基于光热-免疫联合治疗的仿病毒纳米递送系统构建及抑制肿瘤转移研究

The combination of photothermal therapy and immunotherapy has shown great promise in treating patients with both primary tumors and metastases tumors. This project intends to design safe and efficient photothermal agent/immune adjuvant virus-inspired mimics nanoparticle delivery system. This nanovehicles is expected to offer the following benefits: (1) well-defined nanostructures for passive accumulation in solid tumor site by EPR effect, (2) surface charge reversal (negative to positive) under tumor extracellular pH (~6.8) for photothermal agent nanoparticle and immune adjuvant nanoparticle separation, (3) receptor-mediated targeting via coassembly with synergetic units to enhance tumor-specific cellular uptake mimicking viral internalization, (4) combination of photothermal therapy and immunotherapy to procedure and present tumor specific antigen to dendritic cells (DCs) in the tumor microenvironment, activation antigen-specific CD8+ T cells and triggering specific antitumor immunity, resulting in combined anticancer effects against primary treated and distant untreated tumors to inhibit cancer metastasis. To evaluate the performance of the virus-inspired mimics nanoparticle delivery system in vitro and in vivo test, respectively. In this study, to explore the possibilities of that inhibition of metastasis and growth of cancer by combination photothermal and immuno therapy via non-invasive treatment basing on virus-inspired mimics nanoparticle delivery system, in order to provide multi-functional, comprehensive clinical treatment for malignant tumor treatment.

光热-免疫联合治疗为恶性肿瘤原发灶及转移灶的共同治疗开启新的研究思路。本项目拟设计安全高效的仿病毒光热剂/免疫佐剂纳米共递送载体，通过EPR效应实现载体肿瘤组织高富集，利用微酸环境使之有效分离；导航配体实现光热剂纳米粒对癌细胞的主动靶向传输，以光热作用令其消融裂解、释放多种特异性抗原；与此同时，免疫佐剂纳米粒增强DCs对癌细胞多种抗原的摄取提呈，进而激活肿瘤特异性CD8+ T细胞诱导机体产生抗肿瘤免疫应答。本研究合成脂肽树状分子、构建模仿病毒外部结构及侵染过程的光热剂/免疫佐剂纳米共递送系统，通过体外实验及建立高转移性乳腺癌动物模型，分析该纳米递送系统杀灭肿瘤原发部位、转移部位癌细胞的能力，对其抑制转移的机制进行初步探究。本项目为光热-免疫联合治疗提供新的载体设计思路，探索以患者自身癌细胞多种特异性抗原诱导机体产生抗肿瘤免疫应答实现个性化治疗的可能性，对恶性肿瘤转移及免疫疗法具有重要意义。

多方法联合的治疗手段为恶性肿瘤原发灶及转移灶的共同治疗开启新的研究思路。本项目聚焦于联合治疗，结合肿瘤组织特异性开展了一系列纳米共递送系统的研究，完成了各项研究目标，解决了相关的科学问题。实现了肿瘤组织原位的化学-免疫联合治疗，探索了材料自身结构对抗肿瘤治疗的影响；同时利用光热-免疫联合治疗的手段实现了对原发灶及转移灶肿瘤的共同抑制，并对其抑制转移的机制进行了初步探究。本项目为多手段联合治疗提供了新的载体设计思路，对恶性肿瘤转移及免疫疗法具有指导意义。本项目资助的系列研究成果发表在Nanoresearch、Biomaterials Science、Science China Materials and Biomaterials等国际重要期刊共5篇（均标注本项目资助号），申请及授权国家发明专利共2件。