多级复合孔碳酸钙缓控释抗癌药物载体的可控仿生构筑及其构效关系

It is very important to understand the structure-activity relationship between compositions and structures of the anticancer drug carriers and their potential as their controlled/sustained anticancer drug release because it is the key to synthesize an effective controlled/sustained and targeted release drug carrier. To date, inorganic materials as the anticancer drug carriers have attracted great attention duo to the disadvantages of the polymers used in clinic. In this study, CaCO3 materials with hierarchical micro-meso-macroporous structures will be researched as targeted and controlled/sustained release anticancer drug carriers model. CaCO3 materials with hierarchical micro-meso-macroporous structures are the drug carriers with wide development potential and have the advantage of controlled/sustained drug release, which improves drug solubility and stability, enhances efficacy, and reduces toxicity. Firstly, this carrier has good biocompatibility and biodegradability. Secondly, the carriers could possess higher adsorption capacities for anticancer drug and controlled/sustained release anticancer drug because of their large specific surface area and hierarchical micro-meso-macroporous structures. Finally, pH-sensitive of CaCO3 could induce the controlled release of anticancer drug due to the extracellular acid environment in solid tumor tissues or lysosomes inside cancer cells. Based on the theory of biomineralization, we plan to select three systems to biomimetic synthesis the CaCO3 materials with hierarchical micro-meso-macroporous structures, and explore their formation mechanism and the influencing factors. Further research discloses the structure-activity relationship between hierarchical micro-meso-macroporous of CaCO3 and their potential as controlled/sustained anticancer drug release carrier. Furthermore, the results and conclusions can provide experimental evidences and technology references for controlled biomimetic synthesis of novel functional materials with hierarchical micro-meso-macroporous structures.

研究抗癌药物载体的组成、结构及形貌对药物的负载、可控可持续性缓释及靶向传递的影响规律及本质，具有重要的理论意义，是指导合成出具有缓控释性能抗癌药物载体的关键。基于项目组已合成的多孔碳酸钙具有良好的缓控释抗癌药物的性能，本着绿色、简单及可控合成的原则，本项目提出的微孔-介孔-大孔为一体的多级复合孔碳酸钙的抗癌药物载体模型，不仅具有良好的生物相容性及降解性，而且可利用碳酸钙的pH敏感性及其多级复合孔结构，在癌细胞的弱酸性环境下，有望实现选择性传递、大负载量以及逐级可控可持续性缓释药物的效果。经初步实验证明，极具研究前景。基于生物矿化原理，本项目拟选用细胞、蛋白质和糖类为基质，仿生合成多级复合孔碳酸钙微纳米材料。研究影响多级复合孔结构形成的因素及其组装机理，认识材料的结构、性质与药物负载率、体外缓控释放行为及抗肿瘤效果的构效关系。为开发更多种的多级复合孔缓控释药物载体提供理论依据和实验指导。

目前在临床广泛应用的抗肿瘤药物对癌细胞的选择性较低，不能准确到达病灶区域，导致用药次数增加，致使对正常组织器官造成很大的毒副作用，严重的影响了这些药物的临床治疗效果。研究抗癌药物载体的组成、结构及形貌对药物的负载、可控可持续性缓释及靶向传递的影响规律及本质，具有重要的理论意义，是指导合成出具有缓控释性能抗癌药物载体的关键。按照项目计划书的内容，项目组本着绿色、简单及可控合成的原则，选用细胞、蛋白质和糖类为基质，基于生物矿化原理，可控仿生合成出在抗癌药物载体上有着重要应用前景的多孔球状、叶片状，半球状、多层壳以及多核空心球状的多级复合孔碳酸钙微纳米材料，认识影响多级复合孔结构形成的因素及其组装机理。利用碳酸钙的pH敏感性及其多级复合孔结构，在癌细胞的弱酸性环境下，实现选择性传递、大负载量以及逐级可控可持续性缓释药物的效果，进一步分析了材料的结构、性质与药物负载率、体外缓控释放行为及抗肿瘤效果的构效关系。完成了预期的研究任务，达到了预期研究目标，得到了一些有意义的成果。归纳总结实验结果，认识的结论有三个方面：其一，由于生物基质的官能团，空间结构及电荷等的不同，钙离子可能选择性结合，以及反应温度的影响，可能是造成多级复合孔碳酸钙形成不同形貌超结构的主要原因；其二，比表面积大，孔径小，孔结构丰富且分布交错的多级孔碳酸钙不仅吸附药物量大，而且有利于负载药物的稳定性，不宜泄露药物。另外，多级复合孔这种逐孔释放的方式可以减慢药物释放速率、延长释放时间，减少给药次数，降低病人痛苦；其三，不同多级复合孔结构碳酸钙的形貌中，多层壳（多核）结构由于其复杂的孔结构及层层药物释放效果，更有利于其抗肿瘤活性提高。这些研究结果为多级复合孔碳酸钙作为新型的抗癌药物载体在生物学和临床医学领域的应用及新型的抗癌药物载体的开发提供坚实的实验依据和重要的理论指导。目前相关研究成果已发表学术论文9篇，国际和全国会议邀请报告2次，申请国家发明专利6项，其中已有两项授权。