Diels-Alder Hydrogels for Intermittent Antibody Release

• Applicant: Professor Dr. Achim Goepferich, since 4/2016
• Subject Area: Pharmacy ; Biomaterials ; Polymer Materials
• Term: from 2009 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 130928332

Vascular endothelial growth factor (VEGF) inhibiting antibodies, such as bevacizumab and ranibizumab, revolutionized the therapy of neovascular age-related macular degeneration and proliferative diabetic retinopathy. Since the necessary injections are associated with significant discomfort and rare but severe complications, patients would profit from controlled release systems that extend the dosing intervals. Furthermore, there is increasing evidence that chronic blocking of VEGF signaling might have detrimental long-term effects such as the development of geographic atrophy. For that reason, the treatment with VEGF inhibiting antibodies should be intermittent to allow the damaged choriocapillaris to recover during drug-free intervals. The aim of this proposal is to develop hydrogels based on Diels-Alder/retro-Diels-Alder chemistry for the intermittent release of bevacizumab. After intravitreal injection, such hydrogels would encapsulate the drug and form a reservoir inside the eye. The first dose would be released shortly after injection; this would be followed by a phase of extremely slow drug release. After four to six weeks, a second dose of the encapsulated drug would be released. To achieve this goal, fast-gelling hydrogels with long intraocular residence time will be synthesized and characterized (rheological properties, degradation time, average network mesh size, permeability for macromolecules etc.). Cytotoxicity studies will be done to demonstrate the innocuousness of the synthesized macromonomers. Bevacizumab will be entrapped within the hydrogels during gelation; the encapsulated drug will not be released until gel degradation takes effect. To suppress side-reactions during cross-linking, polyanions, such as alginate, hyaluronic acid or polyacrylic acid, will be used as protein-protecting excipients. To achieve intermittent drug release, different types of macromonomers will be combined. The in vitro release of bevacizumab will be investigated; the bioactivity of the released bevacizumab will be determined in cell culture experiments. Eventually, the developed hydrogels may help to improve tolerance and efficacy of the currently available anti-VEGF therapy.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Ferdinand Brandl, until 3/2016