PEOz化米铂脂质体的构建、体内外抗肿瘤活性及作用机制研究

Miriplatin possessed efficient and broad-spectrum anti-tumor activities. Whereas, miriplatin is ineffective in vitro, and freeze-dried powder is the sole clinical formulation of miriplatin for hepatocellular carcinoma by transcatheter arterial chemoembolization. Given that systemic administration of free miriplatin is ineffective and miriplatin is structurally similar to the PEOz-DSPE with self-owned intellectual property, we successfully fabricated miriplatin-loaded liposomes using PEOz-DSPE, which showed high drug loading, pH sensitive targeting ability, and ready for systemic injection. Based on our preliminary study, we aim to fully investigate the PK & PD, distribution, and the anti-tumor mechanisms of miriplatin-loaded liposomes, so as to clarify the in vivo biological characteristics, cellular uptake, intracellular trafficking, degradation/activation, target binding, activation of effector molecules, and the re-editing of tumor microenvironment. The work here would pave way for the research of other platinum drugs loaded nanocarriers, might offer new strategy for the dilemma of accelerated blood clearance phenomenon and protein corona facing liposomes, and broaden the formulation and clinical application of miriplatin, having profound meaning in platinum-based chemotherapy.

米铂广谱抗瘤，疗效确切，体外无活性，仅冻干粉针一种剂型（经肝动脉给药用于肝癌介入化疗）。鉴于米铂独特的化学结构与不能直接全身给药的特点，结合已有自主知识产权的磷脂材料PEOz-DSPE（专利已授权）的特性，设计并成功构建载药量高、酸敏靶向、体内外抗肿瘤活性均显著、可于全身给药的PEOz化米铂脂质体（国内外首创），打破米铂剂型单一的局限，实现多元化给药，拓展临床新适应症，j既有科学意义又有临床应用价值。本项目拟在前期研究基础上，建立和或引入分子生物学的新技术与新方法（研究方法创新），开展系统的药效学、药动学、组织分布及抗肿瘤作用机制等研究，阐明PEOz化米铂脂质体入胞、胞内转运、降解活化、靶点结合、激活多种生物分子等作用机制，阐述PEOz化米铂脂质体体内生物学特征，为其他铂类药物纳米化研究提供科学依据与指导，还可为解决脂质体的“ABC”及“蛋白冠冕”的窘境提供新思路，其科学意义重大。

米铂广谱抗瘤，疗效确切，体外无活性，仅冻干粉针一种剂型（经肝动脉栓塞给药用于肝癌介入化疗，属局部用药范畴）。鉴于米铂独特的化学结构与不能直接全身给药的特点，结合已有自主知识产权的磷脂材料PEOz-DSPE（专利已授权）的特性，设计并成功构建载药量高、体内外抗肿瘤活性均显著、可用于全身给药的米铂脂质体（国内外首创），打破米铂剂型单一的局限，实现多元化给药，拓展临床新适应症，既有科学意义又有临床应用价值。本项目完成了米铂脂质体的构建与表征，开展了体内外抗肿瘤药效学评价、初步的组织分布及药代动力学等研究，建立和或引入分子生物学的新技术与新方法，完成了米铂脂质体入胞、胞内转运、激活的生物分子等抗肿瘤作用机制研究，为其他铂类药物纳米化研究提供了科学依据与指导，其科学意义重大。该项目已实现科技成果转移（技术转让），成交金额1050万元，有望再用5年的时间投入临床使用。