智能靶向人工多泡体包载外泌体和化学药物联合抗肿瘤研究

Exosomes as the platforms carring specific proteins and genetic substances have attracted more and more attention due to their specific immunomodulatory effects in cancer treatment. Exosome release from living cells to surrouding enviorment is a series of complicated processes medied by multivesicular bodies, invovling film forming, inward budding and fusion with the cell membrane. Fabrication of the intelligent carriers to mimic the archetectures and functions of natural multivesicular bodies could not only improve the body's acquired tumor immunity by providing long-term and stable delivery of extenal exosomes, but also could achieve targeted delivery of anticancer drugs after vesicle modification. In this study, we propose the strategy to engineer bio-inspired artificial multivesicular bodies composed of biocompatable poly-L-glutamic acid. It is aimed that these antibody modified carriers can be used for targeted delivery of both exosomes and doxorubicin towards colorecatal cancer. Therefore, effective tumor treatment and further tumor regression could be realized through two routes as exosome stimulated tumor immune activation and doxorubicin-induced cancer cell killing. On the other hand, targeted delivery based on antibody modification allows delivery of these biological substances and drug molecules with high dosage and low side effect; moreover drug resistance of target cells would be reduced to increase drug unptake.

外泌体作为携带特异表达蛋白和遗传物质的整体具有特定的免疫调节作用，在肿瘤治疗中的应用受到越来越多的关注。活细胞向周围环境释放外泌体是通过其载体多泡体的成膜、向内出芽和与细胞膜融合等一系列过程实现。构建一种可以模拟多泡体结构和功能的智能载体，不仅可以长期且稳定的递送外泌体而增强机体的获得性肿瘤免疫，并且对此载体进行特异性修饰还可以实现抗肿瘤药物分子的主动靶向运输。我们首次提出利用优良生物相容性的多聚谷氨酸通过层层自主装技术构建具有仿生学功能的人工多泡体用于包载外泌体和阿霉素；以特异性抗体修饰该人工多泡体，从而实现针对结直肠癌的靶向性运输和抗肿瘤治疗。一方面，外泌体和阿霉素可以分别通过肿瘤免疫活化和对癌细胞的直接杀伤而实现高效肿瘤消退的目的；另一方面，以抗体引导的主动靶向不仅可以实现小副作用且高剂量的药物（生物信息分子和化学药物）递送，同时还可以降低靶细胞的耐药性增加其药物摄取量。

外泌体因其特有的结构和所荷载的完整的母细胞来源的特异性蛋白以及遗传性物质在生物医学领域受到越来越多的关注。利用这一具有特定生物学结构和生物学功能的整体作为抗肿瘤药物的载体，一方面可以极大程度的避免来自于机体清除系统的清除，另一方面通过外泌体所携带的生物信息物质实现基于整合化学治疗和免疫治疗的抗肿瘤联合治疗。为了实现这一目标，我们的研究工作重点围绕两方面展开：1）构建包载外泌体的囊泡结构（人工多泡体）智能平台及其荷载化学药物用于抗肿瘤的研究。2）结构功能完整的外泌体的获取及其抗肿瘤研究。