原位捕获抗原的高效递送系统用于联合免疫疗法与光动力疗法抗三阴性乳腺癌的研究

三阴性乳腺癌是乳腺癌中恶性程度最高的一个亚型，目前临床上缺少有效治疗方案。本项目拟构建基于超支化聚氨基酯的原位捕获肿瘤抗原纳米载体系统，用于携载W-peptide、CpG ODN与Ce6，以期联合免疫疗法与光动力疗法靶向治疗三阴性乳腺癌。纳米共载体系通过EPR效应到达肿瘤组织，并在肿瘤部位高MMP-2的微环境中有效释放Ce6和W-peptide，Ce6经激光照射有效杀伤肿瘤细胞并促进肿瘤细胞释放肿瘤特异抗原，触发有效的抗肿瘤免疫效应，抑制远端肿瘤和肺转移瘤。W-peptide能够招募抗原提呈细胞进入肿瘤部位，超支化聚氨基酯负载的CpG ODN通过胞吞有效进入抗原提呈细胞，增强抗原递呈与非特异性免疫。同时超支化聚氨基酯可以在肿瘤部位原位捕获光动力治疗诱导产生的肿瘤特异性抗原并被抗原提呈细胞有效摄取，增强抗肿瘤免疫效应，从而成功地增强了光动力治疗的远端效应及光动力治疗免疫联合疗法的抗肿瘤疗效。

Triple negative breast cancer is one of the most malignant subtypes of breast cancer, and currently there is no effective clinical therapeutic strategies. Therefore, it is of great significance to explore effective treatment strategies for triple negative breast cancer. In this study, we construct a nanocarrier system based on hyperbranched poly(β-amino ester) to capture tumor antigens in tumor sites and the nanosystem is designed to carry W-peptide, CpG ODN and photosensitive molecule chlorine6 (Ce6), thus hoping to realize the targeted therapy on triple negative breast cancer by combining immunotherapy and photodynamic therapy. In vivo, it can reach tumor tissues through the enhanced permeability and retention (EPR) effect, MMP-2 cleavage sensitive peptides to release Ce6 under high MMP-2 tumor microenvironment, then with laser irradiation leading to high cell cytotoxicity and induced immunogenic cell death with enhanced immunogenic signaling molecules release to promote antitumor immune effects and then inhibit distant tumors and lung metastases. On the other hand, MMP-2 cleavage sensitive peptides to release W-peptide which recruit antigen-presenting cells into tumor sites, and hyperbranched poly(β-amino ester) -loaded CpG ODN enters dendritic cells through endocytosis, enhancing antigen presentation and nonspecific immunity. Meanwhile, hyperbranched poly(β-amino ester) can capture the tumor-specific antigen induced by photodynamic therapy at the tumor site and be phagocytosed by antigen-presenting cells to enhance the antitumor immune effects, thereby effectively suppress the distant tumors and promote antitumor effects by combining photodynamic therapy and immunotherapy.