靶向激活型香豆素光扳机修饰的生物高分子光控释放体系的设计与研究

For common phototriggers, the higher photocleavage efficiency suffers from stricter dark operation before use to prevent the undesired photolysis. So, can we add "insurance" on them and make them just be activated under specific conditions to recover the photocleavage function? Based on this point, coumarin-based target-activated phototriggers are designed in this project: On the one hand, disperse red and nitromidazole groups are selected as the quenching factors ("insurance") into the framework of 7-amino coumarin phototrigger that can be excited either by one-photon long wavelength light or two-photon NIR laser to realize the "insurance" function; On the other hand, three kinds of tumor target-activated factors including disulfide, nitromidazole and ketal groups are introduced to realize the "target-activation" function according to the characters of the higher GSH concentration, hypoxia, and low pH value in tumor cells. Finally, the continuously controllable phototriggers are used as a new platform to chemically conjugate with biocompatible polymer carriers (like chitosan) to efficiently construct photo-controlled drug release/gene transfection systems with targeted activation-light excitation continuous controllability. And the applications for these photo-controlled release systems are further studied including drug delivery, targeted and controlled release, and cancer disease treatment. It will provide a new and promising platform for constructing photo-controlled release system with high selectivity and high temporal and spatial control.

在常用的光扳机中，高的光剪切效率意味着使用前更严格的避光操作以防止不必要的光解发生，那么可否为光扳机加上"保险"，使其只有在特定的情况下才会被激活并发生光剪切呢？本项目以此为出发点设计了香豆素类靶向激活型光扳机：一方面通过在长波长单光子/近红外激光双光子可激发的7-氨基香豆素光扳机上引入分散红和硝基咪唑类淬灭因子来实现其"保险"功能；另一方面根据肿瘤细胞内GSH（谷胱甘肽）含量高、乏氧、pH值低等特性，分别引入二硫键、硝基咪唑、缩酮等三种肿瘤靶向激活因子来实现其"靶向激活"功能。最后，将这类连续可控的光扳机作为一类新的平台与生物相容的高分子载体（如壳聚糖）键联，从而高效地构建靶向激活-光激发连续控制的光控药物释放/基因转载体系，研究该类体系在药物输送/靶向/控释/癌症疾病治疗等方面的应用，为构建高选择性、高时空可控的光控释放体系提供一种新的思路和尝试。

光控释放体系由于具有1）非物理接触（遥控）；2）有效穿透人体组织的光窗口；3）时间空间可控等优势，可实现药物定时、定点、定量的精确光控释放，在药物释放领域具有重要的应用前景。虽然可以通过控制光达到一定靶向控制，但是这种靶向选择性不是很高，还是会波及到周边正常的组织或细胞。本项目针对这个问题，构建了靶向激活型光扳机，即结合癌细胞内部环境特点（肿瘤细胞内GSH含量高、乏氧、pH值低）给光扳机加上“保险”，使其只有在肿瘤细胞内才会被激活发生光剪切，从而实现高选择性、高时空的光控药物释放。同时通过纳米载体的EPR 效应、多重刺激，选择性、靶向地使载药体系富集在肿瘤部位，通过调节光照时间和强度，控制抗癌药物的释放，在有效杀死病变组织的同时降低对正常组织的毒副作用，为癌症、皮肤及妇科等疾病的治疗提供了一种新的尝试和思路。在项目进行后期利用光扳机光释放活性基团进一步发生偶联反应，即光激活偶联，成功构建了生物纳米复合体系和水凝胶功能材料，实现其在蛋白功能化、3D细胞培养领域的应用。