Emerging antiangiogenic therapeutics, like VEGF targeting antibodies, are effective in controlling retinal and choroidal neovascularization-related vision loss. However, the anatomy and physiology of the eye hamper the successful delivery of these macromolecular drugs to the back of the eye. This situation requires the long term and frequent intravitreal injections of these drugs for the treatment of the chronic conditions of these diseases, which results in poor patient compliance and suboptimal treatment. Controlled release technology could improve the existing treatment regimen by extending therapeutic duration, reducing risks and burdens caused by frequent injections, and enabling new drugs to overcome the hurdles of translation.

This thesis reports a polysaccharide-based hy...[ Read more ]

Emerging antiangiogenic therapeutics, like VEGF targeting antibodies, are effective in controlling retinal and choroidal neovascularization-related vision loss. However, the anatomy and physiology of the eye hamper the successful delivery of these macromolecular drugs to the back of the eye. This situation requires the long term and frequent intravitreal injections of these drugs for the treatment of the chronic conditions of these diseases, which results in poor patient compliance and suboptimal treatment. Controlled release technology could improve the existing treatment regimen by extending therapeutic duration, reducing risks and burdens caused by frequent injections, and enabling new drugs to overcome the hurdles of translation.

This thesis reports a polysaccharide-based hydrogel platform as an intraocular depot for the sustained and controllable protein release. The platform also included other important features, such as easily injectable, hydrolytically degradable and biocompatible to accommodate the specific clinical needs. Injectability was achieved through two strategies, including that: 1) to develop in-situ gelling formulations based on Michael-addition type chemical crosslinking between vinyl sulfone and thiol modified polysaccharides at physiological conditions; 2) to fabricate injectable hydrogel microparticles by micronizing the preformed, protein encapsulated hydrogels using w/o emulsion.

Depot degradability was realized by introducing hydrolysis labile ester linkers into the hydrogel network. The hydrogel meshwork degradation and subsequent dynamic mesh size change over time allows the controllable protein release from the depot. In order to screen for appropriate ester linkers and monitor the hydrolysis kinetics of these linkers in a hydrogel, we have established an 1H NMR-based method, and systematically examined the influence of the local environment of the ester bonds on their hydrolysis rate in the hydrogel. The experimental results have expanded our understanding of currently debated views in the field, and guided us to fabricate hydrogel platforms with tunable degradation time frame through synthesizing and grafting a series of ester linkers with variable hydrolytic half-lives (ranging from hours to months) into the hydrogel precursor polymers. Besides ester chemistry, we have invented another new strategy to manipulate the hydrogel degradation behavior by altering the network architecture. This new strategy decoupled the hydrolysable moieties on the polymer network from other formulation parameters, and significantly elongated disintegration time of a hydrogel.

Biocompatibility and the pharmacokinetic analysis of various bevacizumab (an antiangiogenic antibody)-encapsulated hydrogel formulations were evaluated in rabbit eyes. We have discovered that 1) the negatively charged components in the hydrogel significantly improve the depot biocompatibility; 2) the hydrogel depot successfully maintains bevacizumab in the active form; 3) and the hydrogel depot allows the sustained protein release at a therapeutic relevant concentration for at least 6 months.