Development of injectable, resorbable drug-releasing copolymer scaffolds for minimally invasive sustained ophthalmic therapeutics

Copolymers based on N-isopropylacrylamide (NIPAAm), acrylic acid N-hydroxysuccinimide (NAS) and varying concentrations of acrylic acid (AA) and acryloyloxy dimethyl-γ-butyrolactone (DBA) were synthesized to create thermoresponsive, resorbable copolymers for minimally invasive drug and/or cell delivery to the posterior segment of the eye to combat retinal degenerative diseases. Increasing DBA content was found to decrease both copolymer water content and lower critical solution temperature. The incorporation of NAS provided an amine-reactive site, which can be exploited for facile conjugation of bioactive agents. Proton nuclear magnetic resonance analysis revealed the onset of hydrolysis-dependent opening of the DBA lactone ring, which successfully eradicated copolymer phase transition properties and should allow the gelled polymer to re-hydrate, enter systemic circulation and be cleared from the body without the production of degradation byproducts. Hydrolytic ring opening occurs slowly, with over 85% copolymer mass remaining after 130 days of incubation in 37 °C phosphate buffered saline. These slow-degrading copolymers are hypothesized to be ideal delivery vehicles to provide minimally invasive, sustained, localized release of pharmaceuticals within the posterior segment of the eye to combat retinal degenerative diseases.