Yang De-Chao, Zhuang Huamei, Zheng Jiayi, Du Liyang, Chen Jianmin, Liu Jian-Yong
School of Pharmacy and Medical Technology, Putian University, Putian 351100, China.
Key Laboratory of Pharmaceutical Analysis and Laboratory Medicine (Putian University), Fujian Province University, Putian 351100, China.
Mol Pharm. 2025 Sep 1;22(9):5603-5615. doi: 10.1021/acs.molpharmaceut.5c00646. Epub 2025 Aug 13.
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 demonstrated that BAP-DOX NPs exhibit remarkable antitumor activity through synergistic light-driven PDT/PTT and hypoxia-responsive chemotherapy. This research establishes an innovative therapeutic strategy to overcome hypoxia-induced therapeutic resistance through a simple photosensitizer-based nanocarrier that enables photo-enhanced drug release and synergistic chemo/photodynamic/photothermal tumor ablation.
将化疗药物和光敏剂整合到纳米载体中,在联合化疗和光疗的同时降低全身毒性方面具有巨大潜力。然而,缺氧的肿瘤微环境和药物释放不足阻碍了治疗效果。本研究通过缺氧响应性偶氮苯连接体将疏水性硼二吡咯亚甲基(BODIPY)与亲水性聚乙二醇共轭,设计了一种多功能纳米光敏剂BAP。在水性介质中,BAP表现出自组装成稳定的纳米颗粒(称为BAP NPs),其具有双重光疗功能。BAP NPs可通过单波长激光照射激活,启动光动力疗法(PDT)和光热疗法(PTT)。工程化的BAP NPs进一步整合了双模态成像能力,实现了用于纳米载体可视化的荧光和光热成像。为了提高抗肿瘤疗效,将化疗药物阿霉素(DOX)进一步负载到BAP NPs中,形成纳米药物BAP-DOX NPs。正如预期的那样,BAP的偶氮苯连接体对缺氧癌细胞中过表达的偶氮还原酶敏感,促进BAP分解和DOX释放。激光照射后,BAP-DOX NPs中的BAP成分通过PDT和PTT根除浅表富氧肿瘤细胞。PDT导致的氧消耗引发急性缺氧,增强缺氧肿瘤细胞中DOX的释放。体外和体内研究均表明,BAP-DOX NPs通过协同光驱动的PDT/PTT和缺氧响应性化疗表现出显著的抗肿瘤活性。本研究通过一种基于简单光敏剂的纳米载体建立了一种创新的治疗策略,以克服缺氧诱导的治疗耐药性,该纳米载体能够实现光增强药物释放和协同化学/光动力/光热肿瘤消融。