N-desmethyl tamoxifen and quercetin-loaded multiwalled CNTs: A synergistic approach to overcome MDR in cancer cells.

Our aim was to develop multiwalled carbon nanotubes (MWCNTs)-based nanoconstructs for the codelivery of N-desmethyl tamoxifen (N-TAM) and a mild P-gp efflux inhibitor, i.e., quercetin (QT) to treat multiple drug resistant (MDR) cancer cells. The hypothesis banks on three-tier attack on the MDR mechanisms viz. drug derivatization, MWCNT permeation and P-gp inhibition. Tamoxifen was converted to N-TAM and was conjugated to carboxylated MWCNTs mediated by a biodegradable linker, i.e., tetraethylene glycol (TEG). QT was adsorbed on the conjugate to fetch the final product, i.e., N-TAM-TEG-MWCNT-QT. Spectroscopic analysis confirmed successful conjugation of N-TAM and physical adsorption of QT. The in-vitro release of N-TAM from the N-TAM-TEG-MWCNT conjugate was minimal to that of pure drug under physiological conditions, but markedly enhanced under the acidic pH of cancer cells. The developed nanometeric formulation was found to be haemo-compatible. Reduced IC50values and better cellular uptake in drug resistant MDA-MB-231 cells were observed, followed by enhanced drug availability in the systemic circulation of rodents vis-à-vis naïve drug. The smart nanosystem conferred the desired temporal drug delivery, enhanced drug efficacy, biocompatibility and conducive pharmacokinetics, which are the crucial desired attributes to tackle the increasing concern of MDR in cancer chemotherapy.