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Controlled release of bevacizumab (Avastin) in experimental model indicates potential benefits for clinical practice

Research, led by scientists at the Hong Kong University of Science and Technology in China, has shown that a new hydrogel based formulation is capable of retaining bevacizumab in the eye for at least 6 months. The developed formulation was shown to be both biocompatible and safe, maintaining therapeutically relevant concentrations of the anti-VEGF compound over a considerable period. While a variety of anti-VEGF compounds have been shown to be efficacious in multiple trials and clinical practice, the requirement for regular dosing can significantly increase the rate of complications in a number of patients. Any technology capable of reducing the dosing or frequency of injections is likely to benefit patients, clinicians and payors.


Due to the high clearance rates of anti-VEGF compounds in the vitreous, injections as frequently as once per month may be required to satisfactorily manage chronic diseases such as AMD. One way to overcome this limitation is to devise a mechanism to extend the residence time of the compounds within the posterior chamber. To achieve this objective, the Chinese research team evaluated the bio-compatibility and 6-month in vivo release characteristics of bevacizumab from a hyaluronic acid/dextran-based in situ hydrogel, following intravitreal injection. Mixing of the two polymers, vinylsulfone functionalized HA (HA-VS) and thiolated dextran (Dex-SH), together with the therapeutic agent, causes crosslinking after injection where the mixture solidifies and the rate of HA degradation controls the release of the active drug. In experimental rabbit models a transparent gel could be observed in the vitreous after injection however, ERG and histology showed that the gel did not induce any hemorrhage, retinal detachment, inflammation, or any other unwanted effects. Simulation of bevacizumab first order elimination kinetics compared to detection of the compound in eyes injected with the hydrogel formulation showed therapeutically relevant concentrations persisting for at least 6 months.


According to the research data presented by the Chinese research team, the concentration of bevacizumab was about 100 ng/mL by the sixth month after injection (total: 193ng/mL, active: 54ng/mL), a concentration which was calculated to be seven orders of magnitude higher than simulated control drug (2X10^-5 ng/mL). Commenting on the work, the researchers concluded that, “by simply mixing the two precursor polymers with the protein, the mixture can be injected to the eye as a solution and form a gel efficiently without neither the addition of an initiator nor generating any by products. The system was found to be compatible to the rabbit eye and was able to maintain the bevacizumab in the vitreous at therapeutically relevant concentration for at least 6 months. These results show that in situ chemically crosslinkable polymer-polymer hydrogels can be a potent delivery system for the controlled release of proteins in the eye.”