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

Yu Yu; Laurence Chi Ming Lau; Amy Cheuk-Yin Lo; Ying Chau

doi:10.1167/tvst.4.2.5

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

Transl Vis Sci Technol. 2015 Mar 10;4(2):5. doi: 10.1167/tvst.4.2.5. eCollection 2015 Mar.

Authors

Yu Yu¹, Laurence Chi Ming Lau², Amy Cheuk-Yin Lo², Ying Chau³

Affiliations

¹ Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon Hong Kong, China.
² Department of Ophthalmology, The University of Hong Kong, Pok Fu Lam, Hong Kong, China.
³ Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon Hong Kong, China ; Department of Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

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 one-compartment 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 10⁷ 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.

Keywords: Bevacizumab; avastin; controlled release; hydrogel; ocular delivery.