Visible Light Stimulated Degradable Drug Release Devices for Ocular Delivery

Abstract

Delivery of therapeutics including biopharmaceuticals and corticosteroids to ocular tissue has been a challenge due to the complex anatomy of the eye. There is a need to develop novel ophthalmic drug delivery systems to provide a prolonged therapeutic level of drugs and enhance bioavailability. Photoresponsive delivery systems provide spatiotemporal control of their properties in a non-invasive way, which may improve efficacy and reduce drug side effects when compared to existing approaches. In this work, visible-light degradable polymers were designed and investigated for their potential for the preparation of ocular delivery devices. The designed visible-light degradable polymer was derived from poly(5-hydroxytrimethylene carbonate) (PHTMC). The pendant hydroxyl groups of the PHTMC were protected by visible light-labile [7-(diethylamino)coumarin-4-yl]methyl (DEACM). Upon photo-irradiation, the DEACM group is removed, leaving PHTMC which degrades rapidly via intramolecular cyclization. In this work, a visible-light stimulated degradable hydrogel system and a micelle system based on DEACM protected PHTMC were created to provide sustained and controlled drug delivery. The hydrogel system was designed for intravitreal delivery of neurotrophic factors. The hydrogel is capable of providing sustained release of highly bioactive protein with a minimal burst effect and is ultimately degradable when triggered by visible light. The hydrogels exhibited a photo-triggered degradation profile. Hydrogels formed with 4a-PEG-thiol-5k provide sustained release of bioactive cytochrome as a model protein drug for 7 weeks with a minimal burst effect. A photo-responsive release profile was achieved by triggering hydrogel degradation, which altered the drug release rate on demand. A photo-degradable micelle formulation was designed for drug delivery, whose release profile can be remotely controlled by visible light irradiation to enable on-demand delivery. The micelle system was formed by a polycarbonate-based amphiphilic diblock copolymer, whose hydrophobic block was based on DEACM protected PHTMC. Upon the removal of these protecting groups by photo-irradiation, the micelles undergo structural disruption, leading to the release of the payload. The removal of DEACM would also deprotect the pendant hydroxyl groups of PHTMC, leading to PHTMC backbone degradation via iii intramolecular cyclization. To demonstrate proof-of-principle, the release of Nile Red and dexamethasone was examined. These approaches represent the first design as ocular delivery devices and have demonstrated great potential. While further improvements may be needed to enhance certain features, the preliminary assessments have been promising.