内核结构和组成对载药纳米胶束的体内传输和疗效的影响机制

The drug loading capability of polymeric micelles is always limited by the physical-chemical properties of their hydrophobic segments. And the reversible micelle-unimer transition also leads to low drug loading capability, low drug stability in blood circulation, and unsatisfied tumor targeting and penetration towards polymeric micelles. All of above-mentioned drawbacks have brought about great obstacle to the clinical translation of polymeric nanomedicines. To address this issue, we propose to make a kind of physical cross-linked micelle by addition of an additional hydrophobic polymer into the amphiphilic block copolymer micelle. Based on this method, we not only can easily encapsulate different types of anticancer drugs by introducing different hydrophobic polymers in the micelle core, but also can make the drug-loaded micelles more stable due to physical cross-linked character of the micelle core. Moreover, it is also possible to make intracellular stimuli-sensitive polymeric micelles by simply introducing the stimuli-responsive polymers in the micelles core. Finally, based on the detailed in vitro and in vivo studies, we hope to find out the relationships between the core structure (cross-linked or non-cross-linked) and composition (the types of polymers that added and the feed ratio of block copolymer and hydrophobic polymer) of mixed micelles and the drug loading/release behaviors of micelles, and the in vivo transportation and anticancer efficacy of drug-loaded micelles. It is believed that the results of this study would be beneficial for the development of next generation polymeric anticancer nanomedicines with more effective anticancer therapy but less side-toxicity.

高分子胶束对药物的担载性能往往受限于其疏水链段的理化性质，而且，其动态的胶束-单分子平衡状态也使得胶束的载药效率偏低，血液循环稳定性差，甚至肿瘤组织靶向、渗透效果也不强，从而大大制约了高分子载药胶束的临床转化。为此，本项目拟通过在两嵌段高分子胶束的基础上混合疏水性高分子制备具有内核物理交联的纳米复合胶束，这种复合胶束不仅可以通过改变所混高分子的类型来实现对不同性质抗肿瘤药物的高效担载，而且由于物理交联的存在，大大提高了载药胶束的稳定性。进一步通过引入响应性高分子，可以在提高药物担载性能和稳定性的同时,实现细胞内微环境响应性释放。最后，通过仔细的体外、体内对比研究，我们希望能够明晰胶束内核结构（有、无物理交联）和组成（混合疏水性高分子的种类和比例）对胶束的药物担载、释放性能，载药胶束体内传输效率和抗肿瘤治疗效果等影响的内在机制，从而为开发下一代高效低毒副作用的抗肿瘤纳米药物提供有益参考。

利用高分子纳米载体担载化疗药物形成抗肿瘤纳米药物能够有效提高药物的肿瘤组织靶向、增强抗肿瘤效果并且降低毒副作用。然而，由于化疗药物与高分子载体内核材料的理化性质匹配性差，导致载药效率较低以及载药纳米粒子稳定性差等问题，从而严重阻碍了高分子纳米药物的研发和临床转化。为此，本项目根据化疗药物的结构特点发展了多种化学/物理内核交联方式，以及通过在内核材料上引入多种能够与药物分子形成弱相互作用的功能基团，实现了化疗药物的高效担载，增加了纳米药物的稳定性，从而达到高效、稳定传输纳米药物，增强药物治疗效果的目的。具体研究成果如下：（1）发展了多种化学/物理交联方法，制备了多种内核交联的抗肿瘤纳米粒子，系统评价了不同内核交联方式对药物担载和释放，以及抗肿瘤效果的影响；（2）开发了一步聚合/交联制备内核交联的高分子前药纳米粒子，进一步增强了纳米药物的稳定性，实现高效的纳米药物传输；（3）进一步通过在内核材料上引入弱相互作用力基团，实现对药物的高效担载。其中，具有侧链含有2,4-二硝基苯基的二氧化硫前药高分子对阿霉素药物的担载效率可达97.3%，且该载药纳米粒子能够在细胞内还原物质GSH的作用下释放SO2，提升肿瘤细胞内的ROS水平，可用于克服肿瘤耐药。综上，在本项目的资助下，我们发展了多种内核结构交联方式以及功能化内核结构材料，成功实现了对化疗药物的高效担载和稳定传输，并初步探索了内核结构与肿瘤治疗效果之间的构效，该研究成果有望为纳米药物的研发和临床转化提供了有益参考；本项目顺利完成了预期的研究任务，共发表学术论文14篇，申请中国发明专利2项，其中已授权1项。