设计重点实验室, 上海 200237
3. 华东理工大学药学院药剂学系, 上海 200237

收稿日期:2021-08-14 修回日期:2021-09-01 接受日期:2021-09-27 出版日期:2021-12-24 发布日期:2021-12-20
通讯作者: 高峰
作者简介:
+ Tel.: +86-13761708247, E-mail: fgao@ecust.edu.cn
基金资助:
National Key Research and Development Program of China (Grant No. 2019YFA0904800), Science and Technology Commission of Shanghai Municipality (Grant No. 11DZ2260600 and 10DZ2220500), and Shanghai Natural Science Fund (Grant No. 20ZR1414700).

Redox-responsive self-assembly polymeric micelles based on mPEG-β-cyclodextrin and a camptothecin prodrug as drug release carriers

Yiben Lu¹^,³, Miao Zhang³, Yongjun Zheng¹, Xinyu Hou³, Muye He¹^,³, Kaiyan Lou¹^,³, Feng Gao¹^,²^,³^,^*()

1 Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China
2 Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China
3 Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

Received:2021-08-14 Revised:2021-09-01 Accepted:2021-09-27 Online:2021-12-24 Published:2021-12-20
Contact: Feng Gao

摘要/Abstract

摘要：

基于聚合物胶束的刺激响应性药物递送系统可以实现药物的控制释放, 从而改善治疗效果, 降低药物在化疗中不必要的系统毒性和副作用, 但生物相容性高分子材料的功能化往往面临着合成、纯化难度大以及载药率低的挑战。本文报道了一种新型的还原敏感自组装聚合物胶束系统mPEG-β-CD/Ad-SS-CPT, 实现了喜树碱(CPT)的高负载, 以及在还原性环境下的选择性药物释放。主客体超分子聚合物胶束利用聚乙二醇修饰的β-环糊精, 即mPEG-β-CD作为聚合物的主体, 易于合成和纯化; 连有金刚烷(Ad)与CPT的前药Ad-SS-CPT作为客体, 所含有的二硫键作为还原敏感性功能基团。二硫键的选择性断裂和药物在还原性环境中的释放, 有可能降低CPT的系统毒性, 并提高疗效。体外研究表明, mPEG-β-CD/Ad-SS-CPT胶束对HeLa细胞的细胞毒性与游离药物相当。基于主客体的聚合物胶束在多药协同给药方面也显示出巨大的潜力, 为设计刺激响应性药物递送系统提供一种通用、方便的方法。

关键词: mPEG-β-环糊精, 喜树碱前药, 自组装胶束, 还原响应, 超分子

Abstract:

Stimuli-responsive drug delivery systems based on polymeric micelles can achieve controlled drug release to improve the therapeutic outcome and reduce unwanted systematic toxicity and side effects of the cytotoxic drug in chemotherapy but often face challenging synthesis and purification of functionalized biocompatible polymer materials and low drug loading efficiency. In the present study, we reported a novel redox-responsive self-assembly polymeric micelle system, mPEG-β-CD/Ad-SS-CPT, to achieve high loading efficiency and selective delivery of camptothecin (CPT) in a reductive environment inside cancer cells. The host-guest supramolecular micelles utilized a simple β-CD modified PEG, mPEG-β-cyclodextrin (mPEG-β-CD), as the polymeric host with the ease of synthesis and purification. The guest prodrug Ad-SS-CPT contained the disulfide bond as the redox sensitivity group. The selective cleavage of disulfide bond and subsequent drug release in a reductive environment could potentially reduce system toxicity and improve the therapeutic outcome of CPT. In vitro studies showed that the micelles exhibited excellent cytotoxicity against HeLa cells comparable to the free drug. The host-guest polymeric micelles also showed great potentials for multi-drug co-delivery. Collectively, our current findings provided a general and convenient approach to design drug delivery systems based on stimuli-responsive polymeric micelles for disease treatment.

Key words: mPEG-β-cyclodextrin, Camptothecin prodrug, Self-assembled micelles, Redox-responsive, Supramolecular

Supporting:

陆益奔, 张苗, 郑永军, 侯昕宇, 贺牧野, 楼开炎, 高峰. 基于mPEG-β-环糊精和喜树碱前药的还原敏感自组装胶束作为药物释放载体[J]. 中国药学(英文版), 2021, 30(12): 941-955.

Yiben Lu, Miao Zhang, Yongjun Zheng, Xinyu Hou, Muye He, Kaiyan Lou, Feng Gao. Redox-responsive self-assembly polymeric micelles based on mPEG-β-cyclodextrin and a camptothecin prodrug as drug release carriers[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(12): 941-955.

图/表 8

Figure 1. Graphical illustration of?mPEG-β-CD/Ad-SS-CPT self-assembled micelles.

Figure 2. Synthesis of mPEG-β-CD.

Figure 3. (A) 1H NMR spectra and (B) MALDI-TOF-MS spectra of mPEG-β-CD.

Figure 4. Synthesis of Ad-SS-CPT.

Figure 5. (A) 1H NMR spectra and (B) LC-MS spectra of Ad-SS-CPT.

Figure 6. (A) CMC of mPEG-β-CD/Ad-SS-CPT. (B) The size distribution of mPEG-β-CD/Ad-SS-CPT self-assembled micelles incubated in 10 mM GSH solution for 8 h. (C) TEM image of mPEG-β-CD/Ad-SS-CPT self-assembled micelles. (D) In vitro release drug from mPEG-β-CD/Ad-SS-CPT self-assembled micelles in PBS (pH 7.4) containing 0 and 10 mM GSH (n = 3). (E) Mass spectra of reduction compound and (F) Degradation mechanism of Ad-SS-CPT in GSH condition.

Table 1. Physicochemical properties of mPEG-β-CD/Ad-SS-CPT self-assembled micellesa.

Figure 7. (A) Confocal microscopy images of L929 cells pretreated with 10 mM GSH for 2 h or without any pretreatment as control, and then incubated with C6-loaded micelles at 37 oC for 2 h (scale bar: 20 μm). (B) Dose-dependent toxicity of CPT, Ad-SS-CPT, and mPEG-β-CD/Ad-SS-CPT self-assembled micelles in HeLa Cells for 24 h.

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基于mPEG-β-环糊精和喜树碱前药的还原敏感自组装胶束作为药物释放载体

Redox-responsive self-assembly polymeric micelles based on mPEG-β-cyclodextrin and a camptothecin prodrug as drug release carriers

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