pH-响应自降解与靶向性协同作用的安全高效载药体系的构建

Although inorganic drug nanocarrier could enhance the utilization efficiency of anti-cancer drug, most of the inorganic nanomaterials were not biodegradable or have slow biodegradation rate, would cause long-term toxicity. This project proposes to prepare pH-responsive biodegradable hollow mesoporous organosilica nanoparticles, and then modify the nanoparticles with targeting groups to achieve efficient and safe anti-cancer drug nanocarrier: on the one hand, pH-responsive biodegradation would lead to the safe metabolism of nanocarrier, and also would result in the efficient release of drug in tumor cells; on the other hand, targeting not only enhance the utilization efficiency of the anti-cancer drug, but also would facilitate the biodegradation under the intracellular acidic environment of tumor cells. In addition, we will investigate the connection between the reaction conditions and the biodegradation behavior of pH-responsive biodegradable hollow mesoporous organosilica nanoparticles in the acidic conditions, further analyze the influence of nanocarrier on the biodistribution and the inhibition efficiency of anti-cancer drug in vitro and in vivo. The degradation and metabolism of this nanocarrier, as well as the synergistic effects of pH-responsive biodegradation and targeting would be studied. Implementation of this project would provide a effective strategy of exploring safe and efficient anti-cancer drug nanocarrier.

具有独特物理化学性质的无机纳米药物载体可以提高抗肿瘤药物的利用效率，然而无机纳米载体大部分难以自行降解排出体外，易在体内富集导致长期毒性。本项目拟通过合成在肿瘤细胞内部弱酸性环境下可降解的新型pH-响应自降解中空介孔有机硅纳米粒子，并在其表面修饰肿瘤靶向基团，制备可安全代谢的高效抗肿瘤药物载体：一方面，pH-响应自降解既可以实现药物载体的安全代谢，也可以通过肿瘤细胞内部载体降解高效释放药物；另一方面，靶向基团可增大药物载体在肿瘤部位的富集效率，除了能够提高抗肿瘤药物利用效率，还可以利用肿瘤细胞弱酸性环境促进载体的安全代谢。将系统探讨制备条件与纳米药物载体降解性能之间的相关性，分析药物载体对抗肿瘤药物释放行为及抑制肿瘤效率的影响，深入研究纳米药物载体的后续降解及代谢过程，分析pH-响应自降解与靶向性协同作用的机制。本项目的实施将为安全高效的药物载体制备提供有效的途径和方法。

具有独特物理化学性质的无机纳米药物载体可以提高抗肿瘤药物的利用效率，然而无机纳米载体大部分难以自行降解排出体外，易在体内富集导致长期毒性。本项目通过合成新型刺激响应性可降解中空介孔有机硅纳米体系，制备可安全代谢的高效抗肿瘤药物载体：一，设计制备在弱酸性环境下可降解中空介孔有机硅纳米粒子。中空空腔可以作为药物负载的容器，从而大大提高药物负载效率。通过肿瘤细胞的增强渗透效应，负载药物的有机硅纳米粒子可被动靶向富集于肿瘤细胞内部，在细胞内部的弱酸性环境的刺激下有机硅纳米粒子发生降解，达到药物释放和纳米药物载体自身安全代谢的双重目的，通过细胞及小鼠实验验证了上述结论；二，首先合成含有单线态氧敏感桥连基团的中空介孔有机硅纳米粒子，然后在纳米粒子表面修饰石墨烯量子点制备得到光响应可降解中空介孔有机硅纳米复合体系。光照条件下，石墨烯量子点可将游离态氧转换为单线态氧，促使单线态氧敏感桥连基团裂解，进而引起有机硅纳米复合体系的降解。体外和体内实验均表明，光响应可降解中空介孔有机硅纳米复合体系具有较好的药物负载性能，可实现智能化药物控制释放和自身安全代谢的双重目标，为安全高效的药物载体制备提供有效的途径和方法。