Cancer Cell Membrane-Functionalized Oxygen-Nanocarrier for Breaking Hypoxia-Induced Chemoresistance

Abstract

The rapid growth of cancer cells as well as the distorted blood vessels cause low oxygen content in solid tumors. Tumor hypoxia can bring about the chemotherapeutics resistance. To overcome hypoxia-induced chemoresistance, we introduced a cancer cell membrane-modified smart nanosystem with a polymeric core encapsulated natural hemoglobin (Hb) and anti-cancer drug doxorubicin (DOX) for efficient chemotherapy. The well-defined DOX/Hb-loaded and cancer cell membrane-coated nanoparticles (DHCNPs) were constructed from two components, the first is a DOX/Hb-loaded polymeric NPs prepared by single-step assembly. The second is a cancer cell membrane shell extracted from MCF-7 cancer cells and further coated onto pre-formed polymeric NPs by extrusion. The DHCNPs availably retained the cancer cell adhesion molecules (e.g., EpCAM, N-cadherin, and galectin-3) and reserved the oxygen-carrying capacity of Hb [1,2]. Benefited from the homologous targeting of adhesion molecules [3], DHCNPs significantly promoted the DOX endocytosis of MCF-7 breast cancer cells, and enhanced homologous-targeting tumor accumulation. Meanwhile, the oxygen intervention of DHCNPS noticeably downregulated the HIF-1α expression and eventually reduced exocytosis of DOX by the decreased expression of p-glycoprotein. The in vitro MTS assay showed that hypoxic MCF-7 cancer cells treated with DHCNPs caused about 80% cell death, which was 3.2 fold than that of treated with free DOX. DHCNPs treated mice achieved 100.0% survival rate in the in vivo therapeutic experiment. By the interactions of homologous target recognition and oxygen adjustment, the DHCNPs showed highly effective chemotherapy in vitro and in vivo. The biomimetic DHCNPs exhibited the attractive prospects in drug-resistant cancer therapy.