Cetuximab-loaded self-assembled polymeric nanoparticles for the integrin-targeted therapy of glioblastoma
Abstract
The blood-brain barrier (BBB) restricts the delivery of therapeutic small-molecule and macromolecular drugs to the central nervous system and precludes the therapeutic application of monoclonal antibodies in glioblastoma (GBM). In this work, we investigate integrin-targeted polyelectrolyte complex nanoparticles for the delivery of the anti-epidermal growth factor receptor monoclonal antibody cetuximab (CET) across the BBB in GBM. For this, an amphiphilic chitosan-graft-poly(methyl methacrylate-co-acrylic acid) copolymer is functionalized with cyclo(Arg-Gly-Asp-D-Phe-Val) (PEP) to engage ανβ3 and ανβ5 integrins expressed by the BBB endothelium and overexpressed by the GBM cells and co-assembled with sodium alginate using a T-junction microfluidics device. This double self-assembly method results in optimal CET encapsulation efficiency (∼99%) and the formation of loaded nanoparticles with a diameter of ∼322 nm, with very good structural fidelity and ∼16% w/w payload. Nanoparticles show very good compatibility with the human brain microvascular endothelium cell line hCMEC/D3 and the GBM cell line U87. Moreover, PEP-conjugated nanoparticles display significantly greater apparent permeability (Papp) in hCMEC/D3 monolayers grown on semi-permeable membranes, an in vitro model of the BBB, than the unmodified counterparts; Papp values being consistent with macromolecular systems capable of achieving measurable BBB transport in vivo. Cell uptake studies in both cell types using…
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