Red Blood Cell-Membrane-Coated Poly(Lactic-co-glycolic Acid) Nanoparticles for Enhanced Chemo- and Hypoxia-Activated Therapy.

Herein, a membrane-coated nanocarrier for codelivery of chemotherapeutic agents, curcumin (Cur) and the hypoxia-activated molecule, tirapazamine (TPZ), has been developed. Cur and TPZ were loaded into biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) and finally coated with red blood cell (RBC) membrane by an extrusion process. Characterization of drug-loaded membrane-coated NPs (Cur+TPZ@RB) by dynamic light scattering, TEM and FESEM analyses showed that the NPs were of 105 nm size with a surface charge of -31 mV. Experimental results demonstrated long-term stability, biocompatibility and efficient cellular internalization (primarily through caveolin mediated pathway) of the Cur+TPZ@RB. Antiproliferative studies on 2D monolayer as well as hypoxic 3D multicellular spheroids (MCS) confirmed that the drug-loaded NPs were more potent than free drugs, inducing apoptosis via generation of reactive oxygen species and consequent DNA damage. Furthermore, the reduced cell migration in the scratch assay and down regulations mesenchymal markers as a result of Cur+TPZ@RB treatment suggest the potential of the present system in circumventing hypoxic solid tumors.