聚磷酸酯为亲水壳层的抗肿瘤纳米药物研究

How to improve the therapeutic effect anti-cancer polymeric nanomedicine has been a critical issue in the area of cancer therapy. The in vivo fate of nanomedicine has been proven to be closely related to its surface properties. Based on our previous research, we propose to study “how to control the in vivo fate of nanomedicine by regalating their surface properties and thereby to improve the ultimate anti-cancer therapeutic effect. We will synthesize various polyphosphoesters with different chemical properties and prepare nanocarriers with precisely tunable surface properties. We will investigate how surface properties of nanomedicine affect its in vivo blood circulation, tumor accumulation and clearance, extravasation and tumor penetrations, as well as the internalization by tumor and stromal cells. The relationship between their in vivo fate, surface properties, and protein adsorption will be studied by both in vitro models and theoretical calculations. The tumor microenvironment and pathological analysis will also be performed and correlated to in vivo experiments results. Finally, we will evaluate the in vivo anti-cancer therapeutic effect of these nanomedicines in various tumor models, whose results can be further used to guide the design and construction of nanomedicines. The project as a basic study of nanomedicine will provide theoretical support and guidance for anti-cancer nanomedicine design and application.

如何提高分子抗肿瘤纳米药物的治疗效果是急待解决的问题。纳米药物在体内的命运与其表面特性紧密相关。本项目基于前期研究基础，拟围绕“如何调控高分子纳米药物的表面特性调控其在体内的命运，从而提高肿瘤治疗效果”的关键科学问题，通过合成不同化学特性的聚磷酸酯，构建单一特性可精准调控的纳米药物载体；重点研究纳米特性如何影响纳米在体内的循环、肿瘤富集与清除、血管与组织渗透、组织内肿瘤细胞与基质细胞摄取等的联系；同时将纳米特性、体内命运与蛋白吸附等体外模型实验、肿瘤微环境与病理学特症等分析对应，结合计算等探讨其中的机制与原理；进一步优选纳米药物递送体系，进而优选纳米药物递送体系，实现高效抗肿瘤治疗；并同时反馈纳米载体的设计与构建。本项目作为纳米药物体内命运的基础研究，将为载体设计和应用提供理论支持和指导。

如何提高高分子抗肿瘤纳米药物的治疗效果是亟待解决的问题。纳米药物在体内的命运和治疗效果与其表面特性紧密相关。在本项目中，我们围绕如何调控高分子纳米药物的表面特性来调控其体内命运，从而提高其肿瘤治疗效果的关键科学问题，通过合成不同化学特性的聚磷酸酯，构建了表面亲疏水性可精准调控的纳米药物载体；重点研究了聚磷酸酯的不同亲疏水性与纳米颗粒在体内的循环、肿瘤富集与清除、血管与组织渗透、组织内肿瘤细胞与基质细胞摄取等的联系；同时将纳米药物的纳米特性、体内命运与蛋白吸附等体外模型实验、肿瘤微环境与病理学特症等分析对应，结合计算等探讨其中的机制与原理；在此基础上进一步优选纳米药物递送体系，实现了高效的抗肿瘤治疗。我们发现足够高的表面疏水性有助于纳米颗粒的稳定，进而促进纳米颗粒的细胞摄取和血液长循环。我们还发现表面亲水性较高的纳米颗粒会抑制表面蛋白质的吸附，因此很少被单核吞噬系统识别和清除，进而表现出更长的血液循环和更高的肿瘤富集。然而，表面亲水性较高的纳米颗粒同时会抑制肿瘤细胞的摄取，进而限制药物递送至肿瘤细胞。因此，纳米药物的肿瘤治疗效果受两方面的综合制约。此外，我们还设计了具有不同特性的聚合物纳米药物，用于调控乏氧、微酸、免疫抑制等肿瘤微环境，实现了高效的抗肿瘤治疗。本项目研究成果可为高效抗肿瘤纳米药物的设计提供重要参考。