近红外II区荧光成像技术辅助的病毒纳米颗粒活体肿瘤靶向研究

Viral nanoparticles (VNP) are hollow spheres or tubes typically 20-200 nm in size assembled from viral capsid proteins. VNP has been extensively recognized as a category of natural nanomaterials for developing intelligent drug carriers, probes for in vivo imaging, tissue engineering materials, multifunctional theranostic platforms, etc. in recent years. Effective accumulation of VNP at the site of interest in the living body is a critical step in most in vivo biomedical applications of VNP. However, how the surface properties of VNP impact its in vivo distribution and behaviors remains to be elucidated. Ag2S quantum dot (QD), a new kind of nanoprobe with bright near-infrared II (NIR-II) fluorescence, can offer unprecedented performance in in vivo optical imaging. This proposal, which takes in vivo tumor targeting, one of the hottest topics in nanomedicine as a model, will systematically investigate the effects of varied surface co-modification patterns with polyethylene glycol (PEG) and tumor targeting ligands on in vivo distribution and the tumor-homing capability of VNP, with the aid of Ag2S-encapsulation-based NIR-II imaging technique, which is being developed in our lab. We will try to balance the immune shielding of PEG and the tumor recognization of targeting ligands, so that a significantly enhanced tumor-homing efficiency of VNP can possibly be achieved. The project will provide novel methodology and insights to the in vivo studies of protein nanostructures, reveal the rules how surface properties of VNP affect its in vivo behaviors, and pave the way for the breakthrough of nanomedicine enabled by such kind of materials.

病毒纳米颗粒（VNP），是由病毒衣壳蛋白组装形成的典型尺寸20-200 nm的空心球或管，近年来成为发展智能药物载体、活体探针、组织工程材料、多功能诊疗平台的热门天然纳米材料。如何有效的到达目标部位是VNP活体生物医学应用的一个关键问题，而目前对VNP活体分布行为与其表面性质关联性的认识还十分有限。Ag2S量子点是一种新型近红外II区荧光纳米探针，提供空前的活体成像性能。本项目针对最受关注的肿瘤靶向问题，在建立基于"Ag2S包装"的VNP活体成像方法的基础上，结合其他手段，系统研究不同的聚乙二醇和靶向分子共修饰模式对VNP肿瘤靶向性的影响，试图在前者的"屏蔽免疫清除"与后者的"肿瘤识别"功能之间找到平衡，以期显著提高VNP的靶向效率。本项目将为蛋白纳米结构的活体行为研究提供新的方法和思路，揭示VNP活体行为与表面性质之间的关联性规律，也为此类材料生物医学应用的突破奠定基础。

病毒纳米颗粒（VNP），是由病毒衣壳蛋白组装形成的典型尺寸20-200 nm的空心球或管，近年来成为发展智能药物载体、活体探针、组织工程材料、多功能诊疗平台的热门天然纳米材料。本项目严格按照既定目标和内容进行了如下研究并取得系列进展和成果：建立了基于量子点包装的病毒纳米颗粒NIR II区荧光活体成像技术，通过表面聚乙二醇（PEG）修饰，可视化揭示了SV40病毒纳米颗粒表面化学性质依赖的活体分布行为；进行了不同分子量的PEG和RGD肽对病毒纳米颗粒的可调节共修饰，实现了PEG“屏蔽免疫清除”与靶向肽“肿瘤识别”功能间的平衡，显著提高了病毒纳米颗粒的肿瘤靶向效率，PEG链长增加、RGD修饰均能提高病毒纳米颗粒的肿瘤富集量，并进一步揭示了病毒纳米颗粒表面修饰、表面蛋白冠、肿瘤靶向效率之间的关系；在迷你铁蛋白Dps纳米笼表面上对配体RGD进行了数目和位置精确可控的修饰，构建了六种模型，并对这些模型与细胞受体的结合能力、对神经胶质瘤细胞U87MG的靶向效率及对U87MG小鼠皮下肿瘤模型的靶向效率进行了研究，揭示了RGD表面分布模式依赖的肿瘤靶向性能。本项目为蛋白纳米结构的活体行为研究提供了新的方法和思路，揭示了病毒纳米颗粒活体行为与表面性质之间的关联性规律，为此类材料生物医学应用的奠定了一定基础。

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