Wound repair and regeneration represent two distinct processes. The latter is generally restricted to amphibians and primitive organisms, and is characterized by the complete restoration of tissue architecture and function. This is in contrast to wound repair mechanisms, which instead lead to the production of non-specific fibrotic tissue, causing augmentations in cell behavior and organ dysfunction. While mammalian fetal tissue exhibits regenerative capabilities, regeneration is lost in early gestation and replaced by reparative processes. An exception to this observation, however, is the Murthy Roths Large (MRL) mouse. Originally developed as a model for autoimmunity, a serendipitous observation revealed that the MRL was capable of healing wounds through a process emulating salamander limb regrowth. This unusual display of mammalian regeneration is enabled by robust expression of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). Although constitutively expressed in mammalian cells, in normoxia, oxygen-sensitive prolyl hydroxylase domain enzymes (PHDs) usually mark HIF-1α for degradation. To achieve MRL-like HIF-1α expression and subsequent regeneration in non-healing mammals, we report the design of vehicles for the delivery of the PHD inhibitor 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA). By conjugating the hydrophobic drug to PEG via a biodegradable linker, we create amphiphilic prodrugs that self-assemble into stable nanostructures in aqueous environments. Compared to traditional hydrogel systems, these novel prodrugs achieve incredibly high loading of DPCA. By altering the molecular design of DPCA prodrugs, we show that the size, shape, drug release kinetics, and bioactivity of these constructs can be precisely engineered to meet the needs of various injury targets. By studying the effects of transient HIF-1α stabilization in vitro, we also begin to elucidate the pro-regenerative mechanism of DPCA to inform further optimization of our vehicles.

Designing self-assembled prodrug nanostructures for mammalian tissue regeneration

ACS Spring 2022

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