共载化疗药物/光敏剂的脂质体复合递送系统联合逆转黑色素瘤耐药性及机制研究

Melanoma is a type of cancer caused by the cancerization of melanocytes in skin and other organs. It is highly malignant and prone to metastasis even in the early stages. Melanoma is very resistant to many of the current anticancer therapies including surgery, radiotherapy and chemotherapy; and also has high recurrence rate. The combination of all these factors resulted in the high mortality of patients with melanoma. Photodynamic therapy is an emerging minimally invasive anticancer therapy which has already been used for the treatment of several types of cancer. Based on state-of-the- art technology in material science and clinical oncology, we would like to modify the phthalocyanine photosensitiser with novel functional moieties. The chemically modified photosensitiser would eventually be incorporated with the acid-degradable liposome formulation to prepare the melanoma-targeted chemotherapeutic/photodynamic combinational liposomal drug delivery system. The physicochemical behavior of the above liposomal drug delivery system in the extracellular environment and intracellular endosome/lysosomes of melanoma will be investigated both in vitro and in vivo, as well as the drug release profiles triggered by the reactive oxygen species (ROS)under laser stimulation. This project will also cover those studies regarding the mechanism of the multidrug resistance reversal and cancer cell apoptosis through the combined effort of the anticancer drug and the ROS at molecular level, and eventually lay the theoretical and experimental foundation for the clinical application of this type of drug delivery systems.

黑色素瘤恶性度高、转移发生快，对化疗和放疗等治疗方法都容易产生较高的抗性。本项目综合脂质体、化疗药物/光动力学分子的协同治疗优势，构建出具有体内长循环效应的、共载化疗药物/酞菁光敏剂的主动靶向性脂质体纳米复合递送系统，实现靶向的、多位点的逆转黑素瘤细胞耐药性，抑制肿瘤细胞生长。本项目将探究脂质体复合递送系统在肿瘤细胞内单线态活性氧的数量，触发化疗药物的溶酶体逃离行为，以及诱导线粒体等细胞器的物理损伤。项目还拟分析复合递送系统的体内代谢活动、生物稳定性，评价复合递送系统与细胞、动物活体间的相互作用机理，从分子水平上探究协化疗药物与活性氧协同逆转逆转黑色素瘤细胞耐药性、最终诱导细胞凋亡的分子生物学机理，为该类药物递送系统的临床应用提供理论支持。

黑色素瘤是一种黑色素细胞发展而来的癌症，具有极高的致死率与较差的预后。其具有恶性度高、转移发生快等特点，且对化疗和放疗等治疗方法都容易产生较高的抗性。本项目结合光动力学治疗、铁死亡、氧气定位输送与化学药物治疗等手段的优势，针对黑色素瘤中治疗抗性产生的机制，以透明质酸大分子、pH响应性无定形碳酸钙和多孔中空氧化铁纳米颗粒等纳米材料为基体，制备了肿瘤微环境激活的生物级联响应光动力学生物聚合物、肿瘤微环境响应性负载阿霉素-亚铁离子无定形碳酸钙纳米制剂和还原响应性肿瘤靶向载氧氧化铁纳米载药系统，有针对性地抑制了黑色素瘤中包括乏氧和抗凋亡等常见的抗肿瘤机制，提升了对其治疗效果。项目在国家自然科学基金青年项目资助下，目前已成功构建出系列的共载化疗药物/光敏剂纳米药物复合系统，提高了体内循环时间和肿瘤的靶向效率，减少毒副作用。项目提出的化疗/光动力学疗法，协同促进肿瘤细胞凋亡并揭示了相关作用机制，研究结果为复合药物递送系统的临床应用提供实践支撑和理论基础。目前已在Biomaterials、Nanoscale Horizon和 Materials Horizons等国际知名刊物发表10余篇国际权威SCI论文，完成了项目的预定任务。培养博士研究生1名、硕士研究生3名、博士后1名。

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