Hypoxia-Responsive Nano-Photosensitizer Anchored by PEGylated BODIPY: A Single-Laser-Driven Platform for Photo-Enhanced Synergistic Chemo/Photodynamic/Photothermal Cancer Therapy

作者：D. D. YANG, Huamei Zhuang, Jiayi Zheng, Liyang Du, Jianmin Chen, Jian‐Yong Liu · 发表于：Molecular Pharmaceutics · 年份：2025 · DOI：10.1021/acs.molpharmaceut.5c00646 · 被引用次数：5 · 研究领域：Nanoplatforms for cancer theranostics、Nanoparticle-Based Drug Delivery、Cancer, Hypoxia, and Metabolism

The integration of chemotherapeutic drugs and photosensitizers into nanocarriers holds great potential for combining chemotherapy and phototherapy while reducing systemic toxicity. However, therapeutic efficacy is hindered by the hypoxic tumor microenvironment and the insufficient drug release. This study designs a multifunctional nano-photosensitizer BAP by conjugating hydrophobic boron dipyrromethene (BODIPY) with hydrophilic poly(ethylene glycol) via hypoxia-responsive azobenzene linkers. In aqueous media, BAP demonstrates self-assembly into stable nanoparticles (termed BAP NPs) that exhibit dual phototherapeutic functionalities. BAP NPs can be activated by single wavelength laser irradiation to initiate both photodynamic therapy (PDT) and photothermal therapy (PTT). The engineered BAP NPs further integrate dual-mode imaging capabilities, enabling fluorescence and photothermal imaging for nanocarrier visualization. To enhance antitumor efficacy, the chemotherapy doxorubicin (DOX) was further loaded into BAP NPs, forming nanomedicine BAP-DOX NPs. As expected, the azobenzene linkers of BAP are sensitive to the overexpressed azoreductase in hypoxic cancer cells, facilitating BAP disassembly and DOX release. Upon laser irradiation, the BAP component in BAP-DOX NPs eradicates superficial oxygen-rich tumor cells through PDT and PTT. PDT-caused oxygen consumption triggers acute hypoxia, enhancing DOX release in hypoxic tumor cells. Both in vitro and in vivo studies have demonstra...