Multicellular 3D
cancer cell culture (spheroids) resemble to in vivo
tumors in terms of shape, cell morphology, growth kinetics, gene expression and
drug response. However, these characteristics cause very limited
drug penetration into deeper parts of the spheroids. In this study, we used multi
drug resistant (MDR)
ovarian cancer cell spheroid and in vivo
tumor models to evaluate the co-delivery of
paclitaxel (PCL) and a potent NF-κB inhibitor
curcumin (CUR). PCL and CUR were co-loaded into the
polyethylene glycol-phosphatidyl
ethanolamine (
PEG-PE) based polymeric
micelles modified with
transferrin (TF) as the targeting
ligand. Cytotoxicity, cellular association and accumulation into the deeper layers were investigated in the spheroids and compared with the monolayer cell culture. Comparing to non-targeted
micelles, flow cytometry and confocal imaging proved significantly deeper and higher
micelle penetration into the spheroids with TF-targeting. Both in monolayers and in spheroids, PCL cytotoxicity was significantly increased when co-delivered with CUR in non-targeted
micelles or as single agent in TF-targeted
micelles, whereas TF-modification of co-loaded
micelles did not further enhance the cytotoxicity. In vivo
tumor inhibition studies showed good correlation with the 3D cell culture experiments, which suggests the current spheroid model can be used as an intermediate model for the evaluation of co-delivery of anticancer compounds in targeted
micelles.