Association of anti-HER2 antibody with graphene oxide for curative treatment of osteosarcoma

Abstract

The finding of HER2 overexpression in osteosarcoma (OS) makes HER2 a potential therapeutic target. However, studies indicate OS cells are nonresponsive to anti-HER2 antibody trastuzumab (TRA) therapy. We established stable, non-covalent association of TRA with nanomaterial graphene oxide (GO) to generated multivalent TRA/GO complexes that demonstrated markedly enhanced HER2-binding activity and capacity to rapidly kill OS cells. TRA/GO simultaneously induced oxidative stress and HER2 signaling in the target cells, leading to rapid depletion of the cellular inhibitors of apoptosis protein (cIAP) and caspase-8, formation of RIP1/RIPK3/MLKL necroptosome and necroptosis of the OS cells. Intravenous administration of TRA/GO eradicated established xenograft the OS in immunodeficient mice, resulting in indefinite survival of the animals, whereas TRA in its original form failed to do so. No appreciable side effects were observed with TRA/GO therapy. The results demonstrate a novel, nontoxic, curative therapy for a HER2^pos cancer in a preclinical animal model.

Keywords: Caspase-8; Graphene oxide; HER2; Necroptosis; Osteosarcoma; Trastuzumab; cIAP.