近红外光控纳米药物载体输送小干扰RNA和化疗药物用于肺癌治疗的研究

As one of the leading causes of death among all the malignant tumors in the world，lung cancer becomes the biggest health-killer in China．Great improvements have made in the efficient treating of lung cancer with chemotherapy．However, because of the multidrug resistance of lung cancer, as well as the drug delivery systems with low efficacy and high toxicity, chemotherapy has a very high rate of failure. It is very urgent and crucial to reverse the multidrug resistance and develop new safe and efficient drug delivery systems. Based on the fact that nanoparticle drug delivery system has shown greatly enhanced chemotherapy efficient for cancer therapy, this proposal focuses on the development of nanoparticles as targeted drug carriers for smart drug release. This drug delivery system combines RNA interference therapy and chemotherapy to reverse the multidrug resistance and improve lung cancer treatment efficacy. We plan to synthesize phosphorylcholine biomimetic dual NIR responsive amphiphilic triblock copolymers which can self-assemble into core-shell-corona micelles in aqueous solution. The micelles are capable of simultaneously encapsulating and delivering siRNA targeting multidrug-resistance associated protein (MRP siRNA) and doxorubicin into the same lung cancer cells after systemic administration to synergistically inhibit the growth of human non-small cell lung cancer xenograft. The zwitterionic phosphorylcholine induced selective internalization by lung cancer cells will be discussed in detail. The drug delivery system can realize on-demand smart drug release upon NIR irradiation. The MRP siRNA can inhibit the expression of multidrug-resistance associated protein and therefore reverse the multidrug resistance. The doxorubicin can kill the cancer cells. This combination therapy will provide a new strategy for more efficient treatment of lung cancer.

肺癌是我国发病率和死亡率第一的恶性肿瘤，且我国的肺癌发病率仍在不断攀升。在肺癌的临床治疗中，化疗是最常用且有效的手段之一，但由于肺癌细胞对化疗药物的耐药性和化疗药物载运系统的低效高毒，常常导致肺癌化疗的失败。本项目针对肺癌治疗中的多药耐药性、纳米药物载体靶向传递和智能控释的关键科学问题，将磷酸胆碱仿生设计原理与近红外双逆转（电荷逆转、亲疏水逆转）的纳米药物载体相结合，制备磷酸胆碱仿生修饰的带正电荷的两亲性三嵌段共聚物，组装成核-壳-冠结构的胶束，并同时装载和输送靶向多药耐药相关蛋白(MRP)基因的小干扰RNA和化疗药物阿霉素。通过近红外光控实现仿生纳米药物载体的解组装和药物的靶向智能释放，构建基于磷酸胆碱癌症靶向和近红外光控药物释放的新型纳米药物共传递体系，实现对肺癌的联合治疗，逆转和克服肺癌治疗中的多药耐药性，发挥化疗药物和基因药物的协同增效作用，为癌症治疗手段的优化和突破提供依据。

肺癌是我国发病率和死亡率第一的恶性肿瘤，且我国的肺癌发病率仍在不断攀升。本项目针对肺癌治疗中的多药耐药性、纳米药物载体靶向传递和智能控释的关键科学问题，将磷酸胆碱仿生设计原理与近红外双逆转（电荷逆转、亲疏水逆转）的纳米药物载体相结合，设计合成了近红外双逆转的磷酸胆碱细胞膜仿生核-壳-冠结构的胶束，实现了靶向多药耐药相关蛋白(MRP)基因的小干扰RNA（MRP siRNA）和化疗药物阿霉素（DOX）的同时装载和输送。在近红外光照下，实现了聚合物的电荷逆转和亲疏水逆转，达到MRP siRNA和化疗药物近红外光控智能释放的目的，且通过调节近红外光的功率和照射时间，我们能精确调控药物的释放速率。同时，通过程序性的光照，我们能实现药物的脉冲式释放和由近红外激光定位激发的药物可控释放。同时，磷酸胆碱仿生修饰的纳米载体具有比聚乙二醇（PEG）修饰的纳米载体更好的肿瘤细胞选择性内吞能力，更长的血液循环时间，更多的肿瘤组织的富集。因此，我们成功构建了基于磷酸胆碱癌症靶向和近红外光控药物释放的新型纳米药物共传递体系，实现了对肺癌的联合治疗，逆转和克服了肺癌治疗中的多药耐药性，发挥化疗药物和基因药物的协同增效作用，为癌症治疗手段的优化和突破提供依据。