Injectable Chemically Crosslinked Hydrogel for the Controlled Release of Bevacizumab in Vitreous: A 6-Month In Vivo Study

Abstract

Purpose: To evaluate the biocompatibility and 6-month in vivo release of bevacizumab from a hyaluronic acid/dextran-based in situ hydrogel after intravitreal injection in rabbit eye. Methods:The in situ hydrogel was formed by the catalyst-free chemical crosslinking between vinylsulfone functionalized hyaluronic acid (HA-VS) and thiolated dextran (Dex-SH) at physiological condition. The pH 7.4 buffered mixture containing HA-VS, Dex-SH, and bevacizumab were injected into the vitreous of rabbit eyes by a 30-G needle. The biocompatibility was evaluated by intraocular pressure measurement, binocular indirect ophthalmoscope (BIO), full-field electroretinogram (ERG), and histology. The concentrations of both total and active bevacizumab in rabbit vitreous were determined by enzyme-linked immunosorbent assay. The concentration of bevacizumab in rabbit vitreous after bolus injection was simulated by onecompartment first order elimination model. Results:A transparent gel was seen in the vitreous after injection. BIO images, ERG, and histology showed that the gel does not induce hemorrhage, retinal detachment, inflammation, or other gross pathological changes in rabbit eyes after injection. While the bolus intravitreal injected bevacizumab follows the first order elimination kinetics in rabbit eye, the in situ gel formation was able to prolong the retention of bevacizumab in rabbit eye at therapeutic relevant concentration for at least 6 months. The concentration of bevacizumab 6 months after injection was about 10 7 times higher than bolus injection. Conclusions:The new in situ hydrogel formulation of bevacizumab was biocompatible and able to prolong the retention of drug in rabbit eyes in vivo at therapeutic relevant concentration for at least 6 months.Translational Relevance: Although proven to be effective, monthly intravitreal injection of bevacizumab or other protein drugs may cause various complications. Extending the residence time of protein therapeutics in the eye can reduce the injection frequency, its associated complications, and treatment cost, which will be beneficial to both the patients and doctors. In this study, we showed that the in situ hydrogel-based controlled release system is a feasible option to tackle this problem.

Diabetic Retinopathy: Battling the Global Epidemic

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Hydrogels in ophthalmic applications

“…We particularly focus on the different 120 gel-forming polymers, the physicochemical properties of the 121 resulting hydrogels, and the challenges associated with the prepa-122 ration of hydrogel-based drug delivery systems. Recent develop- 123 ments in the field of ophthalmic drug delivery are presented and 124 critically reviewed regarding the potential therapeutic benefits. 125 2.…”

Long‐term therapeutic effect in nonhuman primate eye from a single injection of anti‐VEGF controlled release hydrogel

“…HA‐VS and Dex‐SH were prepared according to our previous publications . Briefly, HA‐VS was made by reacting 1.25x (DVS:OH) molar excess of DVS with HA in 0.1 M NaOH solution and stopped by neutralizing with HCl.…”

“…Previously, we developed an injectable hydrogel composed of hyaluronic acid grafted with vinylsulfone (HA‐VS) and dextran grafted with thiol (Dex‐SH). Using the Blob model as a guidance for rational design, we were able to identify formulations that released bevacizumab in vivo in rabbit eyes for over 6 months with excellent biocompatibility . In this study, we aim to confirm the ocular biocompatibility in nonhuman primates, and evaluate the in vivo pharmacokinetics and long‐term therapeutic effect of the controlled release formulation in a nonhuman primate model with recurrent choroidal neovascularization (CNV).…”