(607c) Controlled, Self-Directed Assembly of Novel in-Situ Forming Biodegradable Nanostructures for the Delivery of Ocular Therapeutics

The physiological and anatomical complexity of the eye make it a highly protected organ, substantially limiting drug delivery despite the ability to treat topically. Designing effective drug delivery systems to target specific areas of the eye is a major research challenge. Currently, topically applied drugs, including eye drops, make up over 90% of the ophthalmic drug market. Eye drops are grossly inefficient delivery vehicles, since less than 5% of the administered dose reaches the intraocular tissues. Thus, there is a considerable unmet need for more efficacious and convenient delivery systems of ocular therapeutics. Our work concentrates on engineering novel physically crosslinked nanocarriers, that are easily formulated using FDA-approved biodegradable polymers. These tailorable carriers provide solubility and prolonged bioavailability and residence time of the ocular therapeutic.

We have developed, designed, and synthesized novel in-situ forming nanocarriers, consisting of amphiphilic PLGA-PEG-PLGA. These nanostructures self-assemble in aqueous environments via reverse thermal gelation. By varying the lactic acid (LA) to glycolid acid (GA) ratio of the hydrophobic PLGA block, the molecular weight of PEG, the PLGA to PEG ratio and the polymer solution concentration, we produce injectable, in-situ forming nanogels that are optically clear at physiological temperatures. Characterization studies include optical property assessments, critical gelation temperature (CGT), rheology, critical micelle concentration (CMC), in-vitro degradation, and controlled and sustained drug release kinetics.

We demonstrate that carriers with a LA/GA ratio between 1 and 15, at compositions between 10%(w/v) and 25%(w/v), allow for over 90% visible light transmittance, gel formation between 34 and 37°C, and sustained and controlled in-vitro polymer degradation and drug release kinetics for over one week. Below the CGT, the triblock copolymer of interest forms a homogeneous micelle therapeutic injectable solution, held together by hydrogen bonding interactions. Above the CGT, the solution swells forming an ordered packing, with hydrophobic forces dominating the 3D nano-network of bridged micelles with the drug embedded within the PLGA units. The controlled self-directed assembly of the amphiphilic molecules allows visible spectrum wavelengths to pass through the core-corona structure, making the gel optically transparent. The self-assembled polyester/polyether matrix slowly degrades via the cleavage of ester bonds, allowing for continuous and controlled drug release.

Changes in the physical and morphological states of the hydrogel are rapid and controllable, making this novel thermosensitive gel attractive for the delivery of ocular pharmaceutics. Our technology offers a more effective and efficient method of ocular therapy by providing a controlled and extended release of medication and has wide and far reaching potential to improve a number of ocular therapies.