THESIS
2014
xvii, 113 pages : illustrations (some color) ; 30 cm
Abstract
Ocular neovascularization diseases including age-related macular degeneration are the
leading causes of blindness in developing countries. Because of the chronic nature of the
disease and the fast elimination of drug in the eye, monthly repeated intravitreal injection are
required to achieve best therapeutic outcome. However, repeated intravitreal injection
increases the risk of developing ocular complications and decreases the patient compliance. In
this thesis, an injectable chemically crosslinked hydrogel formulation of an anti-VEGF
antibody therapeutic for eye diseases was developed and evaluated in vitro and in vivo. We
demonstrated for the first time that the prolonged release of protein therapeutics can be
achieved in the eye for at least 6 months.
Different from previou...[
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Ocular neovascularization diseases including age-related macular degeneration are the
leading causes of blindness in developing countries. Because of the chronic nature of the
disease and the fast elimination of drug in the eye, monthly repeated intravitreal injection are
required to achieve best therapeutic outcome. However, repeated intravitreal injection
increases the risk of developing ocular complications and decreases the patient compliance. In
this thesis, an injectable chemically crosslinked hydrogel formulation of an anti-VEGF
antibody therapeutic for eye diseases was developed and evaluated in vitro and in vivo. We
demonstrated for the first time that the prolonged release of protein therapeutics can be
achieved in the eye for at least 6 months.
Different from previous attempts of using physical hydrogel, chemically crosslinking
between polymer precursors was designed as the gelation method. Vinylsulfone-thiol reaction
pair was chosen for its fast reaction kinetics in physiological condition and biocompatibility.
To modify polymers to contain vinylsulfone groups or thiol groups, we introduced simple
“click” chemistry based reactions which was applicable to a majority of hydroxyl-containing
water soluble polymers including hyaluronic acid, dextran, PVA and alginate with controllable
degree of modification. The development of these simple reactions provided us with wide
varieties of starting materials for formulation optimization. To enable rational design of
formulations for our application, we developed a simple model based on De Gennes’ Blob
Theory to understand hydrogel formation from crosslinking polymer solution. By estimating
hydrogel as a semidilute solution fixed at entanglement points, the relation between polymer
properties and hydrogel properties was evaluated from theoretical perspectives and validated
using experiments. From this model, we can calculate minimum gelation concentration and
estimate hydrogel mesh size based solely on polymer parameters such as molecular weight
and radius of gyration. The model also sheds new insights on the effect of crosslinker density
or degree of modification on hydrogel’s mechanical properties and mesh size. Based on this
model, we controlled the mesh size of hydrogel and minimize the undesirable protein binding between protein and with hydrogel material, and successfully developed an in situ hyaluronic
acid/dextran based hydrogel capable of releasing the model therapeutic protein, Avastin®, for
at least 3 months in vitro with tunable release rate. The biocompatibility and in vivo release of
one formulation was evaluated in rabbit eye. The intraocular pressure (IOP) measurement,
fundus morphology observation using binocular indirect ophthalmoscope (BIO),
electroretinogram (ERG) and histology showed that the gel was well tolerated. Avastin® was
released continuously from the gel formulation and maintained above therapeutically relevant
concentration in the vitreous for least 6 months.
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