基于双器官窗口体系活体跨层次成像解析纳米颗粒代谢

Because of various barriers exist in the systemic delivery, the tumor accumulation of nanoparticles based drugs is still very low (in common less than 3%). Among them, the mononuclear phagocyte system (MPS) is a major barrier to the delivery. Investigating the factor which can avoid the loss of nanoparticles in the MPS, especially in liver and spleen, or enhance the delivery to tumor, is the key for developing high efficient drug in future. It has been no related reports on systemic visualization study now. However, due to the interaction between nanoparticles and regional immune cells is highly dynamic, and the deep anatomic property of liver and spleen, it challenging us to investigate this issue in a true environment comprehensively. We need useful imaging techniques on one hand, and also need systemic imaging window. Thus, in our project, we aim to establish a novel method based on a safe, systemic and intravital dual-organ abdominal imaging window, to dynamically visualize the interaction and movement of different lipid nanoparticles and immune cells in liver and spleen, which are major organs in MPS, in a cross-level (organ, tissue and cell) by using multi-photon microscopic imaging when combing with the whole-body fluorescence imaging and photoacoustic imaging. And revealing the mechanism of nanoparticles biodistribution, thus providing new insights for designing high tumor accumulation of nanoparticles based drugs in future.

由于各种天然屏障，基于纳米颗粒的药物在系统性给药时在肿瘤的摄取率仍非常低（通常＜3%）。其中，单核吞噬细胞系统（MPS）是运输时的一个主要屏障。解析哪些因素能避免在MPS-尤其是在肝脏、脾脏中的损失，抑或是增加到肿瘤组织的递送，都是日后开发高效纳米药物的关键。目前尚无相关系统性、可视化研究的报道。由于肝、脾的深层解剖学特性，纳米颗粒与区域免疫细胞相互作用是高度动态的，如何在真实环境下系统地研究仍是我们面临的挑战。一方面需要有效的成像技术另外也需要系统性的成像窗口。基于此，本项目拟建立一种安全、系统性的活体双器官腹部成像窗口新方法，基于此体系以多光子显微成像为核心技术结合整体荧光成像与光声成像，对不同脂质纳米颗粒在MPS中的主要器官-肝、脾中的相互作用、运动过程进行跨层次（器官、组织以及细胞）的时空光学动态表征，揭示纳米颗粒代谢规律，为日后设计高肿瘤摄取率纳米药物提供新知识。

本项目通过设计成像固定装置、改良显微窗口装置、优化手术方案以及建立一种结合活体成像的细胞相遇数理模型成功建立了一种安全、系统性的活体双器官腹部成像窗口新方法，基于此系统以多光子显微成像为核心技术结合整体荧光成像，对研发的适合跨层次成像的多种纳米颗粒在MPS系统中的主要器官代谢过程进行宏观以及微观的时空光学动态表征，揭示纳米颗粒代谢规律，为日后设计高肿瘤摄取率纳米药物提供指导。开发建立的双器官肝-脾成像窗口可同时系统性地长时程、动态光学表征肝脏以及脾脏。在机体内，器官之间是相互联系彼此调控的，如果只能对单一器官进行光学动态表征则无法真实反映肝脏与脾脏之间的关联。尤其是在国家针对“组织器官区域免疫特性与疾病”重大研究计划已经启动的前提下，开发的活体窗口体系能同时关注“非专职”免疫器官-肝脏以及“专职”免疫器官脾脏则更显得意义重大。本项目资助下申请的实用新型专利：一种动物活体成像盒有进一步产业化的潜力，为日后科学家活体成像研究肝脏提供了一种有力的工具。