基于淋巴结靶向的纳米肿瘤疫苗平台的设计及抗肿瘤机制研究

One of greatest challenges in oncology is eradicating cancer once it has metastasized due to its genetic heterogeneity and ability to evade traditional chemotherapy or targeted drugs. Therapeutic strategies against tumors by developing novel vaccine to promote immune responses are the great interest for their potential to destroy metastatic cancer, because of their low toxicity and broad applicability to diverse human cancers. To enhance the potency of the vaccine in promoting tumor immune responses, we will develop a novel therapeutic strategy to enhance vaccine targeting to lymph nodes, where immune responses are initiated. In this study, we will design and construct a biocompatible nanovaccine to selectively target lymph node and initiate tumor immune response by combination with the anatomical structure of lymph nodes and click chemistry reaction. We will synthesize a set of candidates for lymph node targeting, and determine limits and best strategies for lymph node targeting of antigens and adjuvants. The pharmacokinetics and tumor immune responses of lymph node-targeted nanovaccines in vitro and in vivo will be analyzed by imaging, staining, flow cytometry and western blotting analyses. The capacity of lymph node-targeted nanovaccines to enhance the anti-tumor effects will be investigated using tumor xenografts and tumor cells. This therapeutic nanovaccines are an attractive treatment and a broad application for cancer immunotherapy due to their potential as simple, non-toxic, systemic treatments for metastatic cancer.

利用机体自身的免疫系统预防和治疗恶性肿瘤，具有高特异性、低毒性、克服肿瘤耐药性等优点。淋巴结不仅是产生抗肿瘤免疫应答的主要场所，而且同免疫细胞的迁移、增殖和肿瘤转移密切相关。因此，设计具有主动靶向淋巴结能力的肿瘤疫苗具有很好的临床应用潜力。本研究将采用纳米技术，结合淋巴结独特的生理学特征和点击化学反应，设计并构建可靶向淋巴结的纳米肿瘤疫苗。拟通过对纳米疫苗的功能组分和结构的优化，实现对机体免疫系统的时序性调控，促进携带抗原和佐剂的纳米疫苗诱导免疫细胞激活，增强机体免疫反应和抗肿瘤疗效，控制肿瘤转移进程，降低肿瘤免疫耐受和疫苗的毒副作用，为纳米肿瘤疫苗的设计、制备、临床治疗提供理论依据和实验基础。

恶性肿瘤是威胁我国居民生命健康的头号疾病，而利用肿瘤疫苗通过激活或增强患者的免疫系统来识别和杀伤肿瘤细胞，具有高特异性、低毒性、克服肿瘤耐药性等优点。淋巴结作为抗肿瘤免疫应答的主要场所，设计具有淋巴结富集增强的肿瘤疫苗可以促进抗原呈递细胞成熟，有效增强肿瘤抗原呈递，提升抗肿瘤免疫反应，具有很好的临床应用潜力。因此，通过叠氮基团对淋巴内皮细胞进行表面修饰，构建了一种基于点击化学的淋巴结主动聚集系统，叠氮修饰的脂肪酸链作为前体为二苯并环辛炔修饰的脂质体提供靶点，以改善脂质体内包裹的抗原和佐剂的靶向输送。当装载肿瘤抗原和佐剂时，该疫苗体系在体内引起了增强的细胞反应，诱导更有效的抗肿瘤免疫反应并延长小鼠的中位生存期。此外，项目组还发展多种纳米疫苗体系或纳米药物体系。这些体系均可以对机体免疫系统进行调控，最终实现提升肿瘤免疫治疗效果的目的。