Journal
ACTA BIOMATERIALIA
Volume 64, Issue -, Pages 126-136Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2017.10.015
Keywords
Coaxial electrospinning; Bevacizumab; Controlled release system; Core-shell fibers; Anti-VEGF; Poly-e-caprolactone
Funding
- UCL Overseas Research Student Fund
- National Institute of Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
- Moorfields Special Trustees
- Helen Hamlyn Trust (in memory of Paul Hamlyn)
- Medical Research Council
- Fight for Sight
- Freemasons Grand Charity
- National Institute for Health Research [NF-SI-0512-10101] Funding Source: researchfish
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Medicines based on vascular endothelial growth factor (VEGF) neutralising antibodies such as bevacizumab have revolutionized the treatment of age related macular degeneration (AMD), a common blinding disease, and have great potential in preventing scarring after surgery or accelerating the healing of corneal injuries. However, at present frequent invasive injections are required to deliver these antibodies. Such administration is uncomfortable for patients and expensive for health service providers. Much effort is thus focused on developing dosage forms that can be administered less frequently. Here we use electrospinning to prepare a solid form of bevacizumab designed for prolonged release while maintaining antibody stability. Electrospun fibers were prepared with bevacizumab encapsulated in the core, surrounded by a poly-epsilon-caprolactone sheath. The fibers were generated using aqueous bevacizumab solutions buffered at two different pH values: 6.2 (the pH of the commercial product; F-beva) and 8.3 (the isoelectric point of bevacizumab; F-bevap). The fibers had smooth and cylindrical morphologies, with diameters of ca. 500 nm. Both sets of bevacizumab loaded fibers gave sustained release profiles in an in vitro model of the subconjunctival space of the eye. F-beva displayed first order kinetics with tip of 11.4 +/- 4.4 days, while Fbevap comprises a zero-order reservoir type release system with tip of 52.9 +/- 14.8 days. Both SDS-PAGE and surface plasmon resonance demonstrate that the bevacizumab in F-bevap did not undergo degradation during fiber fabrication or release. In contrast, the antibody released from Fbeva had degraded, and failed to bind to VEGF. Our results demonstrate that pH control is crucial to maintain antibody stability during the fabrication of core/shell fibers and ensure release of functional protein. Statement of Significance Bevacizumab is a potent protein drug which is highly effective in the treatment of degenerative conditions in the eye. To be effective, frequent injections into the eye are required, which is deeply unpleasant for patients and expensive for healthcare providers. Alternative methods of administration are thus highly sought after. In our work, we use the electrospinning technique to prepare fiber-based formulations loaded with bevacizumab. By careful control of the experimental parameters we are able to stabilize the protein during processing and ensure a constant rate of release over more than two months in vitro. These fibers could thus be used to reduce the frequency of dosing required, reducing cost and improving patient outcomes. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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