Modulation of in vitro phagocytic uptake and immunogenicity potential of modified Herceptin®-conjugated PLGA-PEG nanoparticles for drug delivery

Abstract

There is an increasing interest in engineered nanoparticle (NP) conjugates for targeted and controlled drug delivery. However, the practical applications of these NP delivery vehicles remain constrained because of their reactivity with the body's immune system defenses resulting in undesirable off-target effects. In this study, poly(D,L lactide-co-glycolide) (PLGA)-b-polyethylene glycol (PEG) NPs conjugated to different quantities of the commercial antibody Herceptin^® meant to target HER2-positive breast cancer cells were studied for their immune cell uptake and immunogenic properties (using murine macrophages and human dendritic cells). We further modified the Herceptin^®-NP conjugates with short PEG linkers with an aim to increase their biocompatibility. The 50% Herceptin^®-NP conjugate group with short PEG modification to Herceptin^® showed the best reduction in immune cell uptake by 82% along with the reduction by >50% for proinflammatory cytokine response (TNF-α and IL-6). In conclusion, optimum Herceptin^® coverage with improved hydrophilic profile results in reduced phagocytic uptake and immunogenicity of engineered NP-antibody conjugates, potentially minimizing their undesirable off-target effects as a drug delivery vehicle.

Keywords: Cellular uptake; Herceptin®; Immunogenicity; Nanoparticle conjugate; PLGA-PEG.