Nanoparticles as carriers for the delivery of bevacizumab
Keywords: 
Ciencias tecnológicas
Diseño, síntesis y estudio de nuevos fármacos
Ciencias médicas
Evaluación de fármacos
Materias Investigacion::Farmacia::Farmacia y farmacología
Issue Date: 
29-Jan-2019
Defense Date: 
25-Sep-2018
Citation: 
LUIS DE REDÍN, I. "Nanoparticles as carriers for the delivery of bevacizumab". Irache, J. M. y Agüeros, M. Tesis doctoral. Universidad de Navarra, 2018.
Abstract
Bevacizumab is a humanized monoclonal antibody that targets VEGF and its receptors to inhibit angiogenesis. It has been used in the treatment of several cancers, including breast cancer, metastatic non-small cell lung cancer and colorectal cancer (CRC), and off-label in the treatment of ocular pathologies that present neovascularization as diabetic retinopathy and age-related macular degeneration and corneal neovascularization. Although anti-angiogenic therapies, such as bevacizumab, have improved the clinical outcomes in cancer, their efficacy is limited due to the non-specific biodistribution and low tumor penetration. This results in high doses that can lead to undesirable side effects. Also, the use of bevacizumab in the treatment of corneal neovascularization as eye drops yields low bioavailability (<5%), which implies frequent dosing. One possible strategy would be to develop nanoparticles that are able to encapsulate bevacizumab. This could overcome some of the aforementioned drawbacks by: increasing the accumulation in the tumor site, reducing the number of administrations and improving patient compliance. This may be accomplished through the use of human serum albumin (HSA). Albumin nanoparticles have been studied as drug delivery systems because they are biocompatible, biodegradable, non-toxic and they can incorporate a large variety of drugs. As a first approach, bevacizumab-loaded albumin nanoparticles (B-NP) were produced through a desolvation procedure and subsequent freeze-drying. The resulting nanoparticles were stable without any supplementary stabilization process (e.g., cross-linkage with glutraraldehyde) and presented a high payload of active antibody. In order to improve some of the capabilities of albumin nanoparticles these particles were coated with a hydrophilic polymer, polyethylen glycol 35,000 (PEG). These particles showed to develop mucoadhesive interactions with the corneal surface of the eye after topical administration. The efficacy studies of these particles in a rat model of corneal neovascularization revealed that albumin nanoparticles improved the ocular delivery of bevacizumab and its efficacy in comparison to the free antibody. Finally, the nanoparticles were evaluated in an in vivo model of colorectal cancer (CRC). The results revealed that the presence of PEG in the nanoparticles resulted in a more sustained serum levels over 'naked' nanoparticles. Also, pegylated nanoparticles were able to reach the tumor site to inhibit tumor growth, avoiding high antibody levels in the blood (which could lead to undesirable effects).

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Tesis_RedinSubira18.pdf
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