Mucus-penetrating and permeation enhancer albumin-based nanoparticles for oral delivery of macromolecules: application to bevacizumab

Abstract

Abstract The oral administration of therapeutic proteins copes with important challenges (mainly degradation and poor absorption) that make their potential therapeutic application extremely difficult. The aim of this study was to design nanoparticles with mucus permeating and permeation enhancer properties as oral carriers for the oral absorption of an anti-VEGF monoclonal antibody (bevacizumab) as an example of therapeutic protein with high molecular weight and ionizable groups. For this purpose, bevacizumab was complexed with the permeation enhancers sodium deoxycholate (DS) or docusate (DOCU), and then, encapsulated in PEG-coated albumin nanoparticles (mucus-penetrating). Although both types of pegylated nanoparticles (B-DS-NP-P or B-DOCU-NP-P) displayed a similar ability to disrupt the intestinal epithelial barrier in C. elegans, nanoparticles with DS showed higher capability to diffuse in intestinal mucus, when analyzed by multiple particle tracking. In rats, the relative oral bioavailability of bevacizumab incorporated in PEG-coated nanoparticles as a complex with DS (B-DS-NP-P) was 3.7%, a 100-fold increase compared to free bevacizumab encapsulated in nanoparticles (B-NP-P, 0.003% bioavailability). This important effect of DS may be explained not only by its capability to transiently disrupt tight junctions but also to their ability to increase the fluidity of membranes and to inhibit cytosolic and brush border enzymes.