School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, P. R. China.
National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, P. R. China.
ACS Nano. 2022 Jan 25;16(1):721-735. doi: 10.1021/acsnano.1c08232. Epub 2022 Jan 3.
Hypoxia, a common feature of most solid tumors, causes severe tumor resistance to chemotherapy and immunotherapy. Herein, a tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem is designed to overcome hypoxic resistance and enhance chemoimmunotherapy. The nanosystem utilized the tumor-acidity responsive group poly(2-azepane ethyl methacrylate) with a rapid response rate and highly efficient bioorthogonal click chemistry to form large-sized aggregates in tumor tissue to enhance accumulation and retention. Subsequently, another tumor-acidity responsive group of the maleic acid amide with a slow response rate was cleaved allowing the aggregates to slowly dissociate into ultrasmall nanoparticles with better tumor penetration ability for the delivery of doxorubicin (DOX) and nitric oxide (NO) to a hypoxic tumor tissue. NO can reverse a hypoxia-induced DOX resistance and boost the antitumor immune response through a reprogrammed tumor immune microenvironment. This tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem not only helps to counteract a hypoxia-induced chemoresistance and enhance antitumor immune responses but also provides a general drug delivery strategy for enhanced tumor accumulation and penetration.
缺氧是大多数实体瘤的共同特征，导致肿瘤对化疗和免疫疗法产生严重的耐药性。在此，设计了一种基于肿瘤酸度和生物正交化学介导的原位尺寸转变的聚集纳米系统，以克服缺氧耐药性并增强化疗免疫治疗。该纳米系统利用肿瘤酸度响应性聚（2-氮杂环丁烷乙基甲基丙烯酸酯），具有快速的响应速度和高效的生物正交点击化学，在肿瘤组织中形成大尺寸的聚集物，以增强积累和保留。随后，另一种肿瘤酸度响应性马来酸酰胺的响应速度较慢，其可以使聚集物缓慢解离成具有更好的肿瘤穿透能力的超小纳米颗粒，以将阿霉素（DOX）和一氧化氮（NO）递送至缺氧肿瘤组织。NO 可以通过重新编程肿瘤免疫微环境来逆转缺氧诱导的 DOX 耐药性并增强抗肿瘤免疫反应。这种基于肿瘤酸度和生物正交化学介导的原位尺寸转变的聚集纳米系统不仅有助于对抗缺氧诱导的化疗耐药性并增强抗肿瘤免疫反应，而且还为增强肿瘤积累和穿透提供了一种通用的药物输送策略。
