仿生自组装干扰素γ递送囊泡的构建及促抑瘤作用研究

Interferon-γ (IFN-γ) is one kind of important cytokines with multiple-effectiveness. Despite its potential therapeutics roles for cancer immunotherapy, the widespread use of IFN-γ in clinics suffers from some inherent limitations, mainly its short circulation halftime and serious side effects on some non-target tissues. Liposomal formulations for IFN-γ delivery have been reported by several researchers. Unfortunately, the loading efficiency was low due to its bulk size and relatively poor stability of IFN-γ. How to deliver IFN-γ with a stable and high concentration at tumor is a great challenge to elicit the desired response. With the aim to overcome these problems, we will design and synthesize several novel series of amphiphilic polyphosphazenes containing lipid-mimic hydrophobic side groups and orthoester side groups and construct biomimetic self-assembled polymeric vesicles based on the biomimetic concept of interaction between lipid and protein in cell membrane. By taking advantage of the interaction between lipid-mimic hydrophobic groups and IFN-γ, high IFN-γ loading efficiency of vesicles is expected. Due to the pH-responsive hydrolysis of orthoester groups, IFN-γ release in tumor tissues and tumor cells can be controlled. In addition, a popular chemotherapeutics 5-fluorouracil (5-FU) is co-loaded into vesicle with IFN-γ since IFN-γ can induce the metabolic transformation to produce more active products of 5-FU. As a consequence, a novel vesicle system for IFN-γ delivery will be achieved with the unique advantages such as effective loading, stable delivery, pH-responsive release, synergism action of immunotherapy and chemotherapy with significantly improved anti-tumor effect in vivo. In this project, the relationship among polymer chemical structure, physicochemical properties of vesicles and anti-tumor effect of vesicles will also be clarified. The pharmacological mechanism of IFN-γ loaded in vesicles will be discussed. This project will contribute some new ideas and experimental evidence for the application of IFN-γ in tumor therapy.

干扰素γ（IFN-γ）是一种多效能细胞因子，在肿瘤免疫治疗中具有潜在应用价值，但是由于生物半衰期短且常产生毒副作用，临床应用受到很大限制。脂质体等纳米载体通过肿瘤EPR效应靶向递送IFN-γ是解决上述问题常用手段，但是IFN-γ本身分子量大和稳定性差导致载药困难，影响其体内药效发挥。为此，本项目拟参考细胞膜中磷脂与蛋白相互作用，根据仿生原理设计合成以类磷脂和原酸酯为疏水基的系列两亲性聚膦腈，构建仿生自组装囊泡。借助类磷脂与IFN-γ相互作用提高囊泡的载药能力，而原酸酯具pH响应水解性可控制IFN-γ的释放；同时共载5-FU，通过IFN-γ促进5-FU活性代谢产物转化以提高化疗效果，最终获得免疫治疗和化疗协同作用具有显著体内促抑瘤效果的新型IFN-γ纳米递送系统。通过研究，阐明载体化学结构与囊泡性质的内在关系和规律，揭示载体介导的药效作用机制，为IFN-γ治疗肿瘤提供新思路及充分实验依据。

干扰素γ（IFN-γ）是一种多效能细胞因子，在肿瘤免疫治疗中具有潜在应用价值，但是由于生物半衰期短且常产生毒副作用，临床应用受到很大限制。脂质体等纳米载体通过肿瘤EPR效应靶向递送IFN-γ是解决上述问题常用手段，但是IFN-γ本身分子量大和稳定性差导致载药困难，影响其体内药效发挥。为此，本项目借鉴细胞膜中磷脂与蛋白相互作用，根据仿生原理设计合成以类磷脂为疏水基的系列两亲性聚膦腈，构建仿生自组装囊泡。借助类磷脂与IFN-γ相互作用提高囊泡的载药能力，并通过IFN-γ促进5-FU活性代谢产物转化以提高化疗效果，最终获得免疫治疗和化疗协同作用具有显著体内促抑瘤效果的新型IFN-γ递送系统。通过研究，阐明载体化学结构与囊泡性质的内在关系和规律，并将含类磷脂基团纳米囊泡的应用推广到其它生物大分子的递送，也表现出药物高效装载和促进药效的优势，为生物大分子药物的递送提供了新思路。研究成果以通讯作者发表SCI论文9篇，邀请会议报告2次，授权国家发明专利2项，培养博士生3名、硕士生2名、博士后1名。本项目按计划已完成，达到研究目标。