期刊
ACS NANO
卷 16, 期 1, 页码 721-735出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c08232
关键词
hypoxia; chemoresistance; on-site size transformation; bioorthogonal chemistry; immunogenic cell death; nitric oxide
类别
资金
- National Natural Science Foundation of China [51873072, 52073101]
- Science and Technology Program of Guangzhou [202102010025]
- Guangdong Provincial Pearl River Talents Program [2019QN01Y088]
- Special Fund for the Construction of High-level Key Clinical Specialty (Medical Imaging) in Guangzhou
- Guangzhou Key Laboratory of Molecular Imaging and Clinical Translational Medicine
- Open Fund of Key Laboratory of Biomaterials of Guangdong Higher Education Institutes
- Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development
In this study, a clustered nanosystem was designed to overcome hypoxic resistance in tumors and enhance chemoimmunotherapy. This system utilized tumor acidity-responsive groups and bioorthogonal click chemistry to form large-sized aggregates in tumor tissue, which then slowly dissociated into ultrasmall nanoparticles for enhanced drug delivery. This system not only addressed hypoxia-induced chemoresistance and enhanced antitumor immune responses but also provided a general drug delivery strategy for improved tumor accumulation and penetration.
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.
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