具有化疗-光疗协同作用的金属配位交联的超分子纳米凝胶

Cancer is one of the leading causes of death in the world. According to a forecast by the United Nations, 20.3 million new cancer cases will be emerged in 2030 and 13.2 million cancer-related deaths will appear worldwide by 2030. Although chemotherapy is the important primary treatment for cancer, traditional chemotherapeutic drug is difficult to selectively accumulate at tumor site, resulting in undesired side effects and anticancer eficacy. Nanotechnology-based delivery system, which carries chemotherapeutic drug by chemical bonding or physical entrapment, has improved its pharmacokinetics and biodistribution profile via EPR effect, leading to potentially enhanced anticancer effect. A number of drug or drug candidates based on nanotechnology have been approved for clinical applications. Due to the molecular complexity of many diseases, combination therapy is becoming increasingly important for a better long-term prognosis and to decrease side effects.'Combination therapy' for the treatment of a disease generally refers to either the simultaneous administration of two or more pharmacologically active agents or to the combination of different types of therapy (e.g. chemotherapy and radiotherapy). Unlike single-agent therapy, multi-agent therapy can modulate different signalling pathways in diseased cells, maximise the therapeutic effect and, possibly, overcome drug resistance. A major goal of this proposal is to construct a kind of intelligent supramoclecular nanogels as drug carriers which can combine with chemo-therapy with photodynamic therapy,and therefor,can help overcome tumor drug resistance. Learning from naturally occurring systems,intracellular pH-sensitive metallo-coordinated supramolecular nanogels (MSN) were prepared by mimicking the way in which haemoglobin carries oxygen efficiently by means of the interaction of oxygen, iron-porphyrin and histidine. Herein, dextran, a homopolysaccharide of glucose, is chosen as a polymeric backbone due to its biodegradability, wide availability and nonfouling property. Then dextran-based supramolecular nanogels are fabricated by the metallo-coordination between histidine and metallo-porphin. At the physiological normal environment pH (～7.4), drug is loaded in the nanogels by suparmolecular interaction, while at pH of 6, the intracellular environment of tumors, loaded-drug can release out due to the dissociation of metallo-Por from histidine stalk. At the mean time, the introduction of prophin, a kind of photosensitizer, makes it possible to combine chemotherapy with photodynamic therapy, providing a powerful mean for delivering and releasing cargoes at the tumor sites with improved therapeutic efficacy and decreased toxicity.

目前，肿瘤已经成为威胁人类健康的最大杀手之一，如何最大限度降低药物的毒副作用，提高病人用药舒适度，实现肿瘤治疗疗效最大化是癌症治疗的重点。结合两种或多种药物或治疗方法的联合治疗已经成为肿瘤治疗的新趋势。本项目选用具有良好生相容性、易于功能化的葡聚糖作为载体骨架，模拟生物体血红蛋白携氧机理，利用金属卟啉和组氨酸的金属配位超分子作用，构建了具有肿瘤细胞内pH响应的超分子载药纳米凝胶。该体系优点：（1）通过组氨酸与卟啉的金属配位作用，不仅实现了超分子纳米凝胶的合成，还进一步改善了卟啉的水溶性，使其能够在体内长循环；（2）由于金属卟啉的光敏剂作用，超分子载药纳米凝胶具有化疗-光动力疗法双重功能，实现联合治疗的效果；（3）超分子载药纳米凝胶具有肿瘤细胞内pH响应性，在肿瘤细胞内低pH条件下解交联，快速释放药物。该载药超分子纳米凝胶在肿瘤临床联合治疗方面有很好的应用前景。

目前，肿瘤已经成为威胁人类健康的最大杀手之一，如何最大限度降低药物的毒副作用，提高病人用药舒适度，实现肿瘤治疗疗效最大化是癌症治疗的重点。结合两种或多种药物或治疗方法的联合治疗已经成为肿瘤治疗的新趋势。. 本项目模拟生物体血红蛋白携氧机理，利用金属卟啉和组氨酸的金属配位超分子作用，构建了肿瘤细胞内酸响应的纳米药物体系用于肿瘤的光动力-化疗联合治疗。主要完成了以下的工作：. 1. 基于金属配位作用构建肿瘤细胞内酸响应的超分子纳米药物输送体系用于肿瘤的光动力-化疗联合治疗。首先将组氨酸修饰到葡聚糖骨架上，并利用组氨酸与金属卟啉的配位超分子作用，构建肿瘤细胞内酸响应的纳米凝胶，在中性条件下，实现了光敏剂卟啉和化疗药物的共载和输送，到达肿瘤部位后，超分子纳米凝胶解组装同时释放光敏剂和小分子药物，实现光动力和化疗的联合应用；. 2. 制备肿瘤细胞内逐级pH响应释放的纳米药物体系用于肿瘤光动力-化疗联合治疗；. 3. 制备了光触发释放的纳米键合药体系。选用葡聚糖为基本骨架，利用ROS敏感的TK键合酯键分别将化疗药和光敏剂键合到骨架上，构建聚合物键合药，到达肿瘤细胞后，光照后，ROS敏感的TK键断裂，释放化疗药物，有效地控制药物的定点释放，实现光动力-化疗的联合应用。. 研究结果表明：（1）通过组氨酸与卟啉的金属配位作用，简便地构建了纳米药物输送体系，改善了卟啉的水溶性，使其能够在体内长循环；（2）实现了光敏剂和化疗药物的共载和释放， 具有化疗-光动力疗法双重功能，实现联合治疗；（3）构建的纳米药物体系具有肿瘤细胞内pH响应性，在肿瘤细胞内低pH条件下解组装，快速释放药物；（4）实现了肿瘤细胞内光定点定时触发释放，可以更好地控制肿瘤治疗。该系列纳米药物输送体系可以更好地实现可控地光动力-化疗联合治疗，可以更有效地抑制肿瘤生长，在肿瘤临床联合治疗方面有很好的应用前景。