pH/GSH dual responsive nanosystem for nitric oxide generation enhanced type I photodynamic therapy

Jianhua Zou; Zheng Li; Yang Zhu; Yucen Tao; Qing You; Fangfang Cao; Qinghe Wu; Min Wu; Junjie Cheng; Jianwei Zhu; Xiaoyuan Chen

doi:10.1016/j.bioactmat.2023.12.023

pH/GSH dual responsive nanosystem for nitric oxide generation enhanced type I photodynamic therapy

Bioact Mater. 2024 Jan 10:34:414-421. doi: 10.1016/j.bioactmat.2023.12.023. eCollection 2024 Apr.

Authors

Jianhua Zou^{1

2}, Zheng Li^{1

2}, Yang Zhu^{1

2}, Yucen Tao^{1

2}, Qing You^{1

2}, Fangfang Cao^{1

2}, Qinghe Wu^{1

2}, Min Wu³, Junjie Cheng^{1

4}, Jianwei Zhu^{1

5}, Xiaoyuan Chen^{1

2

6

7}

Affiliations

¹ Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore.
² Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
³ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, Shanghai, 200011, PR China.
⁴ Department of Chemistry Center for Bioanalytical Chemistry, University of Science and Technology of China, Hefei, 230026, PR China.
⁵ College of Life Science, Nanjing Normal University, 1 Wenyuan Road, Nanjing, 210023, PR China.
⁶ Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
⁷ Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.

Abstract

Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy (PDT) due to oxygen consumption. Type I PDT, which can operate independently of oxygen, is a viable option for treating hypoxic tumors. In this study, we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment (TME) to enhance type I PDT through glutathione (GSH) depletion. Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals (O₂^-.) while minimizing their consumption. The diisopropyl group within PEG-IR820 serves a dual purpose: it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820, facilitating efficient O₂^-. generation. Simultaneously, the release of JSK leads to GSH depletion, resulting in the generation of nitric oxide (NO). This, in turn, contributes to the formation of highly cytotoxic peroxynitrite (ONOO^-.), thereby enhancing the therapeutic efficacy of these NPs. NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy.

Keywords: NIR-II imaging; NO gas therapy; TME responsive; Type I PDT.