光响应序贯式递药系统化疗、抗血管生成和抗MDSC多模式肿瘤治疗研究

抗肿瘤联合治疗纳米递送系统是当前纳米药物研究的热点领域。现有的研究多是将具有药理学协同作用的药物共同递送至肿瘤细胞内，然而，当联合递送的药物的作用靶点分别位于肿瘤细胞内和细胞外时，则需发展可序贯式递送药物（sequential drug delivery）的纳米系统。本项目在前期工作基础上，构建近红外光触发的新型序贯式递药系统，该系统具有近红外光（660 nm）快速响应（10 min）特性，药物分级递送的效率和性能显著优于已有文献报道。以B16F10黑色素肿瘤为模型，该系统可将化疗、抗血管生成治疗和抗MDSC（骨髓来源的抑制性细胞）免疫治疗等有机结合，实现肿瘤多模式联合治疗。本项目可为序贯式纳米药物递送系统的设计提供借鉴，也可为纳米技术肿瘤多模式综合治疗的基础和临床转化研究提供新的理论思路和指导，相关研究国内外未见报道，具有很高的创新价值。

“Combo” nanosystem that enables co-delivery of multi-modal therapeutics for efficient and targeted cancer therapy is one of the hottest fields in nanomedicine research. Most existing studies have focused on co-delivering drugs with synergistically pharmacological activity into tumor cells. However, the development of sequential delivery system is urgently required when the targets of the therapeutics locate in the extracellular and the intracellular compartment of tumor cells, respectively. In this proposal, a photoresponsive nanosystem is engineered for sequential drug delivery. The nanosystem is super-sensitive (10 min) to the irradiation of infrared light (660 nm), which triggers the rapid drug release for extracellular target (antiangiogenic and anti-MDSC immunotherapy) and quick size shrinkage for enhanced uptake by tumor cells and penetration in tumor tissues for intracellular target therapy. Both the efficiency and the performance of the first- (extracellular target) and the second- (intracellular target) order drug delivery are significantly superior to those reported in the literature. Using B16F10 melanoma as model, the nanosystem can smartly integrate chemotherapy, antiangiogenic therapy, and ani-MDSC immunotherapy. This innovative investigation will provide new theoretical ideas and guidance for the development of sequential drug delivery system, and the basic and translational research of nanosystem-based multimodal cancer therapy.