Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 10607, Taiwan.
Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 10607, Taiwan.
Int J Mol Sci. 2020 Dec 25;22(1):154. doi: 10.3390/ijms22010154.
Development of stimuli-responsive supramolecular micelles that enable high levels of well-controlled drug release in cancer cells remains a grand challenge. Here, we encapsulated the antitumor drug doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (5-ALA) within adenine-functionalized supramolecular micelles (A-PPG), in order to achieve effective drug delivery combined with photo-chemotherapy. The resulting DOX/5-ALA-loaded micelles exhibited excellent light and pH-responsive behavior in aqueous solution and high drug-entrapment stability in serum-rich media. A short duration (1-2 min) of laser irradiation with visible light induced the dissociation of the DOX/5-ALA complexes within the micelles, which disrupted micellular stability and resulted in rapid, immediate release of the physically entrapped drug from the micelles. In addition, in vitro assays of cellular reactive oxygen species generation and cellular internalization confirmed the drug-loaded micelles exhibited significantly enhanced cellular uptake after visible light irradiation, and that the light-triggered disassembly of micellar structures rapidly increased the production of reactive oxygen species within the cells. Importantly, flow cytometric analysis demonstrated that laser irradiation of cancer cells incubated with DOX/5-ALA-loaded A-PPG micelles effectively induced apoptotic cell death via endocytosis. Thus, this newly developed supramolecular system may offer a potential route towards improving the efficacy of synergistic chemotherapeutic approaches for cancer.
开发对刺激具有响应性的超分子胶束，以使癌细胞能够高度控制药物释放，这仍然是一个巨大的挑战。在这里，我们将抗肿瘤药物阿霉素（DOX）和前光敏剂 5-氨基酮戊酸（5-ALA）封装在腺嘌呤功能化的超分子胶束（A-PPG）中，以实现有效的药物传递结合光化学疗法。所得的 DOX/5-ALA 负载的胶束在水溶液中表现出优异的光和 pH 响应行为，并且在富含血清的介质中具有高药物包封稳定性。可见光的短时间（1-2 分钟）激光照射会导致胶束内的 DOX/5-ALA 复合物解离，从而破坏胶束的稳定性，并导致物理包封的药物从胶束中迅速立即释放。此外，细胞内活性氧生成和细胞内化的体外测定证实，载药胶束在可见光照射后表现出明显增强的细胞摄取，并且胶束结构的光触发解组装迅速增加了细胞内活性氧的产生。重要的是，流式细胞术分析表明，用 DOX/5-ALA 负载的 A-PPG 胶束孵育的癌细胞的激光照射通过内吞作用有效诱导了细胞凋亡。因此，这种新开发的超分子系统可能为改善癌症协同化学疗法的疗效提供了一种潜在途径。
