新型花形聚合物前药载体的设计、合成及其肿瘤靶向性能研究

项目名称： 新型花形聚合物前药载体的设计、合成及其肿瘤靶向性能研究

项目编号： No.51473072

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 一般工业技术

项目作者： 魏华

作者单位： 兰州大学

项目金额： 85万元

中文摘要： 抗癌药物和聚合物通过化学键合得到的聚合物前药载体，在癌症治疗方面显示出高效和低毒副作用的优势，有希望成为癌症治疗的新途径。而树枝形高分子具有的超支化结构和多功能化表面使其成为聚合物前药载体的理想候选材料之一，但其复杂多步的制备过程、高代数树枝形高分子因空间位阻效应引起的低药物键合率、表面修饰疏水药物导致的分子间聚集等缺点大大限制了其应用。本项目拟合成新型花形聚合物前药载体，它以环状聚合物为内核，以辐射状的高分子链段为臂，利用对肿瘤酸性pH敏感的腙键，将抗癌药物键合到其环状内核上，同时将对肿瘤具有良好靶向性的配体键合到其臂的末端，实现前药载体对肿瘤细胞的主动靶向。本项目将优化合成条件，研究花形聚合物多级组装行为，筛选出同时具有长循环半衰期和在肿瘤组织处良好渗透能力的花形聚合物的最优化组成和尺寸，揭示花形聚合物前药载体在体外和体内的抗癌效果，为发展一类新型前药载体奠定技术基础。

中文关键词： 花形聚合物；前药载体；可控活性自由基聚合；肿瘤酸性敏感；肿瘤靶向

英文摘要： Covalent conjugation of anticancer drug to polymer backbone forms so-called polymeric prodrug. This provides a powerful means for drug modification and represents a better approach for the construction of polymer therapeutics, motivating increasing attention for improved cancer chemotherapy with reducing off-site toxicity. Dendrimers are considered to be one of the ideal candidates for the construction of polymeric prodrug because of their low dispersity, nanosize, hyper-branched structure, and multiple functional groups on the surface for drug conjugation. But their progress has been hampered by several significant drawbacks. Synthesis of dendrimers is complex and multi-step, resulting low yield, restriction to smaller constructs, batch-to-batch variations, and difficulties in scale-up. Higher generations of dendrimers (>8) are difficult to prepare and drug conjugation efficiency is low due to increasing steric hindrance. In addition, conjugation of hydrophobic drugs to the dendrimer periphery have been reported to induce aggregation between dendrimer molecules resulting in dramatic increases in particle size. The goal of this project is to develop a new class of materials, called sunflower polymeric prodrug for tumor-targeted chemotherapy. Sunflower polymers are synthesized by using controlled living radical polymerization from a cyclic macro-initiator template from which rays are polymerized that radiate from the cyclic core. Sunflower polymers therefore combine the structural complexity displayed by dendrimers with the relative ease of synthesis of traditional linear polymers. We hypothesize that sunflower polymers can be optimized as drug carriers to provide preferential tumor delivery while maintaining effective tumor penetration. Anti-cancer drug, doxorubicin (DOX) is readily conjugated via pH-cleavable hydrazone linkages to functional monomers in the sunflower core, and targeting ligands, folic acid is decorated to the termini of polymer rays to increase uptake in cancer cells. We propose to optimize the synthesis condition, to prepare sunflower polymers of various sizes, to investigate hierarchical self-assembly behaviors of sunflower polymers, to determine optimal composition and size for tumor accumulation and penetration, and to functionalize the polymers for tumor-targeted chemotherapy delivery in vitro and in vivo. Successful completion of this project would lead to a delivery system that could be easily synthesized with controlled size and surface properties, functionalized with a range of targeting ligands, and conjugated to one or even multiple drug entities. This versatility allows the material to be tailored for specific cancer applications. Importantly, these materials will be well-characterized and easily scaled, facilitating eventual manufacturing and clinical translation.

英文关键词： sunflower polymer;pro-drug;controlled living radical polymerization;tumor acidic responsive;tumor targeting