Co-administration of tariquidar using functionalized nanostructured lipid carriers overcomes resistance to docetaxel in multidrug resistant MCF7/ADR cells

Abstract

To overcome multidrug resistance (MDR) and to enhance the efficacy of docetaxel (DTX), tariquidar (TRQ) was co-administered with DTX using nanostructured lipid carriers (NLC) functionalized with polyethylene glycol (PEG) and RIPL peptide (P/R). DTX- and TRQ-loaded plain NLC and P/R-NLC (P/R–N) were prepared using the solvent emulsification evaporation technique. All NLC samples showed a homogeneous spherical morphology and nano-sized dispersion (<210 nm) (zeta potential, −19 to −6 mV). DTX or TRQ was successfully encapsulated in NLC formulations (encapsulation efficiency >95%; drug loading 73–90 μg/mg). All NLC formulations were stable for 4 weeks when stored at 4 °C. Drug release was diffusion-controlled. DTX/TRQ combination at a 1:1 w/w ratio showed the highest synergism with a combination index value of 0.285 and was selected as the optimum combination. TRQ-P/R–N significantly enhanced the intracellular accumulation of Rhodamine 123 in MCF7/ADR cells. The co-administration of drug-loaded P/R-Ns led to potent and dose-dependent cytotoxicity and high MDR reversal efficiency. Co-treatment with DTX-P/R–N and TRQ-P/R–N increased apoptosis and enhanced G2/M cell cycle phase distribution in MCF7/ADR cells. These results indicate that the co-administration of DTX and TRQ using P/R-Ns may be a promising strategy to overcome MDR by P-gp inhibition in tumor treatments.