基于肿瘤血管正常化的纳米基因药物设计和机制研究

Tumor blood vessels are structurally and functionally aberrant, leading to tumor progression and inhibition of uniform drug distribution. NgBR, a cell surface receptor overexpressed in vascular endothelial cells and pericytes, has been reported to regulate angiogenesis during embryonic development and wound healing. However, the role of NgBR in tumor blood vessels remains unknown. In this project, we will screen the expression of vascular NgBR in various cancer types and design a tumor-responsive nanocarrier for delivery of small interfering RNA against NgBR. We will dynamically examine tumor angiogenesis and vascular normalization after NgBR knockdown, and subsequently investigate tumor growth, metastasis, different drug distribution, and combination therapeutic efficacy. Through integration of nanotechnology and tumor biology, this project will ultimately provide a novel tumor vascular target and a potential vascular-targeted nanomedicine. Strategies for tumor vessel normalization will provide clues for overcoming the bottlenecks in suppression of tumor metastasis and improvement of drug delivery.

实体瘤内部血管的形态、结构和功能异常，导致肿瘤恶性进展并阻碍抗肿瘤药物的渗透和分布。NgBR是一种高表达于血管内皮细胞和周细胞表面的受体蛋白，参与调控胚胎发育和伤口愈合过程中的血管新生，但有关NgBR在肿瘤血管中的功能尚无研究报道。本项目拟筛选血管NgBR高表达的肿瘤类型，构建肿瘤微环境响应性的纳米载体输送NgBR干扰RNA，实现特异降低肿瘤血管中NgBR的表达水平，并系统研究由此引起的肿瘤血管生成和血管正常化的变化，以揭示NgBR在肿瘤血管调控中的重要功能；同时将进一步研究抑制NgBR引起的肿瘤血管正常化对肿瘤生长、转移和抗肿瘤药物在肿瘤组织中的分布及疗效的影响。本项目将通过纳米技术与肿瘤生物学研究的有机结合，为肿瘤血管靶向治疗提供一个新靶点，并构建一种潜在的新型肿瘤血管靶向纳米基因药物，为解决肿瘤转移和药物输运等瓶颈问题提供新思路。

本项目筛选血管NgBR高表达的肿瘤类型，构建了肿瘤微环境响应性的纳米载体输送NgBR干扰RNA，实现了特异降低肿瘤血管中NgBR的表达水平，并研究了由此引起的肿瘤血管生成和血管正常化的变化，揭示了NgBR在肿瘤血管调控中的重要功能；同时研究了抑制NgBR引起的肿瘤血管正常化对肿瘤生长、转移和抗肿瘤药物在肿瘤组织中的分布及疗效的影响。通过纳米技术与肿瘤生物学研究的有机结合，为肿瘤血管靶向治疗提供了一个新靶点，并构建了一种潜在的新型肿瘤血管靶向纳米基因药物，为解决肿瘤转移和药物输运等瓶颈问题提供了新思路。