具有靶向和量子点示踪功能的水溶性聚酯高分子键合药研究

The project was proposed to prepare a kind of water-soluble aliphatic polyester, which have reactive hydrophilic group (such as hydroxyl and carboxyl group) in the side chain. Furthermore, folic acid as targeting molecule and quantum dots as fluorescent labeling and tracing role could be conjugated in the terminal group. Anticancer drug could be conjugated to side groups on the polymer via stimuli-responsive chemical bond (such as hydrazones, ester or disulfide), in order to controll the drug release behavior under specific physiological microenvironment (such as low pH, reducing environment). And finally, a novel anticancer drug carrier and conjugate were prepared with good water-solubility, biocompatibility, and biodegradability, which provides several unique properties such as targeting delivery, fluorescent labeling and tracing role, and intelligent release. The self-assembly, drug release assessment and material degradation behavior in vitro should be studied. The cytotoxicity and cell-targeted behavior will also be conducted in vitro and vivo. Meanwhile, with fluorescence imaging technology through quantum dots, the endocytosis of cell, intake behavior, enrichment in the tumor cell and tissue, and the behavior of circulating in vivo should be studied, which should contribute to discover the mechanism and the influencing factors. These insights should provide more basis and guidance toward the design and development of novel drug carriers and dosage system for anticancer application.

本项目提出制备一种水溶性脂肪族聚酯，侧链键接具有反应活性的亲水基团（如羟基、羧基），在此基础上将叶酸靶分子和量子点通过化学修饰键合到聚合物链的端基上，以达到药物的靶向给药和荧光标记示踪作用，同时通过选择不同的化学键（腙键、酯键、二硫键）来进行抗肿瘤药物分子与聚合物侧基官能团的键合反应，以实现药物在肿瘤组织所具有的特定的生理微环境下的智能释放（如低pH，还原性环境），最终制备一种水溶性的、可降解和具有良好生物相容性的，具有靶向、示踪和智能释放功能的抗肿瘤药物载体和键合药，并对其自组装行为，体外药物释放行为和材料降解行为进行研究，通过体外细胞和体内细胞实验，对其细胞毒性和细胞靶向行为进行研究，并通过量子点的荧光成像，研究这载药体系的细胞内吞和体内摄入行为，和在肿瘤细胞与组织中的富集及体内循环行为，探讨其作用机理与影响因素，为进一步设计与制备新型药物载体和给药体系提供依据和指导。

合成具有反应活性官能团的脂肪族聚酯，制备可降解的、具有亲水性和良好的生物相容性，具有靶向、示踪和智能释放功能的抗肿瘤药物载体和键合药，实现构筑肿瘤诊断治疗一体化纳米平台(theranostic nanoplatforms) 是本项目的主要目标。通过课题组的努力，我们制备了以生物素为靶分子，CdSe/ZnS 量子点作为荧光示踪探针，不同的化学键（酯键、腙键、二硫键）作为抗肿瘤药物分子与所合成的官能化的两亲性脂肪族聚酯聚合物之间的键合反应，得到了多种聚合物键合药的纳米化平台，测试结果表明我们制备的聚合物前药纳米体系对癌细胞有很好的抑制作用，量子点的示踪效果也非常明显，智能响应性好和良好的靶向性。主要研究内容包括：（1）具有靶向和示踪功能的可降解聚合物抗肿瘤药物前药-纳米阿霉素聚合物前药的制备；（2）具有诊断和治疗功能的紫杉醇前药纳米颗粒的制备；（3）具有pH敏感响应性的可降解的紫杉醇前药的制备；（4）具有氧化还原响应性的两亲性嵌段共聚物紫杉醇前药的制备；（5）具有肿瘤靶向功能和pH响应性的阿霉素键合药的制备；（6）具靶向和氧化还原响应性的喜树碱前药的的制备；（7）基于mPEG和侧醛基官能化的PCL组成的两亲性嵌段共聚物作为具有pH响应性药物载体的研究；（8）基于聚ε-己内酯水溶性紫杉醇前药的制备。通过本项目的四年的实施，目前已发表标注基金资助的论文7篇，投稿3篇，申请中国专利10项，已经授权3项。在本项目的资助培养下，已有7名硕士研究生顺利毕业。