“续灌-触发”式脑靶向诊疗系统的研究

探索靶向调控脑肿瘤微环境诊疗系统对脑胶质瘤早期诊疗意义重大。本项目摒弃传统单一的重组脂蛋白，以吐温-80修饰的柔性重组脂蛋白系统为血脑屏障（BBB）高渗透载体，脂质锚定肿瘤靶向穿膜iRGD肽以攻克血瘤屏障（BBTB），采用物理包埋、siRNA压缩技术联合运载诊疗药物吲哚菁绿（ICG）和治疗型si-HIF-1α，构建“续灌-触发”式脑胶质瘤靶向的“光敏剂/基因”诊疗系统。该系统逐级穿透BBB及BBTB后，可在近红外触发下，诱导ICG荧光原位特异性诊断、经光化学反应产生高热量和单线态氧以及提高si-HIF-1α定位释放和转染效率等特质，实现脑胶质瘤原位高效、灵敏、特异地无损监测、诊断及光动力学/光热力学（PDT/PTT）联合基因沉默的肿瘤原位治疗。通过细胞水平及体内外药效实验，探讨该系统的脑胶质瘤的靶向续灌、触发诊疗机制，为脑胶质瘤的精准定位和早期诊断、靶向联合治疗提供新思路和新方法。

The exploration of glioma-targeted theranostic system response to brain tumor microenvironment is significant for early theranostics. We discarded conventional single lipoprotein-like nanoparticles, and a Tween-80-modified flexibly reconstituted lipoprotein system, as blood brain barrier (BBB) penetrating biomimetic nanovector is developed, with lipophilic anchor of iRGD peptide into the surface for overcoming blood-brain tumor barrier (BBTB). The model drug group of combination theranostics (indocyanine green, and si-HIF-1α) is loaded in the lipid core of lipoproteins by different carrying technologies such as physical embedding and siRNA compressing, to build a co-delivery system of photosensitizer and gene for anti-glioma synergistic theranostics based on the “continued irrigation and trigger” manner. The system could sequentially cross BBB and BBTB, and possess characteristics of the near-infrared triggered specific fluorescent diagnosis, photochemical reaction for yields of singlet oxygen and high calories, and enhaced si-HIF-1α located release, transfection efficiency induced by indocyanine green. It not only provides a new design pattern for glioma diagnosis in situ, but a new platform for the identical target site and co-therapy of photodynamic, photothermal therapy and RNA interference. The mechanisms of continuously irrigated barin-targeting, NIR-trigged theranostics will be investigated by in vitro and in vivo studies, which will provide a new strategy and technology on glioma-targeted theranostic combination research.