外泌体介导的超小铁氧颗粒用于三阴性乳腺癌的靶向诊疗研究

Triple-negative breast cancer (TNBC) is the most terrible cancer threatening the health of women. The fast development of nanomedicine provides a new strategy in early detection and effective therapy of TNBC. Based on the previous successful synthesis of various MRI-based theranostic nanoagents for effective cancer treatment, this project aims to design and synthesis of ultra-small superparamagnetic iron oxide (USPIO) nanoparticles with positive contrast for MRI and TNBC cell-derived exosomes with therapeutic siRNA loading (targeting and therapeutic) as the multifunctional T1-weighted MRI contrast agent for simultaneous early diagnosis and siRNA-based efficient therapy of TNBC, which can enhance the MRI signal intensity and suppress tumor growth concurrently. Our preliminary research results have demonstrated that these novel un-targeted USPIO nanoparticles have superior T1 contrast effect and are featured with high dispersity in vitro. The potential advantages of isolated exosomes have also been further identified by the presence of specific markers on the membrane, which provides the solid experimental data on the smooth progress of this project. This project, which innovatively combines nanomedicine with clinical biomedical requirements, is expected to provide a paradigm to augment targeted-TNBC and accomplish the simultaneous high-performance MRI-based imaging diagnosis and treatment of TNBC.

三阴性乳腺癌（TNBC）严重威胁女性生命健康。纳米生物技术的发展为实现TNBC早期诊断及高效治疗提供了新的策略。研究团队前期成功研制出多种MRI纳米诊疗剂，显著提高了MRI造影性能及肿瘤疗效。在此基础上，本项目将设计和制备具有T1加权MRI造影功能的超小铁氧体纳米颗粒，结合靶向TNBC并具有治疗作用的外泌体，构建一种高效的TNBC靶向、T1加权MRI成像和肿瘤治疗一体化的新型多功能MRI分子影像探针。本项目将调控铁氧体纳米颗粒的微观结构，优化并评价靶向、治疗型TNBC外泌体的性能，从而实现TNBC靶向（外泌体靶向）、基因药物运输（小干扰RNA基因治疗）和高分辨率成像（T1加权MRI成像）的多功能诊疗一体化分子探针，实现TNBC的精准诊断与治疗。本项目利用纳米生物技术提高TNBC的靶向诊断和疗效，力争实现对TNBC的MRI早期诊断和有效治疗。

纳米催化药物在抑制肿瘤进展方面具有巨大潜力。研究团队将乳酸氧化酶(LOD)包载超小超顺磁性氧化铁纳米颗粒(USPION)，实现乳腺癌纳米催化治疗及T1加权MRI成像一体化。同时体外引入超声协同增强肿瘤纳米催化反应，初步构建了高效的乳腺癌纳米治疗体系。团队成功构建智能双金属型金属有机框架纳米系统，促进高效的基因传递和表达，通过内源性RNA干扰和外源性酸性物质的双重效应提高细胞内的酸代谢，进而诱导细胞凋亡和铁死亡初步实现三阴性乳腺癌纳米催化治疗。利用免疫印迹法及转录组测序分析得到该智能纳米体系基因治疗机制。研究团队成功构建了高生物相容性的新型T1加权MRI造影剂，初步实现乳腺癌纳米催化治疗，以及实现了对三阴性乳腺癌模型的高效纳米催化协同基因治疗，并探索并完善了其相关治疗机制，具有临床转化意义。