pH响应细胞膜仿生纳米微载体多药共传递体系用于肝癌协同治疗的研究

Hepatoma is one of the leading causes of cancer death in the world. Chemotherapy has become one of the most important methods in the treating of hepatoma. However, because of the multidrug resistance and metastasis of hepatoma, 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, make an effective treatment of metastases 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 anti-inflammatory therapy and chemotherapy to reverse the multidrug resistance and improve gastric cancer treatment efficacy. We plan to synthesize phosphorylcholine biomimetic pH responsive amphiphilic block copolymers prodrug which can self-assemble into core-shell micelles in aqueous solution. The micelles are capable of simultaneously encapsulating and delivering anti-inflammatory and anti-cancer drugs into the same cancer cells after systemic administration to synergistically inhibit the growth of hepatoma xenograft. The zwitterionic phosphorylcholine induced selective internalization by gastric cancer cells will be discussed in detail. The drug delivery system can realize smart drug release after uptake by cancer cells. The anti-inflammatory drug 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 hepatoma.

肝癌是人类最常见的恶性肿瘤之一。在肝癌的临床治疗中，化疗是最常用且有效的手段之一，但由于肝癌对化疗药物的耐药性、中晚期肝癌易发生转移以及化疗药物载运系统的低效高毒，常常导致肝癌化疗的失败。本项目针对肝癌治疗中的多药耐药以及癌细胞极易发生转移、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pH响应聚合物前药相结合，制备磷酸胆碱仿生修饰的两亲性嵌段共聚物前药，同时装载和输送抗炎药物和化疗药物，构建基于磷酸胆碱癌症靶向、多药协同增效以及pH调控药物释放的新型纳米药物共传递体系。通过细胞膜仿生修饰同时提高纳米药物载体的血液循环时间和癌细胞选择性富集能力，进一步在肿瘤细胞内涵体微酸环境下实现多种药物的智能释放，最终实现对肝癌的联合治疗，逆转和克服肝癌治疗中的多药耐药性，降低癌细胞的侵袭转移能力，发挥化疗药物和抗炎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。

肝癌是人类最常见的恶性肿瘤之一。在肝癌的临床治疗中，化疗是最常用且有效的手段之一，但由于肝癌对化疗药物的耐药性、中晚期肝癌易发生转移以及化疗药物载运系统的低效高毒，常常导致肝癌化疗的失败。本项目针对肝癌治疗中的多药耐药以及癌细胞极易发生转移、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pH响应聚合物前药相结合，成功制备了磷酸胆碱仿生修饰的两亲性嵌段共聚物前药，同时装载和输送抗炎药物布洛芬和化疗药物阿霉素，构建了基于磷酸胆碱癌症靶向、多药协同增效以及pH调控药物释放的新型纳米药物共传递体系。该纳米载药体系可以有效提高纳米药物载体的血液循环时间和癌细胞选择性富集能力，进一步在肿瘤细胞内涵体微酸环境下实现两种药物的智能释放，通过两种药的共同作用，有效的逆转和克服肝癌治疗中的多药耐药性，降低癌细胞的侵袭转移能力，同时发挥了化疗药物和抗炎药物的协同增效作用，有效的抑制了肿瘤的生长和转移，为癌症治疗手段的优化和突破提供依据。