Abstract
HIF-1α (hypoxia induced factor-1α), a vital protective signal against hypoxia, has a short lifetime after myocardial infarction (MI). Increasing HIF-1α stability by inhibiting its hydroxylation with prolyl hydroxylases inhibitors such as DPCA (1,4-dihydrophenonthrolin-4-one-3-carboxylic acid) presents positive results. However, the optimal inhibitor administration profile for MI treatment is still unexplored. Here, injectable, thermosensitive hydrogels with programmable DPCA release are designed and synthesized. Hydrogel degradation and slow DPCA release are coupled to form a feedback loop by attaching pendant DPCA to polymer backbone, which serve as additional crosslinking points through π-π and hydrophobic interactions. Pendant carboxyl groups are added to the copolymer to accelerate DPCA release. Burst release in the acute phase for myocardial protection and extended near zero-order release across the inflammatory and fibrotic phases with different rates are achieved. All DPCA-releasing hydrogels upregulate HIF-1α, decrease apoptosis, promote angiogenesis, and stimulate cardiomyocyte proliferation, leading to preserved cardiac function and ventricular geometry. Faster hydrogel degradation induced by faster DPCA release results in a HIF-1α expression eight times of healthy control and better therapeutic effect in MI treatment. This research demonstrates the value of precise regulation of HIF-1α expression in treating MI and other relevant diseases and provides an implantable device-based modulation strategy.