Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, Shanghai, 200237, China; Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai 200062, China; Central Lab, Shanghai 200062, China.
Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, Shanghai, 200237, China; Shanghai Key Laboratory of Functional Materials Chemistry, Shanghai, 200237, China; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Int J Pharm. 2022 Aug 25;624:122018. doi: 10.1016/j.ijpharm.2022.122018. Epub 2022 Jul 14.
Photodynamic therapy (PDT) induces tumour cell death by producing reactive oxygen species (ROS), and hypoxia is one of the main factors that limits its efficiency. In our previous study, bufalin (BU) enhanced photosensitizer mTHPC-mediated PDT therapy in colorectal cancer (CRC) cells, but its mechanism was not elucidated. To explore a strategy for improving the efficacy of PDT, we designed iRGD-modified nanoparticles to co-capsuled mTHPC and BU for simultaneous delivery to the tumour site and explored the underlying mechanism of the synergistic anti-CRC effect. In our study, mTHPC&BU@VES-CSO/TPGS-RGD nanoparticles (T-B@NP) had a particle size of 148.3 ± 2.5 nm and a zeta potential of 22.8 ± 2.0 mV. Specifically, these nanoparticles passively accumulated in tumour cells, and under laser irradiation, mTHPC induced cell apoptosis and death. In addition, the sustained release of BU inhibited HIF-1α and reduced VEGF-mediated angiogenesis by targeting the SRC-3/HIF-1α pathway, which induced a strong PDT effect against CRC. In vivo studies demonstrated that codelivery of the nanoparticles under laser irradiation exhibited a superior antitumour effect (84.2%) and significantly prolonged survival time of mice, with the mechanisms of alleviating hypoxia and inhibiting angiogenesis. In summary, mTHPC and BU codelivery via nanoparticles efficiently enhances the therapeutic effects of PDT by inhibiting the SRC-3/HIF-1α pathway in CRC. This work provides an effective strategy to combat hypoxia-induced tumour resistance and overcome the barriers of PDT treatment.
光动力疗法（PDT）通过产生活性氧（ROS）诱导肿瘤细胞死亡，而缺氧是限制其疗效的主要因素之一。在我们之前的研究中，蟾毒灵（BU）增强了光敏剂 mTHPC 介导的结直肠癌（CRC）细胞 PDT 治疗，但机制尚未阐明。为了探索提高 PDT 疗效的策略，我们设计了 iRGD 修饰的纳米粒来共包封 mTHPC 和 BU，以同时递送到肿瘤部位，并探讨协同抗 CRC 作用的潜在机制。在我们的研究中，mTHPC&BU@VES-CSO/TPGS-RGD 纳米粒（T-B@NP）的粒径为 148.3±2.5nm，zeta 电位为 22.8±2.0mV。具体来说，这些纳米粒被动地聚集在肿瘤细胞中，在激光照射下，mTHPC 诱导细胞凋亡和死亡。此外，BU 的持续释放通过靶向 SRC-3/HIF-1α 通路抑制 HIF-1α 并减少 VEGF 介导的血管生成，从而对 CRC 产生强烈的 PDT 作用。体内研究表明，在激光照射下共递纳米粒表现出优异的抗肿瘤效果（84.2%）和显著延长了小鼠的生存时间，其机制为缓解缺氧和抑制血管生成。总之，通过纳米粒共递送 mTHPC 和 BU 可通过抑制 SRC-3/HIF-1α 通路有效增强 CRC 中 PDT 的治疗效果。这项工作提供了一种有效策略来对抗缺氧诱导的肿瘤耐药性并克服 PDT 治疗的障碍。
