新型聚乙二醇修饰小分子抗癌药物的研究

Small molecule anticancer drugs as the main chemotherapy drugs, have many shortcomings, such as poor water solubility, non-specific, easily filtered by kidney, and toxicity. To design a rational, high efficient drug delivery system is very important and urgent. Drug delivery systems to date also have many shortcomings, such as poor water solubility and biocompatibility of carrier, less targeting of conjugates, and uncontrollable drug-release. In this proposal, we are going to design and synthesize a group of novel multifunctional poly(ethylene glycol)s(mfPEG), which having similar physical and chemical properties as general PEG with typical structures and multiple functional groups, as drug carriers to overcome the limitation of general PEGs on the market which having less functional groups and simple structure. Conjugated the anticancer drug using a enzyme-cleavable peptide (such as F-S-I-P↓L-T-A) as linker, and conjugated a tumor-targeting agent, such as folate, RGD or antibody simultaneously to the multifunctional PEGs, followed with self-assembling of novel PEG-drug conjugates in aqueous solution, a novel PEG based targeting，enzyme-cleavable anticancer nanomedicine was prepared. Its antitumor effect for cancer cell in vitro and for xenograft tumor in nude mice in vivo are going to be studied and demenstated. Through these studies, we will not only deepen the understanding of the anticancer mechanism of small molecule anticancer drugs, but also will set up a platform for pegylation of low molecule drugs effectively to improve the research and development of pegylation of small molecule drugs, even antibody-drug conjugates and nanomedicine.

小分子抗癌药物作为目前主要的化疗用药，存在水溶性较差、非特异性、易被肾过滤、毒性大等缺点。建立合理、高效的小分子药物传输体系，显得特别重要和迫切。本项目针对目前传输体系存在的载体材料水溶性及生物相容性差，偶联物靶向性不高、药物难以控制释放等问题，拟设计、合成具有良好水溶解性及生物相容性、化学结构及活性官能团数量明确、可控的新型聚乙二醇作为载体材料，与小分子抗癌药物，如顺铂、阿霉素等通过一定的连接桥（如多肽F-S-I-P↓L-T-A）偶联，并与肿瘤靶向性分子，如叶酸、RGD或抗体（Fab')等偶联，以合成多种具有肿瘤靶向作用的聚乙二醇偶联抗癌药物。由于药物的疏水性，当载药量提高时，偶联药物可在水溶液中自组装成纳米药物。通过对此项目的研究，将有助于加深小分子药物在肿瘤治疗中作用机理的理解，建立聚乙二醇修饰小分子药物的研发模型，将促进小分子药物聚乙二醇化、甚至抗体偶联药物、纳米药物的研究和开发。

本项目针对目前传输体系存在的载体材料水溶性及生物相容性差，偶联物靶向性不高、药物难以控制释放等问题，拟设计、合成具有良好水溶解性及生物相容性、化学结构及活性官能团数量明确、可控释放的新型聚合物基，特别是聚乙二醇基药物载体。与小分子抗癌药物，如顺铂、白藜芦醇、阿霉素等，通过化学偶联或包覆的方法，合成了多种具有肿瘤靶向作用的聚合物基纳米药物。通过对此项目的研究，将有助于加深小分子药物在肿瘤治疗中作用机理的理解，建立聚乙二醇修饰小分子药物的研发模型，将促进小分子药物聚乙二醇化、甚至抗体偶联药物、纳米药物的研究和开发。本课题主要在于设计合成聚合物基药物载体，特别是聚乙二醇基药物载体，