Topology and mechanism in self-immolation chemistry

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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.