Overcoming multidrug resistance by reversan and exterminating glioblastoma and glioblastoma stem cells by delivering drug loaded nanostructure hybrid lipid capsules (nHLCs)

Abstract

AbstractGlioblastoma multiforme (GBM) is regarded as highly aggressive brain cancer with poor prognosis. There is increase in expression of P-glycoprotein (P-gp), responsible for multidrug resistance (MDR), making it a potential target for improving drug responses. Additionally, presence of glioblastoma stem cells (GSCs) increases resistance to chemo- and radiotherapy and play a major role in cancer relapse. In this study, we targeted P-gp using a small molecule inhibitor, reversan (RV), to inhibit MDR that prolonged the retention of drugs in the cytosolic milieu. For elimination of GBM and GSCs, we have used two well established anti-cancer drugs, regorafenib (RF) and curcumin (CMN). To improve the pharmacokinetics and decrease systemic delivery of drugs, we developed nanostructure hybrid lipid capsules (nHLCs), where hydrophobic drugs can be loaded in the core and theie physicochemical properties were determined by dynamic light scattering (DLS) and cryo-scanning electron microscopy (SEM). Inhibition of MDR by RV has also shown enhanced retention of nHLC in GBM cells. Co-delivery of drug loaded nHLCs, pre-treated with RV, exhibited superior cytotoxicity in both GBM and GSCs than their individual doses and effectively reduced size and stemness of tumor spheres and accelerated the rate of apoptosis suggesting a promising treatment for glioblastoma.