无机纳米粒子/转铁蛋白复合载药体系的设计合成及其针对脑胶质瘤的高效诊疗研究

Inorganic nanoparticles play important roles in cancer diagnosis and treatment, but the issues of biodegradable property, dispersion and stability in physiological medium have restricted the further clinical application. Aiming for the low efficiency problem existing in the current clinical treatment of glioma, it is proposed to design and synthesize the biodegradable and targeted transferrin based inorganic nanoparticles drug delivery systems (DDSs) by using the characteristics of high expression of the transferrin receptor on the surface of glioma cells and blood brain barrier (BBB). The influence of different sizes of composite DDSs on the performance of acrossing BBB will be investigated to obtain the optimize size for highly efficient targeting of brain glioma. The optimized particle size of DDSs, combining with transferrin targeted features enables them with high dispersion and stability to meet the basic requirements of clinical intravenous, on one hand, and endows them high efficiency through BBB and active targeting enrichment in glioma tissues on the other hand. Herein, two types of novel transferrin/inorganic nanoparticle composite DDSs will be constructed via a modified self-assembly process, including (1) Fe3O4@DOX@Tf-mPEG nano DDS with ultra-small size of Fe3O4 nanoparticles and chemotherapeutics DOX co-loaded into transferrin carrier to achieve the enhanced performance of T1-MRI and concurrently targeted chemotherapy; and (2) Bi2S3@DOX@Tf-CAT nano DDS with bismuth sulfide nanoparticles, DOX, and catalase co-loaded into transferrin carrier to realize the enhanced performance of CT imaging guided the synergy of oxygen radiotherapy sensitization and chemotherapy. Detailed biological safety evaluations will be conducted. The active targeting mechanism and the role of nanometer size effect on crossing the BBB will be investigated. Also the effect of optimized composition/structure design on the synergistic mechanism of efficient tumor treatment will be revealed. This research, as we believed, will bring new train of thought and scientific support for more safety and more efficiency in the clinical application of the brain glioma therapy.

无机纳米粒子在肿瘤诊断与治疗中发挥着重要作用,不过其生物可降解性,生理介质中的分散性、稳定性等问题一直制约着其临床应用。本项目围绕当前脑胶质瘤治疗存在的效率低等难题，提出利用脑胶质瘤细胞和血脑屏障细胞表面转铁蛋白受体高表达这一特征，筛选高生物相容性的无机功能纳米粒子，设计制备生物可降解、基于转铁蛋白修饰的靶向型无机纳米载药体系。通过优化工艺参数，研究并筛选复合纳米颗粒穿越血脑屏障的合适粒径，同时结合转铁蛋白靶向特性，一方面赋予蛋白复合的无机纳米颗粒更高的分散性与稳定性以满足临床静脉注射基本要求，另一方面赋予其高效穿越血脑屏障，主动靶向富集于脑胶质瘤组织。设计合成具有T1磁共振成像与靶向化疗功能的超小氧化铁与转铁蛋白共组装的复合纳米载药体系；以及具有CT成像引导的氧增强型放疗增敏与化疗协同作用的硫化铋粒子，过氧化氢酶与转铁蛋白共组装的复合体系，系统开展其肿瘤诊疗效果研究与生物安全性评价。

本项目针对脑胶质瘤诊断及治疗中存在的临床难题，通过蛋白基无机纳米粒子的功能化设计，构建具有临床应用价值，能满足静脉注射基本要求的高分散、生物可降解的蛋白基纳米药物。经过4年的研究，成功设计合成出三类（白蛋白、铁蛋白、转铁蛋白）、十余种性能优良的蛋白基有机无机复合纳米诊疗平台。重点开展了以下三方面研究：（1）创新构建一系列具有主动靶向脑胶质瘤能力，具有微环境响应增强的T1磁共振成像、肿瘤组织深穿透功能与多种治疗模式的转铁蛋白基纳米制剂，成功实施对原位脑胶质瘤模型的高效靶向、实时MR成像增强与原位声动力治疗或精准化疗，系统开展生物安全性评价，揭示靶向复合载体及其纳米尺度对穿越生物（血脑）屏障的作用与机制。（2）兼顾蛋白基纳米制剂的生物安全性与功能性，构建了一类可在正常组织中快速代谢、在肿瘤组织高效富集的响应型蛋白基纳米诊疗一体平台，有效规避纳米颗粒长期滞留在正常组织中引发的安全隐患，并揭示其生物体内安全性与生物学机制。（3）针对高效精准肿瘤治疗，通过简便仿生矿化方法，创新构建有机无机复合的蛋白基多功能纳米制剂，用于打破肿瘤细胞内的氧化还原平衡，通过负载的MnOx组分氧化谷胱甘肽（GSH），降低GSH含量，提高顺铂的化疗效果，进一步抑制了GPX-4酶的表达，削弱肿瘤细胞抗氧化屏障。同时原位产生O2可用于缓解乏氧，在活体层面表现出良好的肿瘤治疗效果。为实现更安全、更高效脑胶质瘤治疗的临床研究及应用提供新的策略和科学支撑。相关研究发表标注课题号的中科院一区SCI学术论文27篇，申请专利4项，获授权2项，培养毕业博士研究生4人，圆满完后项目的预期目标与研究内容。