具有特殊形貌的靶向无机微纳米抗肿瘤药物载体的设计合成及构效关系研究

Because of the obvious advantages of the targeted antitumor drug delivery systems over the free antitumor drugs, including the significant enhancement of the therapeutic effects and the decrease of the toxic side effects, these systems are crucial to the clinical therapy of human tumors. However, hitherto, the existing antitumor drugs' carriers suffer from the poor biocompatibility and loading efficiency, the seriously sharp release of the drugs and the severely toxic side effect. Because of the ideal biocompatibility, biodegradability and low residual toxicity, the insoluble inorganic calcium salts including calcium carbonate and calcium phosphates might be used as the potential antitumor drug carriers. In this project, using target ligands with ability to highly specific combine with the over-expressed receptors of tumor cells as morphological regulating agents and targeting agents, the hybrid carriers of insoluble inorganic calcium salts/target molecules with special morphologies including composite porous materials and multishell materials will be synthesized through carefully design. The studies will be performed from three aspects. Firstly, the regulation effects of the preparation methods, preparation conditions, and structures of target ligands on the morphologies and physico-chemical properties of the carriers will be studied. Secondly, the structure-performance relationship between the compositions, structures and physico-chemical properties of the carrier and the corresponding drug delivery performance of the carriers will be systematically explored. Thirdly, the pathway and mechanism of the interactions between the carriers and the tumor cells will be discovered. The results can develop the strong theoretical bases for the design and preparation of the active targeted carriers of antitumor drugs with ideal biocompatibility, biodegradability and low residual toxicity to efficiently treat the human tumors.

靶向药物传输体系可显著提高药物疗效并降低其毒副作用，对肿瘤临床治疗具有重要意义。然而目前的抗肿瘤药物载体材料生物相容性较差，负载性能不佳，易发生药物暴释，毒副作用严重。碳酸钙、钙磷酸盐等难溶无机钙盐因其理想的生物相容性、生物可降解性和低残留毒性有可能成为潜在的抗肿瘤药物载体材料，因而本项目拟利用可与肿瘤细胞表面受体特异性结合的靶向分子为形貌调控剂和靶向试剂，设计合成复合多孔和多级空壳等特殊形貌无机钙盐/靶向分子杂化抗肿瘤药物载体材料并开展以下三方面研究。一是研究合成方法、合成条件和靶向分子结构对载体材料形貌及理化性质的调控规律；二是探索载体材料组成、结构及理化性质等因素与载体药物传输性能之间的构效关系；三是研究载体与肿瘤细胞相互作用的途径和机理。本项目的研究结果可为设计合成具有主动靶向性、良好生物相容性、生物可降解性、低残留毒性的抗肿瘤药物载体材料并有效治疗肿瘤提供坚实的理论和实验依据。

靶向药物传输体系可显著提高药物疗效并降低其毒副作用，对肿瘤临床治疗具有重要意义。然而目前的抗肿瘤药物载体材料生物相容性较差，负载性能不佳，易发生药物暴释，毒副作用严重。碳酸钙、钙磷酸盐等难溶无机钙盐因其理想的生物相容性、生物可降解性和低残留毒性有可能成为潜在的抗肿瘤药物载体材料，因而本项目利用可与肿瘤细胞表面受体特异性结合的靶向分子为形貌调控剂和靶向试剂，设计合成了复合多孔和多级空壳等特殊形貌无机钙盐/靶向分子杂化抗肿瘤药物载体材料并开展了以下三方面研究。一是研究了合成方法、合成条件和靶向分子结构对载体材料形貌及理化性质的调控规律，创新了特殊形貌无机微纳米材料的绿色合成新方法，合成了包括碳酸钙/硫酸软骨素介孔微米棒、羟基磷灰石/硫酸软骨素介孔微米棒、碳酸钙/叶酸多级孔空心球、碳酸钙/透明质酸介孔空心球、SiO2/碳酸钙双层壳空心纳米球和SiO2/羟基磷灰石双层壳空心纳米球等多个系列具有多种特殊形貌的微纳米载体材料。同时通过深入研究上述特殊形貌微纳米材料的形成过程，分别提出了生物分子调控合成多孔空壳碳酸钙的自组装--奥斯特瓦尔德熟化机理、生物分子调控合成介孔碳酸钙微米棒的表面能控制形成机理和介孔羟基磷灰石微米棒的定向连接--表面转化机理等。二是探索了载体材料组成、结构及理化性质等因素与载体药物传输性能之间的构效关系，发现靶向分子种类、载体材料的化学组成、比表面积和孔结构对其抗肿瘤药物控释性能具有明显影响。三是研究了载体与肿瘤细胞相互作用的途径和机理，发现所合成的载体材料主要是通过巨胞饮作用靶向进入肿瘤细胞内部。本项目的研究结果为设计合成具有主动靶向性、良好生物相容性、生物可降解性、低残留毒性的抗肿瘤药物载体材料并有效治疗肿瘤提供了坚实的理论和实验依据。