多糖基长循环脂质体的构建与载体的多功能集成

The feature of long-circulating in nanoscale drug carriers is the most important prerequisite for efficient targeted cancer therapy and becomes a key issue in the related fields for decades. PEG-based long-circulating liposomes have been widely used in clinic, but still exhibit toxic side effects and poor functionality. The aim of this proposal is trying to modify liposomes by polysaccharides as an alternative to PEG. Through the mild modification methods, polysaccharide-based long-circulating liposomes will be built based on the principle of self-assembly, and further integrated with properties of targeting, magnetic-responsive and controlled-releasing. Surface chemistry and multiple imaging methods will be utilized to study the mechanism of polysaccharide-based liposomes. In addition, the pharmacokinetics and pharmacodynamics will be assessed from cell and animal experiments, high efficient anticancer drugs for integrated cancer imaging and therapy will be screened. This proposal will gain better insight on natural polymers, functionalization of polymers and self-assembly, and provide useful information for developing more effective targeted anticancer drugs.

长循环性质是纳米药物载体满足高效靶向癌症治疗的首要前提，是相关领域专家几十年来一直关注的关键科学问题。针对目前临床上抗肿瘤药物的毒副作用和聚乙二醇(PEG)长循环脂质体功能性单一的不足，本项目提出采用易功能修饰的多糖替代PEG，通过温和的改性方法和运用自组装原理来构建多糖长循环脂质体，并在此基础上进一步集成生物靶向、磁响应、控制释放等多功能性质，采用表面化学方法和多元成像方法研究多糖脂质体的长循环作用机制，从细胞和动物水平进行药代学、药效学评估，筛选安全高效和诊疗一体化的抗肿瘤药物。项目的开展将丰富天然高分子、功能高分子和自组装化学的内容，为研发安全高效的抗肿瘤靶向药物提供实验参数和理论依据。

针对目前临床上抗肿瘤药物的毒副作用和聚乙二醇（PEG）修饰脂质体功能性单一的不足，本项目提出采用易功能修饰的多糖替代PEG，通过温和的改性方法和运用自组装原理来构建多糖修饰脂质体，并在此基础上进一步集成长循环、生物靶向、磁响应、控制释放等多功能性质。上述工作为天然高分子的功能改性提供了新的思路，充分认识了天然高分子与药物的作用机制，并在此指导下成功构建了其他高效的药物载体。创新性成果主要体现在以下几个方面： （1）构建了羧甲基葡聚糖（CMD）修饰的磁性脂质体，具有核磁成像、磁场响应释放药物功能，有利于诊疗一体化；（2）分别制备了PEG和CMD修饰姜黄素脂质体，发现CMD修饰不仅提高脂质体的稳定性，还能促进癌细胞对脂质体的吞噬，进而提高药效；（3）制备了负载近红外荧光染料ICG的CMD修饰脂质体，小动物活体荧光成像研究表明CMD修饰脂质体比PEG修饰脂质体具有更好的长循环性质；（4）设计并制备了两种具有类印迹功能的多糖修饰胶束，葡聚糖修饰的胶束使姜黄素的水溶性提高4个数量级，姜黄素的口服生物利用度也得到显著提高，而半乳甘露聚糖修饰的胶束能够选择性地靶向HepG-2肝癌细胞；（5）基于主客体化学合成了双亲水性多糖超分子聚合物——葡聚糖修饰聚乙烯亚胺，研究了它与多酚物质EGCG的共组装行为，组装得到的胶束能有效降低聚乙烯亚胺的细胞毒性，减缓EGCG的释放；（6）基于结冷胶的可注射性多功能水凝胶在生理温度下具有很好的可注射性和自愈合性质，可同时包覆抗肿瘤药物DOX和CuS纳米粒子，瘤内注射后在近红外光照射下可达到化疗和光热治疗的协同效果。我们顺利并超额完成了研究任务，并取得了多项积极的研究成果。