Topology and mechanism in self-immolation chemistry

自焚（SI）化学是一项技术，可用于许多“智能”材料，反应或感知其环境的物质，如可生物降解聚合物，靶向前药物和各种各样的传感器和污染物，酶，pH值，温度和光的分析，仅举几例。SI化学通常用于在目标位点提供程序化反应。常见的SI设计具有“线性拓扑”，其中靶向或固定基团连接到触发组，然后连接到SI连接体，最后连接到释放以提供所需效果的报告分子。这个过程是由一个触发事件启动的，该触发事件激活SI连接体，然后SI连接体解开（或自我牺牲）以释放报告分子。可生物降解的聚合物可以将SI基团连接在一起，并在光照或pH值变化下分解，或在暴露于酶或其他触发输入时释放活性物质。SI通常被设计为快速，因为重要的是响应是局部的，但这样的SI分子可能相当不稳定。事实上，在许多报道的病例中，SI步骤实际上相当缓慢（从几分钟到几小时），在报告分子被释放之前，触发的中间体有时间从其定位位点扩散出去，从而可能失去靶向作用。

Self immolative (SI) chemistry is a technology that finds use in many “smart” materials, substances that react or sense their environment, such as biodegradable polymers, targeted pro-drugs and a wide variety of sensors and assays for pollutants, enzymes, pH, temperature and light to name but a few. SI chemistry is often employed to deliver a programmed response at a targeted site. A common SI design has “linear topology” where a targeting or immobilizing group is attached to triggering group and then to an SI linker and finally to a reporter molecule that is released to provide the desired effect. The process is started by a triggering event that activates the SI linker that then unravels (or self-immolates) to releases the reporter molecule. Biodegradable polymers may link SI groups together and disintegrate in response to light or pH change or release active substances in response to exposure to an enzyme or some other triggering input. SI is often designed to be fast as it's important that the response is localized but such SI molecules can be rather unstable. In many reported cases in fact, the SI step is in fact rather slow (from minutes to hours) and the triggered intermediate has time to diffuse away from its localized site before the reporter molecule is released and the targeting may be lost. Nonetheless, a slow and controlled SI step can be advantageous and provide a sustained localized effect if the targeting integrity can be maintained. An answer to this problem is to design an SI molecule with a “branched” topology where the targeting or immobilizing moiety is separated from the triggering event. This research program proposes to design stable SI linker technologies with “branched” topology where the targeting or immobilized moiety attached to the SI linker and separated from the triggering moiety. Primary focus will be to provide predictable and “tunable” release (sustained release) of a wide variety of reporter molecules without losing targeting. In the shorter term the program will focus on SI cyclization linkers based on ethylenediamine (EDA) and electronic cascade SI linkers based on para-aminobenzyl alcohol (PABA). Through iterative design, synthesis and kinetic analysis on model SI monomers we will 1) determine the best sites for installation of a branching chain for targeting; 2) identify substitutions on the SI linker elements that can be varied to predictably tune rates of SI and reporter molecule release; 3) identify branched SI molecules that are inherently very stable but are triggered for slow release of a reporter molecule by changes in pH. In the longer term we will 1) evaluate the effects on SI rates of immobilization into micelles or onto particles and 2) develop new SI linkers to deliver reporter molecules not reliably delivered with current SI technologies. These program studies will provide principles for design of SI chemistry for sustained response in a wide variety of smart materials.