纳米载体系统同时输送针对肿瘤细胞和肿瘤干细胞的药物用于癌症治疗

Cancer stem cells (CSCs) are responsible for tumor initiation, growth, and development, which may be closely correlated to the efficiency of treatment and prognosis of cancer. Increasing evidences indicate that merely targeting the bulk non-CSCs enriches CSCs while non-CSCs may reprogramme to CSCs in the treatment. Thus, the development of drugs targeting CSCs will confront adverse conditions. Nanocarrier-based agents targeting cancer cells and CSCs may address this problem and enhance the efficacy of cancer therapy. This project will design nanocarrier that can deliver drug targeting cancer cells and drug targeting CSCs to tumor. We will utilize rationally designed nanoparticles to simultaneously deliver chemotherapeutic drug and therapeutic agents (small molecules or siRNA) that can block key signaling pathways implicated in self-renewal or differentiate CSCs to improve the sensitivity to chemotherapeutic drug and to efficiently eliminate tumor. We will investigate how nanoparticles mediate the influence of stemness of CSCs and drug accumulation and distribution in vivo. Meanwhile, the inhibition of tumor growth, percentage of CSCs in tumor following treatment, initiating ability of tumor cells, tumor recurrence and metastasis following the intravenous administration of nanoparticles will be examined. This project can provide novel and effective strategy for treatment of cancer.

肿瘤干细胞与肿瘤发生、发展、治疗及预后密切相关。单纯杀伤普通肿瘤细胞，易导致肿瘤干细胞富集；此外有研究证实，普通肿瘤细胞可转变成肿瘤干细胞，这使得针对肿瘤干细胞的药物研发面临挑战。利用纳米药物载体系统，同时输送针对肿瘤细胞和肿瘤干细胞的药物，可望提供新的解决方案，有助于增强肿瘤治疗效果。本项目拟构建纳米载体，同时将针对普通肿瘤细胞的药物及针对肿瘤干细胞的药物输送到肿瘤组织和细胞。项目将利用纳米载体输送化疗药物的同时，输送阻断肿瘤干细胞关键信号通路或促进肿瘤干细胞分化的小干扰RNA或小分子药物，以增加肿瘤干细胞对化疗药物的敏感性，更有效杀伤肿瘤。项目将研究纳米载体输送药物对肿瘤干细胞干性的影响，研究药物在体内的循环和分布，研究其抑瘤效应及对肿瘤干细胞比例、肿瘤恶性转移、复发的影响，从而揭示纳米载体同时输送针对肿瘤细胞和肿瘤干细胞的药物用于癌症治疗的优越性，为肿瘤治疗提供新的有效途径。

本项目旨在发展多种纳米载体系统输送药物用于肿瘤干细胞治疗，开发了多种针对肿瘤干细胞的治疗策略，实现了对肿瘤治疗效果的有效提升。主要成果包括：（1）阻断肿瘤干细胞维持生存信号通路；（2）促进肿瘤干细胞分化；（3）调控肿瘤干细胞糖代谢；（4）增强肿瘤干细胞化疗敏感性。基于这些纳米载体策略，我们实现了同时杀伤肿瘤细胞和肿瘤干细胞，为肿瘤治疗提供新的有效途径。相关研究成果在Biomaterials、J. Controlled Release、Adv. Drug Delivery Rev.等SCI刊物上发表研究论文13篇，培养博士生8人、硕士研究生3人。完成了预期目标。