多级纳米递送系统输运核酸类免疫激活佐剂增强实体瘤免疫治疗的研究

Dendritic cells (DC) are central regulators of immune-anticancer treatment, it is an important prerequisite to active the DC in tumor and sentinel lymph node for recognizing and killing tumor cells. Nucleic acid-based immunoadjuvant (such as CpG ODN) can promote the antigen presentation ability of dendritic cells and activation of T cells mediated tumor killing. Some challenges limit nucleic acid immunoadjuvant in vivo application, cooperation with nanoparticle can improve its stability and cellular internalization ability, there exist a series of complex biological barriers in the path of a nanoparticle from the site of administration to the site of action. In this proposal, we will develop a multiple tumor-microenvironment responsive multistage system for highly efficient nucleic acid-based immunoadjuvant delivery, to the DC in tumor site and sentinel lymph node simultaneously. Thus, for promoting the activation and antigen presentation of DC, enhancing antitumor immunotherapy efficacy. In the blood environment, the PEG surface offering stealth and protection, prolong blood circulation and decrease cell-particle interaction. Then, the tumor specific microenvironment triggers the size transforming and dePEGylation, that enable deep tumor penetration and transportation to the sentinel lymph node, realizing simultaneous deliver to DC in tumor and lymph node. Finally, the nucleic acid-based immunoadjuvant can be rapidly trigger-released in target cells to activate it and lead to immune system activation and tumor killing.

树突状细胞（DC）在肿瘤免疫治疗中发挥重要作用，有效激活肿瘤及引流淋巴结中DC是激活机体免疫系统识别并杀伤肿瘤的重要前提。一些核酸类免疫激活佐剂（如CpG，ODN）可以促进DC活化并提升其抗原提呈能力，促进T细胞介导的肿瘤杀伤。但核酸类物质难以直接用于体内，借助纳米载体虽然可以提升其体内稳定性及细胞摄取能力，但纳米载体仍需面临体内多重屏障以及无法有效递送至引流淋巴结等问题。对此，申请人基于前期工作，在本项目中拟利用肿瘤微环境响应性多级纳米载体，同时将免疫佐剂递送至肿瘤及引流淋巴结中的DC，促进DC活化并增强抗实体肿瘤免疫治疗效率。该载体在血液中有较大尺寸并PEG化，可保护佐剂并延长血液循环，降低正常部位DC摄取；进入肿瘤后肿瘤微环境触发小尺度颗粒释放并增强实体瘤渗透，穿透实体瘤致密间质并通过淋巴管转运至引流淋巴结，同时脱去PEG保护利于效应部位DC摄取；细胞内微环境触发佐剂释放，发挥效应。

通过激活自身免疫系统对肿瘤进行杀伤是目前研究的热点与难点，然而实体肿瘤中免疫抑制性微环境以及较低的抗原提呈效率都限制了肿瘤免疫疗法的最终效果。本项目针对这一难点，发展了基于肿瘤微环境响应性的多级纳米递送载体，能够高效将免疫佐剂CpG递送至实体胰腺癌肿瘤中。此外，多级纳米载体中的小尺寸正电荷颗粒可以有效携载免疫佐剂CpG进入肿瘤中的树突状细胞，从而树突细胞的活化，提升肿瘤抗原的提呈能力。通过研究表明，该递送体系能够极大增强肿瘤中树突状细胞中免疫佐剂的含量。此外，联合化疗药物阿霉素，该递送策略能够更加有效抑制肿瘤的生长，相比于阿霉素单药治疗，肿瘤生长抑制率有近60%的提升。更进一步，联合免疫检查点阻断剂PD1，则能实现十分优越的肿瘤生长抑制，相比于化疗药物单独处理在40天内小鼠全部死亡，该治疗策略即使在治疗后60天仍有20%小鼠存活。本项目的顺利实施，为发展肿瘤靶向性免疫佐剂的递送提供了一种策略，同时也证明通过协同化疗以及免疫佐剂和免疫检查点联合疗法，能够十分有效地对胰腺癌肿瘤进行治疗。

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