多功能聚氨基酸纳米水凝胶的制备与药物控制释放应用

Chemotherapy is one of the most important means for malignant tumor treatment. However, many faults of clinical antitumor drugs, such as poor targeting, short circulation time, easy to produce drug resistance, etc. result in the low efficacy and severe side effects. This project is to prepare the poly(amino acid) nanogels with multi-stimuli-responsiveness, and actively targeting and fluorescent functions as intelligent carriers of chemotherapeutic agents. The nanogels has the following advantages: 1) The poly(ethylene glycol) on the surface of the nanogels can prevent nonspecific adsorption of proteins and prolong their circulation half-life in vivo; 2) Adopted poly(L-glutamic acid) is biodegradable, biocompatible, modifiable and pH responsive; 3) The crosslink, i.e. diselenide bond is oxidation, reduction and γ-ray responsive, and selenium has a role in inhibition of tumor growth; 4) The bonding of folic acid and other active groups endows the nanogels with initiative targeting and more effectively achieves its enrichment in tumor tissue; 5) The nanogels are fluoresent, and their metabolic behaviors in vitro and in vivo can be tracked. Through systematic study of the endocytosis and prolification inhibition of tumor cells, drug metabolism and tumor growth inhibition of drug-loaded nanogels, the improved efficacy and reduced side effects of antitumor drugs will be performed, and novel smart antitumor formulation will be developed.

化疗是恶性肿瘤治疗最重要的手段之一。然而，临床上存在药物靶向功能差，代谢时间短，易产生耐药性等问题，导致药效低和毒副作用大。本项目拟制备多功能聚氨基酸纳米水凝胶作为化疗药物的智能载体。该纳米水凝胶具有以下优点：1）纳米凝胶表面上的聚乙二醇可以阻止其对蛋白质的非特异性吸附，延长其在体内循环的半衰期；2）采用的可降解聚(L-谷氨酸)组分生物相容性好，具有可修饰的基团和pH响应性；3）作为交联键的二硒键可以对氧化、还原和γ射线等多种刺激作出响应，且硒元素自身可以抑制肿瘤生长；4）键合的叶酸等活性基团具有主动靶向功能，更有效地实现其在肿瘤组织的富集；5）具有荧光功能，可以实现其在体外和体内代谢行为的示踪。通过系统地研究载药纳米水凝胶的肿瘤细胞内吞及生长抑制，体内药物代谢行为及其肿瘤生长抑制效果，实现利用药物包载和靶向定点释放提高疗效和降低毒副作用，开发智能抗肿瘤药物新剂型。

目前，化疗是恶性肿瘤治疗最重要的手段之一。然而，临床上存在药物靶向功能差，代谢时间短，易产生耐药性等问题，导致药效低和毒副作用大。为了解决上述问题，本项目以肿瘤组织和细胞的特殊微环境为基础设计并制备了一系列环境刺激响应和肿瘤靶向的多功能聚氨基酸纳米凝胶，以增强药物在肿瘤组织的渗透、提高肿瘤细胞摄取并实现细胞内高选择药物释放。经过肿瘤靶向、抗肿瘤活性和机体毒性等证实了本项目所开发的多功能聚氨基酸纳米凝胶能够靶向炎性组织，增强小分子药物活性。在本项目的资助下，在国际知名学术期刊上发表研究论文42篇、会议论文2篇、申请中国发明专利17项，其中授权17项。