以硼酸酯为连接键的嵌段聚合物前药的合成及其组装胶束对肿瘤微环境主动有序响应行为

Prodrug micelles with ideal structure can make fast, positive, and programmed response to tumor microenvironment, which achieve the goal of intracellular drug release with sentinal, fast and sufficient dose manner, and help to decrease the drug side effects and overcome the drug resistance. As well known, boric acid ester bond is sensitive to acidic microenvironment of tumor tissue, and phenylboronic acid can form the strong binding force with sialic acid of cytomembrane. Herein, the block copolymers with phenylboronic acid catechins ester as linker are synthesized. The prodrugs are obtained by conjugation of 9-nitro camptothecin with block copolymers via disulfide bonds. And the core-crosslinked prodrug micelles with disulfide bonds are fabricated. The side effects and anti-pancreatic tumor activity is evaluated. The positive and programmed response behavior of prodrug micelles to tumor microenvironment is studied (the prodrug micelles enrich pancreatic tumor tissue via EPR effects after prolonged circulation, then the PEG shell is deattached by the acidolysis of boric acid ester bonds, and then achieve the phenylboronic acid-mediated enhanced endocytosis due to the exposed phenylboronic acid, and fast intracellular drug release due to the decrosslinked core). The exposed phenylboronic acid helps to the positive response of endocytosis. The fast diffusion of the hydrophilic polymer produced by the degradation of the core helps to the drug escape the enclosure of polymer carrier. This project enriches the fabrication strategy of drug delivery system with response behavior to tumor microenvironment. The design of programmed response and positive endocytosis show the novelty. The results of the study give the way and basis to improve the druggability and potential clinical application of camptothecin analogues.

科学设计的前药胶束对肿瘤微环境可做出快速、主动、有序响应，实现抗肿瘤药物的定点、快速、足剂量释放，有效降低毒副作用、克服耐药性。利用硼酸酯键对微酸环境敏感及苯硼酸与细胞膜唾液酸能强结合的特点，本项目合成以苯硼酸酯为连接键的两嵌段共聚物，经二硫键负载9-硝基喜树碱模型药物，构建核以二硫键交联的前药胶束，评价其毒性及抗胰腺癌活性。研究前药胶束在体内的有序响应行为（经EPR效应富集于肿瘤组织后，硼酸酯键对胞外微酸环境响应而断裂脱去PEG壳，裸露出的苯硼酸介导增强细胞内吞，继而二硫键交联的核对胞内还原环境响应，崩解快速释药），其中裸露苯硼酸赋予了前药对胞吞的主动响应，核在胞内还原降解及生成的水溶性聚合物快速溶解扩散促使药物能立即脱离载体包裹发挥治疗作用。该研究丰富了肿瘤微环境响应载药体系的构建策略，有序响应性和胞吞主动性的设计具有创新性，为改善喜树碱类药物的成药性、促进其临床应用提供了途径和依据。

科学设计的前药胶束对肿瘤微环境可做出快速、主动、有序响应，实现抗肿瘤药物的定点、快速、足剂量释放，有效降低毒副作用、克服耐药性。利用硼酸酯键对微酸环境敏感及苯硼酸与细胞膜唾液酸能强结合的特点，本项目合成以苯硼酸酯为连接键的两嵌段共聚物，或直接物理包裹阿霉素模型药物构建纳米胶束，或经共价键负载喜树碱模型药物构建前药胶束，评价其毒性及抗肝癌活性。研究载药胶束在体内的有序响应行为（经EPR效应富集于肿瘤组织后，硼酸酯键对胞外微酸环境响应而断裂脱去PEG壳，裸露出的苯硼酸介导增强细胞内吞，继而对胞内还原环境响应，崩解快速释药），其中裸露苯硼酸赋予了前药对胞吞的主动响应，在胞内还原降解及释放药物脱离载体发挥治疗作用。该研究丰富了肿瘤微环境响应载药体系的构建策略，有序响应性和胞吞主动性的设计具有创新性。该研究设计并制备的纳米胶束药物具有200nm以下的粒径，具有较好的被动靶向性能和稳定性；体外研究表明给药系统的药物释放具有缓释和控释系统的特性，能够实现苯硼酸介导的增强的细胞内吞，同时改善了阿霉素和喜树碱类药物的成药性；体内研究表明给药系统与阳性药对照组相比能够显著提高治疗效果，荷瘤小鼠经静脉注射药物治疗后，抑瘤率达到70%，且基于该构建策略的给药系统生物相容性良好，与阳性药对照组所导致的小鼠体重下降相比，给药系统组的小鼠没有明显体重下降，由此可见给药系统能够降低体内毒副作用。该研究已形成了1份完整的研究资料，申请发明专利6项，发表标注基金资助的SCI研究论文13篇，会议论文摘要3篇。培养具有材料学、生物医学及纳米技术交叉学科背景的研究生10名。