一种简便的策略制备改良稳定性、增强生物相容性、pH控释的聚乙二醇化硼替佐米前药纳米制剂

A Facile Strategy for PEGylated Nanoprodrug of Bortezomib with Improved Stability, Enhanced Biocompatibility, pH-Controlled Disassembly, and Release

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MACROMOLECULAR BIOSCIENCE

影响因子:4.1

分区:医学4区 / 高分子科学3区生化与分子生物学4区材料科学：生物材料4区

发表日期:2025 Feb

作者: Naikuan Fu, Yinan Zeng, Jing Zhang, Peng Zhang, Hong Zhang, Shicheng Yang, Jianhua Zhang

DOI: 10.1002/mabi.202400383

摘要

硼替佐米（BTZ）的治疗效果常因溶解度低、体内稳定性差及非特异性毒性而受限。本文首次合成了具有儿茶酚官能团的聚乙二醇（mPEG-CA），并利用其与BTZ通过动态硼酰键形成共价结合，制备出具有pH控释能力的PEG化BTZ前药（mPEG-CA-BTZ）。详细分析了其结构、形貌、物理化学性质、药物装载与释放性能以及体外细胞毒性。结果显示，mPEG-CA-BTZ能在生理pH（pH 7.4）条件下自组装成具有均一粒径和稳定分散性的纳米结构，同时能响应肿瘤微环境的酸性，通过酸触发硼酰键断裂、分解mPEG-CA-BTZ，促使纳米粒子解体，实现pH控释。此类纳米粒子有望成为BTZ药物制剂的理想平台，增强治疗效果、降低副作用。考虑到其易得性、生物相容性及简便的制备工艺，此策略为将PEG化和pH敏感性功能集成于硼酸基小分子药物提供了一种简便且具有前景的方法。

Abstract

The therapeutic efficacy of bortezomib (BTZ) is often limited due to low solubility, poor stability in vivo and nonspecific toxicity. Herein, a kind of catechol-functionalized polyethylene glycol (mPEG-CA) is first synthesized and then mPEG-CA is readily used to conjugate with BTZ by the formation of dynamic boronate bonds to obtain PEGlyated BTZ prodrug (mPEG-CA-BTZ) with the ability of pH-controlled disassembly and drug release. The structure and morphology, physicochemical characteristics, drug loading, and release as well as in vitro cytotoxicity of mPEG-CA-BTZ nanoparticles are investigated in detail. The results demonstrated that mPEG-CA-BTZ can not only self-assemble into nanostructures with uniform size and stable dispersion in physiological pH condition (pH 7.4) but also respond to the tumor acid microenvironment and achieve pH-controlled BTZ release by acid-triggered cleavage of boronate bonds, decomposition of mPEG-CA-BTZ and thus disassembly of mPEG-CA-BTZ nanoparticles. mPEG-CA-BTZ nanoparticles are expected to have great potential as a promising nanoplatform for pharmaceutical formulations of BTZ to increase therapeutic efficacy and decrease side effects of BTZ. Considering the easily available and biocompatible excipients and simple preparation process, the strategy designed herein provides a facile and promising approach to synergistically integrate the function of PEGylation and pH-sensitiveness into boronic acid-containing small molecule pharmaceutical agents.