具有主动靶向的抗肿瘤药物智能高分子载体的研究

Polymer carrier for targeted controlled release of anticancer drugs is an important research field for biomedical polymer. This is the key to the problem of anti-cancer drug and one of international research focus areas. Tumor tissues and cells have low pH and high glutathione (GSH) concentration. Endocytosis and uptake are usally difficult for long-circulating nanoparticles. Some specific receptors exist on the tumor cell surface. According to the characteristics of tumor environment, this project is intended to prepare a series of intelligent polymeric carriers with active targeting for the loading of cisplatin and doxorubicin using functional poly-β-amino ester, aliphatic polyester, poly(amino acids). Zwitterionic polymer, pH sensitive moiety, GSH concentration sensitive moiety, near-infrared fluorescent dyes and active targeting ligands are introduced to develop active targeting drug delivery systems including pH-responsive micelles systems, GSH-concentration-sensitive nano-micelle systems, GSH-concentration- sensitive nanogels systems, pH and GSH-concentration dual responsive nano gel systems, charge flipping nano-hydrogel systems, as well as shell separation nano-gel systems. The solution behavior of the drug delivery systems will be studied in detail to clarify the release mechanism of anti-cancer drugs under different environmental stimuli. In vivo safety, pharmacokinetics, biodistribution, targeting and inhibitory effect on tumor growth of the nano-drug carrier systems will also be Investigated.

抗肿瘤药物的靶向控制释放高分子载体是生物医用高分子领域的重要研究方向，是解决抗肿瘤药物的关键问题，是国际上研究的热点领域之一。本项目根据肿瘤组织和细胞具有的低pH值和高谷胱甘肽浓度的特点，针对长循环纳米粒子较难被内吞和摄取等问题，结合肿瘤细胞表面存在的特殊受体，拟以功能化聚β-胺酯、脂肪族聚酯、聚氨基酸为主要载体材料，引入聚两性离子、pH敏感、还原敏感、近红外荧光染料以及主动肿瘤靶向基团，制备一系列具有主动靶向功能的抗肿瘤药物高分子载体，用于担载顺铂和阿霉素。具体讲开发具有主动肿瘤靶向基团、pH响应性、还原响应性、pH和还原双响应性的纳米凝胶体系、肿瘤组织pH响应性电荷翻转纳米水凝胶体系以及肿瘤组织pH响应性壳分离纳米凝胶体系。并详细研究载药体系在溶液中的释放行为，阐明药物在不同环境刺激下的释放机制。考察和评价纳米载药体系的体内安全性、代谢行为、生物分布、各种靶向智能性及肿瘤生长抑制效果。

抗肿瘤药物的靶向控制释放高分子载体是生物医用高分子领域的重要研究方向，是降低抗肿瘤药物毒副作用并提高疗效的关键。本项目根据肿瘤组织和细胞具有的低pH值和高谷胱甘肽浓度的特点，针对长循环纳米粒子较难被内吞和摄取等问题，结合肿瘤细胞表面存在的特殊受体，以功能化生物可降解高分子为主要载体材料，制备了一系列具有主动靶向功能的抗肿瘤药物高分子载体，用于担载小分子抗肿瘤药物，如顺铂、阿霉素、紫杉醇、康普瑞汀A4等。设计和制备的主要载药体系包括：具有氧化还原和pH双响应的PEG-聚氨基酸键合紫杉醇体系、顺铂交联的pH响应葡聚糖担载阿霉素纳米药物、LHRH多肽修饰的葡聚糖顺铂纳米药物、基于c(RGDfk)修饰的聚氨基酸接枝共聚物的顺铂和多西紫杉醇的共传输纳米药物、肿瘤微环境高表达酶敏感聚乙二醇-阿霉素键合药、血管阻断剂高分子纳米药物、血管阻断剂与纳米药物联合治疗系统、基于凝血机制的肿瘤靶向输药体系、用于胶质瘤治疗的脑靶向纳米基因载体、顺序响应壳堆叠纳米药物和受体与微环境双重可识别的抗肿瘤纳米凝胶。提出了“中心与边缘”协同治疗策略，解决了纳米药物瘤内渗透性差，对实体肿瘤中心区杀伤能力不足的问题。提出了基于“凝血靶向”机制的纳米药物肿瘤靶向新策略，通过联用血管阻断剂，显著提高了高分子载体纳米药物的肿瘤靶向能力。发现纳米粒子的实体瘤内低渗透性可提高血管阻断剂的血管靶向能力，大幅度提高了血管阻断剂的抗肿瘤效果，为纳米技术在抗肿瘤领域的应用拓展了新方向。