基于超分子自组装的可示踪纳米粒子共载基因与化疗药物用于癌症治疗的研究

Multi-drug resistance (MDR) is an important reason leading to failure of chemotherapy. Currently, novel and effective approach to overcome MDR and improve patient survival rate are crucial issues in cancer therapy. Recent studies have shown that the novel drug delivery system (DDS) with the capacity to co-deliver gene and chemotherapy drug exhibited enhanced therapeutic effects. However, this approach requires design of novel drug carriers with higher complexity. In preliminary studies, we have demonstrated that the cyclodextrin-based supramolecular structures could be utilized as novel drug carriers due to their good biocompatibility and drug loading ability by specific molecular recognition and self-assembly. In this project, we propose to use our cationic derivatives of cyclodextrin, with low toxicity and high drug delivery efficiency, and trackable quantum dots for the synthesis of multi-functional drug carrier; after that, we choose paclitaxel with the ability to form specific host-guest inclusion complex with cyclodextrin as model drug to test the drug loading ability of this novel supramolecular carrier; considering the high expression of Bcl-2 protein in drug-resistant cancer cells, we will utilize Nur77 as a model gene with the ability to reverse the anti-apoptotic function of Bcl-2 protein; moreover, co-delivery ability of gene/chemotherapy drug by using this novel carrier will be tested and its trackable ability or bio-safety will also be investigated. In short, we are trying to explore a novel approach for improved cancer therapy by using trackable supramolecular nanocarrriers with the ability to co-deliver gene and chemotherapy drug.

药物耐药性是导致肿瘤化疗失败的重要原因，研究克服耐药的有效新途径、提高患者存活率是当前肿瘤治疗中迫切需要解决的课题。最近研究表明，新型药物传递系统共载基因与化疗药物进行联合治疗具有良好的协同增效作用，然而该方法对于药物载体的设计提出了更高的要求。前期研究中，我们发现基于环糊精的超分子结构由于其良好的生物相容性和分子识别自组装能力使其在药物载体的设计上拥有独特的优势。在本项目中，我们将利用已获得的高效低毒环糊精阳离子衍生物结合可发光的量子点组装为多功能药物载体；选择可与环糊精形成主客体复合物的紫杉醇作为模型化疗药物，评价其药物装载能力；针对耐药癌细胞中高表达的Bcl-2蛋白，利用可逆转其抗凋亡功能的Nur77作为模型基因；研究该新型载体的基因/化疗药物共载能力，同时考察其示踪功能及安全性；探索超分子自组装纳米粒子共载基因/化疗药物协同增强肿瘤治疗效果的新方法。

药物耐药性是导致肿瘤化疗失败的重要原因，研究克服耐药的有效新途径、提高患者存活率是当前肿瘤治疗中迫切需要解决的课题。最近研究表明，新型药物传递系统共载基因与化疗药物进行联合治疗具有良好的协同增效作用，然而该方法对于药物载体的设计提出了更高的要求。前期研究中，我们发现基于环糊精的超分子结构由于其良好的生物相容性和分子识别自组装能力使其在药物载体的设计上拥有独特的优势。通过本项目的实施，我们在前期已获得的高效低毒环糊精阳离子衍生物基础上，创新性地设计并合成了能够以自组装方式装载化疗药物紫杉醇及Nur77质粒的纳米复合药物beta-NC@Nano-polyplex。该设计的优势在于其能够利用纳米增强渗透和保留效应来增强肿瘤组织对于该药物的特异性摄取；更为重要的是所共载的Nur77基因能够诱导Bcl-2的构象转变，使其转变为癌细胞凋亡蛋白，以“化敌为友”的策略提高其对于耐药肿瘤的治疗效果。有关成果发表了9篇Sci文章（均有标注本基金资助；Nanoscale, 2016, 8: 18876 (IF: 7.760); Adv Healthc Mater, 2016, 5: 2679 (IF: 5.797); Biochem Pharmacol, 2017, 124: 19. (IF: 5.091); RSC Adv, 2016, 6: 44506 (IF: 3.840); J Chromatogr A, 2016, 14556: 169 (IF: 4.169); RSC Adv, 2016, 6: 25416 (IF: 3.840); Macromol Chem Phys, 2016, 217: 175 (IF: 2.616); J Chromatogr B, 2015, 997: 179 (IF: 2.729); J Chromatogr A, 2015, 1406: 215 (IF: 4.169) ），并申请了3项专利。综上，我们已完成了项目所规定的任务和预期目标，并在开展课题过程中有新的发现和进展。

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