基于肿瘤微环境修复和治疗的纳米递药系统与肿瘤微环境修复机制研究

Crosstalk between neoplastic and stromal cells contributes to tumor growth, progression and recurrence. Tumor microenvironment provides appropriate conditions for tumor growth and metastasis, and builds a “fence” to resist tumor treatment. In our previous study, we found that dexamethasone combined with antitumor drugs in nanoscale delivery system which possessed procedural releasing specialty, acted on tumor microenvironment and neoplasm, remodeled or re-educated the tumor microenvironment, significantly inhibited tumor growth and metastasis. Based on the characteristics of the tumor microenvironment and the mechanism of multiple targets treatment for tumor, with dexamethasone and zoledronate as the main drugs, we build a novel nano-drug delivery system for specific targeting to M2 macrophages and tumor cells. The nano-drug delivery system has diversified abilities on remodeling the tumor microenvironment, such as modifying of inflammatory cytokines and monocyte, activating the immune system, reversing immunosuppression and blocking immune escape, decreasing angiogenesis, promoting vascular perfusion, and reducing tumor high interstitial fluid pressure. So the “fence” is pulled down and tumor is exposed to drugs, paving the way for tumor therapies in multimodality and synergy therapeutic mechanisms. Meanwhile, the nano-drug delivery system could reduce the drug distribution in normal tissue, and minimize drugs dosage, therefore to reduce the side effects of drugs. According the crosstalk between tumor and its microenvironment on the molecules, cells, tissues, and whole animal levels, we engage to obtain a number of originality researches in the nano-drug to improve the effect of tumor treatment, and to improve the international competitiveness in the nano-medicine filed.

肿瘤微环境与肿瘤相互作用形成了有利于肿瘤生长、转移、复发的条件，构成抵抗肿瘤治疗的壁垒。我们在研究中发现，地塞米松与抗癌药物联用的纳米递药系统，程序性释放，修复肿瘤微环境，显著地抑制了肿瘤生长和转移。基于肿瘤微环境的特点和多靶点治疗的机理，我们以地塞米松和唑来膦酸为主要的模型药物，构建特异靶向M2型巨噬细胞和肿瘤细胞的多功能纳米递药系统。首先修复肿瘤微环境，调节肿瘤微环境中的炎性因子和细胞，激活免疫系统，逆转免疫抑制与阻断免疫逃逸，抑制血管新生，增加肿瘤血管灌注，降低肿瘤的间质液压，拆掉“壁垒”。随后针对肿瘤细胞和肿瘤微环境进行多靶点治疗，协同提高肿瘤的治疗效果，降低毒副作用。在分子、细胞、组织和整体动物水平上开展肿瘤和微环境交互作用的研究，在纳米药物提高肿瘤治疗效果领域取得一批原创性的重要研究成果，提高我国在纳米生物医药领域的国际竞争力。

肿瘤微环境与肿瘤细胞相互作用,共同促进肿瘤的生长与转移。肿瘤微环境不但阻碍药物对肿瘤细胞杀伤，也会通过分泌细胞因子、合成蛋白来影响肿瘤细胞的生存状态，并能协助肿瘤细胞逃避人体的免疫监视，形成治疗抵抗，制造适于肿瘤发展和转移的“生存微环境”。本项目基于肿瘤微环境与肿瘤的关系，研究肿瘤微环境修复，联合肿瘤细胞杀伤药物，提高抗肿瘤效果。.例如，微环境调控药物地塞米松和细胞毒性药物多西他赛的序贯释放脂质体实现促进抗肿瘤药物递送的两个目标:调节肿瘤间质和促进药物在肿瘤中的渗透和积累，使更多的药物能在肿瘤内有效杀伤肿瘤细胞，并将全身毒性降至最低。利用双波段疗法，肿瘤相关成纤维细胞抑制剂破坏微环境与肿瘤细胞的相互作用，修复肿瘤微环境，联合胶束递送抗肿瘤药物多西他赛，对实体瘤实施“双重打击”。基于化学药和小干扰RNA不同抗肿瘤机制，以肿瘤微环境敏感的穿膜肽修饰新型三层核壳结构的纳米粒，共递送沉默VEGF基因的siRNA与化疗药物紫杉醇，增强载药纳米粒的肿瘤组织特异性，促进肿瘤细胞对纳米粒的摄取，协同增加治疗效果。针对肿瘤免疫抑制微环境中的Treg，将靶向于Treg的anti-GITR抗体与增效光疗策略相结合，促进免疫原性细胞死亡，消除肿瘤免疫抑制，激活有效的免疫功能，增强对原发肿瘤和远端转移肿瘤的治疗。针对肿瘤乏氧微环境，设计构建基于白蛋白纳米诊疗探针，增强脑胶质瘤多模态成像和治疗效果等等。.这些系列研究对肿瘤与微环境的相互作用机制以及肿瘤纳米靶向治疗和诊断的研究具有重要的参考价值。这些发现为克服肿瘤递送障碍提供了思路，并为提高纳米药物的抗肿瘤疗效提供了合理的策略，具有实用价值。研究的部分内容在Journal of Controlled Release, Biomaterials, ACS NANO, Acta Pharmaceutica Sinica B, NPG Asia Materials等学术期刊发表。