Surface engineering of macrophages with nanoparticles to generate a cell–nanoparticle hybrid vehicle for hypoxia-targeted drug delivery

Abstract

Christopher A Holden1, Quan Yuan1, W Andrew Yeudall2,3, Deborah A Lebman3,4, Hu Yang11Department of Biomedical Engineering, School of Engineering, 2Philips Institute of Oral and Craniofacial Molecular Biology, School of Dentistry, 3Massey Cancer Center, 4Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USAAbstract: Tumors frequently contain hypoxic regions that result from a shortage of oxygen due to poorly organized tumor vasculature. Cancer cells in these areas are resistant to radiation- and chemotherapy, limiting the treatment efficacy. Macrophages have inherent hypoxia-targeting ability and hold great advantages for targeted delivery of anticancer therapeutics to cancer cells in hypoxic areas. However, most anticancer drugs cannot be directly loaded into macrophages because of their toxicity. In this work, we designed a novel drug delivery vehicle by hybridizing macrophages with nanoparticles through cell surface modification. Nanoparticles immobilized on the cell surface provide numerous new sites for anticancer drug loading, hence potentially minimizing the toxic effect of anticancer drugs on the viability and hypoxia-targeting ability of the macrophage vehicles. In particular, quantum dots and 5-(aminoacetamido) fluoresceinlabeled polyamidoamine dendrimer G4.5, both of which were coated with amine-derivatized polyethylene glycol, were immobilized to the sodium periodate-treated surface of RAW264.7 macrophages through a transient Schiff base linkage. Further, a reducing agent, sodium cyanoborohydride, was applied to reduce Schiff bases to stable secondary amine linkages. The distribution of nanoparticles on the cell surface was confirmed by fluorescence imaging, and it was found to be dependent on the stability of the linkages coupling nanoparticles to the cell surface.Keywords: anticancer drug, cellular vehicle, confocal microscopy, dendrimer, drug delivery, hypoxia, nanotechnology