肿瘤弱酸响应电转磺胺两性离子增强抗肿瘤疗效的研究

Long blood circulation and tumor cell targeting ability are two basic requirements for drug delivery systems with high efficiency, which is, however, only achieved by complicated synthesis and modification process. Therefore, designing a simple material which could achieve long blood circulation and tumor cell targeting ability at the same time can not only enhance the tumor therapeutic efficiency but also greatly simplify the current complicated nanomedicine preparation process. In this project, a simple zwitterionic sulfadiazine monomer with charge-conversional ability is synthesized which could keep stealthy zwitterionic state in blood environment, leading to long blood circulation. After arriving the tumor tissue, zwitterionic sulfadiazine could rapidly convert to a strongly positive charged state, which leads to effective tumor cellular uptake promoted by electrostatic interaction. Therefore, zwitterionic sulfadiazine monomer is proposed to coat on the surface of Fe3O4, endowing Fe3O4 with long blood circulation and tumor cell targeting which could promote the better application of Fe3O4 in photothermal theranostics of breast cancer. In addition, the influence of surface charge (negative, neutral and positive) on the interaction between nanomedicine and proteins, macrophages or tumor cells is investigated. Meanwhile, the influence of surface charge on the tumor cellular uptake efficiency and uptake pathway is studied, which may offer train of thought to optimize the nanomedicine designment.

血液长循环和肿瘤细胞靶向是高效的纳米药物输送系统的两大基本需求；然而，为了同时实现这两点，当前的纳米药物需要较为复杂的合成与修饰过程。因此，设计一种简单的材料可同时实现纳米药物的血液长循环性和肿瘤细胞靶向性，不仅能增强纳米药物的肿瘤治疗效率还可简化当前复杂的纳米药物制备过程。本项目拟合成一种简单的电转磺胺两性离子单体，在血液中可保持两性离子隐匿的特性，具有血液长循环的性能，到达肿瘤组织后可迅速地转变为较强的正电性，通过与带负电的肿瘤细胞膜静电吸引，高效地被肿瘤细胞摄取。本项目拟将该磺胺两性离子包覆到Fe3O4表面，同时赋予Fe3O4血液长循环及肿瘤细胞靶向性，促进Fe3O4在乳腺癌光热诊疗领域更好的应用。此外，本项目拟探究表面电荷的类型(电负性、电中性及正电性)对纳米粒子与蛋白质、巨噬细胞及肿瘤细胞等相互作用及对肿瘤细胞摄取效率与内吞路径的影响，为纳米药物的优化设计提供思路。

血液长循环和肿瘤细胞靶向是实现纳米药物高效递送的必要条件；为了同时实现以上的两个条件，当前的科研工作者通常采用较为复杂的设计与制备过程，阻碍了纳米药物向临床的有效转化。因此，本项目拟设计一种简单的磺胺两性离子聚合物以同时实现血液长循环和肿瘤细胞靶向，以简化当前复杂的纳米药物设计过程，取得的重要研究成果如下：一、首创性地设计了一种可在微波辅助下特异性释放抗癌药物的热敏感磺酰胺两性离子聚合物纳米凝胶，研究发现该磺酰胺纳米凝胶在血液中具有比常规聚乙二醇纳米凝胶更长的血液循环时间，到达肿瘤组织后在微波加热下纳米凝胶具有显著增强的肿瘤细胞摄取效率，动物实验证明该磺酰胺载药纳米凝胶可高效用于肝癌微波消融-化学治疗的协同疗法，相关成果发表在国际顶级期刊Advanced Functional Materials (第一作者，IF=19.924)上，并被国内多家学术媒体报道。二、创新性地开发了一种乏氧响应的磷酰胆碱载药微球用于乏氧实体肿瘤(包括肝细胞肿瘤和脑胶质瘤)的精准药物递送，相关成果发表在国内创办的药剂学顶级期刊Acta Pharmaceutica Sinica B (第一作者，IF=14.903)和国际顶级杂志Chemical Engineering Journal (共同通讯作者，IF=16.744)上，相关成果已申请中国发明专利。三、首次开发了一种在近红外二区激光激发下可特异性释放硒化氢气体的纳米药物，用于光热增强的癌症自噬治疗，不仅能有效地抑制肿瘤的生长还可以抑制肿瘤向肝脏和肺脏的转移(Nano Today, 第一作者，IF=18.962)。基于以上系列研究成果，受邀撰写了相关的综述文章，总结了该领域的发展现状，文章已被国际顶级杂志Nano Today (共同通讯作者，IF=18.962)和Advanced Science(第一作者，IF=17.521)接收。在该项目的支持下，项目主持人入选中国科协青年人才托举工程，获中国抗癌协会科技进步一等奖和珠海市科技进步特等奖等荣誉，并于2021年获批国自然基金面上项目。