THESIS
2020
xii, 110 pages : illustrations (some color) ; 30 cm
Abstract
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...[
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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.
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