多功能病毒样颗粒用于恶性胶质瘤非侵入性脑内成像和靶向治疗

Malignant glioma is the most common type of primary malignant tumor in brain. The diagnosis and treatment of malignant glioma remains challenging because of the special location in cranial cavity, highly infiltrative growth of malignant glioma cells, low specificity of current chemical drugs and low permeability of the blood-brain barrier (BBB). Finding a way to deliver therapeutic agents overcoming the BBB to target the glioma while image the tumor area with high precision is an urgent demand. This project will carry out the research of malignant glioma imaging and targeted therapy via intranasal administration using multifunctional viral nanoparticles, in order to realize the non-invasive targeted theranosis of malignant glioma. We will construct a self-assembly multifunctional virus-like particle of Simian virus 40 (SV40) by displaying glioma-targeting function unit and nose-to-brain-delivery-facilitating function unit on the surface, loading intratumor selectively releasing cytotoxic peptide and packing quantum dots inside. This newly built viral nanoparticle with functions of tumor-targeting, nose-to-brain delivery, controllable drug releasing and near-infrared imaging then will be used for mouse malignant glioma imaging and targeted therapy in vivo. This study will provide a non-invasive imaging and targeted therapy platform to malignant glioma theranosis, holding great significance for the diagnosis and treatment of malignant glioma.

恶性胶质瘤是发病率最高的脑原发性恶性肿瘤。由于恶性胶质瘤位置特殊、对脑实质的高浸润性、化疗药物缺乏特异性、血脑屏障对药物递送的阻碍等原因，其诊断和治疗仍面临极大挑战。如何突破血脑屏障，向肿瘤组织靶向给药，并对肿瘤组织浸润范围精准识别，是恶性胶质瘤诊断和治疗中亟需解决的问题。本申请将开展多功能病毒纳米颗粒经鼻递送用于恶性胶质瘤标记成像和靶向治疗的研究，以期实现脑恶性胶质瘤非侵入性靶向诊疗。拟构建自组装多功能SV40病毒样纳米颗粒，使其表面展示肿瘤靶向识别功能单元和促进经鼻至脑运输功能单元，内部携带在肿瘤内选择性释放的细胞毒性肽，并包装近红外荧光量子点，获得具有靶向、可经鼻至脑、可控释药以及近红外荧光成像等多重功能的SV40病毒样纳米颗粒探针，并用于小鼠活体内脑恶性胶质瘤的标记成像和靶向治疗。本研究将为恶性胶质瘤提供非侵入性脑内成像和靶向治疗新技术，对恶性胶质瘤的诊断和治疗具有重要意义。

非侵入性脑内成像和靶向治疗是恶性胶质瘤诊疗中亟需解决的难题。本项目利用猴空泡病毒SV40的病毒样颗粒，通过在病毒样颗粒上融合组装多种功能性分子，并在内部包装量子点，构建了具有经鼻入脑、荧光标记、靶向和杀伤等多种功能的纳米颗粒，经鼻递送用于恶性胶质瘤非侵入性标记成像和靶向治疗。利用猴空泡病毒SV40主要衣壳蛋白VP1病毒样颗粒的自组装体系，在VP1 DE环上插入胶质瘤细胞靶向肽CGKRK，并包装量子点，获得了表面修饰靶向肽的颗粒；在VP1 N端连接可被组织蛋白酶B特异性切割释放的蜂毒肽，实现了该纳米颗粒对于胶质瘤细胞的杀伤功能；在颗粒表面HI环进一步展示辅助运输肽狂犬病毒G蛋白衍生肽，在小鼠活体水平基于脑内荧光成像验证实现其经鼻入脑效果等，成功构建了具有经鼻入脑、荧光标记、肿瘤靶向的多功能病毒样颗粒。该多功能病毒样颗粒为恶性胶质瘤提供了非侵入性脑内成像和靶向治疗新材料和新技术，对恶性胶质瘤的诊断、外科切除和治疗具有重要意义。在完成以上计划任务之外，构建了一种精准靶向及细胞核内调控释放纳米载药体系，提出了一种纳米药物在肿瘤细胞内精准核内靶向递送和智能调控释放的新策略；也构建了一种新型基于肠道病毒71型的靶向恶性胶质瘤新型溶瘤病毒。相关研究成果在Molecular Therapy、ACS Applied Materials & Interfaces、Advanced Therapeutics等发表文章7篇。项目执行期间，项目负责人获国家杰出青年基金、国际先进材料协会杰出科学家等资助或奖励。