体内止血材料以及缓释给药体系的光合成策略

The minimally invasive technique has been widely used in many clinical fields. Hemorrhage control is critical to the success of surgery. However, it is difficult to put the traditional polymeric hemostatic materials thread through a narrow working tunnel into the active bleeder because most of them are formed in vitro. To solve this problem, multiple-olefin sucrose esters (MOSE) and multiple-thiol oligopeptides(MTOP) will be synthesized to prepare poly(glycopeptide) by thiol-ene photoclick polymerization for the hemorrhage control in vivo (in situ light-curing technology, ISLC). Moreover, the above binary system may also be updated into a ternary system by addition of unsaturated vegetable oil(UVO). Since the UVO and MOSE polymerized with different rates, the photopolymerization induced phase separation(PIPS) will occur as the polymerization continues. Such a formulation may be used as a sustained released system if a photostable drug exhibits the different solubility between two phases. The ISLC is particular in solving the problem of injection of polymer. It will be extended to prepare a delivery system by PIPS for the photostable drugs.

微创手术已经广泛应用在临床各个领域，止血是微创手术成败的关键环节之一，但是高分子止血材料难以通过狭小的工作通道进入人体，严重制约其在新技术的应用。在前期巯炔加成制备多肽类仿生材料和醇酸树脂光固化的研究基础上，本项目拟采用原位光固化(ISLC)解决以上难题，在实施其技术过程中，进而提出采用光聚合诱导相分离(PIPS)构建缓释给药体系，开创多渠道多功能临床治疗新模式。具体范例：采用多乙烯基蔗糖酯和多巯基肽作为二元体系的单体，经由微导管直达体内出血点，进而采用光点击巯基-烯烃聚合技术，固化成拟聚糖肽止血。辅之植物油为第二烯烃构建三元体系，根据植物油和不饱和蔗糖酯两种烯烃聚合速率的差异，诱使产生PIPS现象，利用药物在两相内出现差异化溶解，最终出现缓释效应。ISLC不单为体内止血材料的产业研发提供创新技术支持，还可针对光稳定性好的药物引申出PIPS，为构建缓释给药体系提供崭新的制备技术通道。

微创手术已经广泛应用在临床各个领域，止血是微创手术成败的关键环节之一，但是高分子止血材料难以通过狭小的工作通道进入人体，严重制约其在新技术的应用。本项目采用原位光聚合，通过微通道输送，定点注射，光调控体内成型止血，解决微创手术中面临的流动性与粘附性的难题。研究发现SAE蔗糖单体在HMPP引发下具有快速聚合特性，材料流动性良好，止血效果明显，材料安全性较高，符合微创手术的操作条件，达到预期效果；合成并且研究多肽单体PPLGgPEO-b-PPO-b-PPLGgPEO，发现其具有自组装行为和热响应特征；依据硫烯光点击反应过程的特点，采用含时密度泛函方法和实时光谱技术，研究以硫杂蒽酮为例的光引发剂激发态性能，得到包括淬灭速率常数、激发能等结果；并且同时开展提氢反应过渡态的研究，对比线性过渡态与非线性过渡态的差异，获得相关过渡态的构象，得到包括焓变、熵变以及反应驱动力等热力学属性和包括指前因子、反应速率常数、活化能、隧穿因子和Polanyi因子等动力学描述子，阐明光活性物质的激发机制，明确原子转移反应的机理，为开发更新微创材料提供参考依据。