Bioresponsive theranostics for activity on demand delivery of Vascular Endothelial Growth Factor (VEGF)

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Bioresponsive VEGF165 delivery features this potential therapeutic for future application following e.g. myocardial infarction. VEGF165 delivery is triggered through peroxide and / or protease gradients within the diseased vs. healthy tissue. To this end, we are proposing linker structures, responding to one or both gradients with VEGF165 unload from the conjugate. The conjugates - consisting of polyethyleneglycol (PEG) - Linker - VEGF165 - particularly benefit from two foci of this proposal, (i) linker development and (ii) site directed conjugation to VEGF165, engineered by means of an expanded genetic code. Through site directed VEGF165 conjugation, the linker-PEG is strategically located close to VEGF165's low affinity receptor binding sites, thereby blocking VEGF165 activity during circulation. Within the target tissue, however, the linker-PEG is bioresponsively removed from VEGF165, thereby switching the growth factor on at target sites. We expect a reduction of side effects and - as of a reduced volume of distribution - reduced doses required for efficacy, leading into improved pharmaceutical properties through 'activity on demand'. Furthermore, diagnostic features of the peroxide linker are deployed for the peroxide-responding structures. This interdisciplinary project is the cooperative outcome of Inorganic Chemistry and Pharmaceutical Sciences.