Delivery of therapeutics remains a major challenge in existing cancer therapies despite recent technological advances. Delivery vehicles that enable local and sustained release of therapeutics and allow tailoring of release profiles from patient to patient are needed for improved clinical outcomes. Toward tunable release profiles and patient-specific treatments, we are investigating approaches for degradation-mediated cargo release from injectable hydrogels through the incorporation of novel responsive chemistries. Specifically, poly(ethylene glycol)-based hydrogels were formed by Michael-type reactions for in situ network formation and microenvironment-mediated degradation. Dual degradability of these hydrogels was achieved by incorporation of thioether succinimide linkages that undergo 1) ester hydrolysis and 2) cleavage of the click linkage in reducing microenvironments. Due to abnormal proliferative activities of cancer cells, the concentration of glutathione (GSH), a reducing peptide, is elevated in carcinoma tissues as compared to surrounding healthy tissues. Utilization of reducing-sensitive chemistries thus provides opportunities for microenvironment-responsive degradation and release of cargo molecules over time, with increased rates of release in carcinoma tissues. Due the rapid rate of Michael-type addition, crosslinking was achieved within 20-40 seconds, depending on the identity of thiol groups. Aryl thiol based thioether succinimide (dually degradable, D2ER) linkages exhibited rapid degradation as compared to alkyl thiol based thioether succinimide linkages (solely hydrolytically degradable, D1E), owing to fast click linkage cleavage and thiol exchange reactions. The release of a model cargo protein depended on the rate of degradation of the hydrogel with a 2.5-fold difference in protein release for D2ER as compared to D1E and a non-degradable control. Overall, these results demonstrate the utility of click reactions for the formation<i> and</i> degradation of injectable hydrogels, where the rate of degradation can be tuned through incorporation of select thiol functional groups. This approach presents considerable opportunities for designing hydrogel based drug carriers for triggered therapeutic delivery.

Reducing-environment sensitive synthetic hydrogels for controlled delivery of therapeutics

249th National Meeting (2015)

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