尺度“可塑”的纳米载体分级递送药物杀伤肿瘤细胞及肿瘤相关巨噬细胞的研究

Polymeric nanocarriers face multiple biological barriers in the process of delivering anticancer drugs in vivo, however, it varies for the requirement on the property of a nanocarrier to overcome each barrier. An ideal nanocarrier should be able to achieve multi-step cascade of responses to the tumor microenvironment. Therefore, it is critical how to design and establish a polymeric nanocarrier drug delivery system which can be subject to self-tailoring a variety of nano-features responsive to different microenvironment to overcome continuously multiple layers of biological barriers, and to improve the efficacy of drug delivery and anti-cancer treatment. Our previous study showed that a “from big to small” size-tailorable clustered nanocarrier can be disintegrated from a clustered structure into ultra-small nano-scale structures in response to pH change in a simulated tumor acidic environment, which is expected to continuously overcome multiple biological barriers in a staged manner. In this project, on the basis of the previous findings, we will optimize and construct the size-tailorable clustered nanocarrier through the design and synthesis of pH-sensitive polymeric nanoparticles for staged delivery of drugs into the tumor-associated macrophages (TAMs) and tumor cells, thereby achieving in both overcoming comprehensive in vivo delivery barriers and killing tumor cells as well as TAMs which are closely related to tumor development. The current proposal on the size-tailorable clustered nanocarrier delivery system will provide a new strategy for staged drug delivery and combination of cancer therapy and immunotherapy against cancers.

高分子纳米载体在输送抗肿瘤药物的过程中面临多重生物屏障，然而克服各屏障对载体的特性要求不尽相同，理想的载体应能对肿瘤微环境实现多步级联的响应。因此，如何设计、构建高分子纳米药物载体系统，在合适的微环境自我调节其纳米特性，连续克服药物递送的多重生物屏障，对提高药物递送效率和肿瘤治疗效果非常关键。我们前期研究初步表明，由大变小的尺度“可塑”集束化纳米载体在模拟的肿瘤酸度环境下从集束化结构崩解，释放小纳米尺度颗粒，可望连续克服药物递送多重生物屏障。本项目中，我们将在此基础上通过pH响应高分子载体的设计和合成，优化构建尺度“可塑”的集束化纳米载体，并实现药物分级递送至肿瘤相关巨噬细胞和肿瘤细胞，在综合克服纳米载体体内输送屏障和杀伤肿瘤细胞的同时，进一步杀伤与肿瘤发展密切相关的肿瘤相关巨噬细胞。本项目的尺度“可塑”的纳米载体研究将为药物分级递送，及化疗和免疫疗法相结合的肿瘤联合治疗提供新的策略。

通过高分子纳米材料发展肿瘤微环境敏感的药物递送体系，克服体内给药短半衰期、肿瘤组织富集渗透、肿瘤细胞摄取释放等诸多障碍，提高抗肿瘤治疗效果。尺度“由大变小”集束化纳米载体在肿瘤酸度环境下从集束化结构崩解，释放小纳米尺度颗粒，可望较好克服药物递送多重生物屏障；同时针对肿瘤免疫微环境中相关免疫细胞如肿瘤相关巨噬细胞（TAM）、T细胞、B细胞以及肿瘤细胞自身特性（如低pH酸性环境、组织缺氧、ROS）等进行联合干预、调控，发挥联合/协同抗癌治疗效应。本项目已合成、构建和表征尺度“可塑”的肿瘤酸度（pH）响应性集束化纳米载体药物载体用于输送化疗药物（铂类药物）和针对TAM的小分子药物（CSF-1R抑制剂BLZ945），并在细胞水平验证了集束化纳米载体系统在微酸性pH条件下释放小尺寸颗粒，递送抗癌药物杀伤肿瘤细胞；构建了多种肿瘤（包括乳腺癌、结肠癌和胰腺癌等）模型，证明了该纳米颗粒能够增强铂类药物在肿瘤组织富集，明确了集束化纳米载药颗粒在肿瘤组织的药物释放与靶细胞摄取效应；获得输送铂类化疗药和针对TAM的小分子BLZ945药物的纳米输送载体，验证了针对不同靶细胞的肿瘤治疗优势，为肿瘤治疗提供新手段；以上研究部分结果已整理1篇相关学术论文，进入投稿阶段；同时，进一步探索了结合基于ROS针对肿瘤组织缺氧靶点的联合抗癌治疗策略，以及基于人源化小鼠模型的纳米免疫学相关研究；相关论文发表于《Biomaterials Science》和《Immunotherapy》国际杂志。