铂类药物蛋白纳米粒的仿生合成及在耐药肿瘤协同治疗中的应用

低溶解性铂类抗肿瘤药物的载体研究是肿瘤靶向传输领域的难点，构建高效的新型靶向载体，是提高其疗效的关键所在。本项目拟通过单分子白蛋白模板的仿生合成，构建载铂类药物（如顺铂及其衍生物）纳米晶的白蛋白纳米粒，并进一步在其表面修饰碳菁染料Cypate，制备出具有化疗/光热治疗作用的载药蛋白纳米粒，并探索其在耐药肿瘤协同治疗中的应用。通过对模板内铂类药物纳米晶生长的调控，优化蛋白纳米粒的粒径、释药行为等理化特性，增强其肿瘤靶向及细胞摄取能力；在近红外光激发下，蛋白纳米粒中碳菁染料通过光热效应直接产生肿瘤光热治疗作用，并抑制肿瘤细胞中耐药蛋白的表达，从而降低铂类药物的外排；同时，通过碳菁染料产生的胞内活性氧自由基破坏溶酶体膜，促进铂类药物的胞浆转运，增强其化疗效果，最终实现耐药肿瘤的热化疗协同治疗作用。本项目对探索铂类药物新制剂以及耐药肿瘤的协同治疗新策略具有重要的理论意义和实用价值。

It is a major challenge to develop the drug vehicles for platinum-based anticancer drugs with poor solubility in the field of cancer-targeted drug delivery, and thus the exploration of highly effective nanocarrier plays a key role for improving their chemotherapeutic efficacy. In this application, we propose to prepare the albumin nanoparticles incorporating platinum-based drug and Cypate for cancer thermo-chemotherapy, which are achieved through the fabrication of the nanocrystals of platinum-based agents such as cisplatin and its derivatives using single-molecule albumin-based biomimetic synthesis, and subsequent functionalization with a near-infrared cyanine dye, Cypate. Moreover, the ability of albumin nanoparticles to treat resistant tumor is further explored through their synergistic effect. The physicochemical properties of albumin nanoparticles such as diameter and drug release behavior are optimized to improve their tumor accumulations and cellular uptakes through the regulation of drug nanocrystal growth within the single-molecule albumin template. Under near-infrared light irradiation, Cypate within albumin nanoparticles is able to exhibit remarkable photothermal therapy owing to its photothermal effect, and also inhibit the expression of resistance proteins in resistant cancer cells, thereby leading to the decrease of drug efflux. Meanwhile, Cypate can induce the disruption of lysosomes through intracellular reactive oxygen species, and thus facilitate the drug translocation into cytoplasm for enhanced chemotherapy, which finally results in the synergistic thermo-chemotherapeutic efficacy against resistant tumor. This work is highly valuable to explore new formulations of platinum-based anticancer drugs, as well as synergistic strategy to treat resistant tumor.