多功能可控释siRNA载体系统的构建及其对肿瘤微环境中巨噬细胞表型的调控作用研究

In view of the limitations of traditional treatment for tumor, especially for tumor metastasis, tumor immunology therapy has gained much attention in recent years. Macrophages in the tumor microenvironment play important roles in tumor immunoregulation process and its phenotypes is high relative to their antitumor activity. The goal of this study is to provide a safe and effective method for siRNA dilivery and down-regulate the expression of certain genes of M2 type macrophages in tumor microenvironment.This may recover the ability of M2 type macrophage to selicit tumor immunology.We designed a new multi-level carrier to break through several barriers in siRNA delivery in vivo and thereby increase the efficacy of siRNA-mediated gene silencing. In addition, the combination of MRI contrast agents and photosensitizers make it possible to monitor the real-time state of carriers and control the realease speed in target area.

鉴于传统治疗手段在对抗肿瘤特别是肿瘤转移中的局限性，肿瘤的免疫学治疗近年来得到了越来越多的关注。而肿瘤微环境中的巨噬细胞对于肿瘤免疫调节过程极为关键,其表型与抗肿瘤活性密切相关。本课题旨在发展一种更加安全高效的siRNA载体，并利用其将siRNA药物高效递送到肿瘤微环境中的巨噬细胞中，下调M2巨噬细胞相关基因的表达，恢复其抗肿瘤免疫活性。为了实现这一目标,我们设计了一种全新的具有多级构造的载体,使其可以顺利突破siRNA递送过程中的几个关键性生理屏障，提高转染的效率。此外，通过偶合核磁成像探针及光敏剂,能实现对载体体内状态的实时监控，并且可以达到利用外部的物理信号调控siRNA干扰部位及作用时间的目的。

鉴于肿瘤微环境中的巨噬细胞对于肿瘤免疫调节过程极为关键,其表型与抗肿瘤活性密切相关。如果能够开发一种能在体内肿瘤环境中有效发挥作用的核酸药物载体，就有望通过递送核酸药物调控巨噬细胞的表型，提高机体的抗肿瘤免疫活性。为了实现这一目标,我们设计了一种全新的多功能核酸载体，能够突破siRNA 递送过程中的几个关键性生理屏障，并能够在外部光线照射下，实现高效可控的siRNA递送，达到利用外部的物理信号调控siRNA 干扰部位及作用时间的目的。并初步评价了新型载体材料在对巨噬细胞表型调控中的作用。这些结果对于发展肿瘤免疫新技术、治疗克服传统治疗手段在对抗肿瘤特别是肿瘤转移中的局限性方面具有重要意义。