International Journal of Nanomedicine (Nov 2018)
Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells
Abstract
Wenting Xu, Eun Ju Bae, Mi-Kyung Lee Department of Pharmaceutical Sciences, Woosuk University, Jeonbuk, South Korea Purpose: The aim of this study was to show enhanced anticancer activity of paclitaxel (Ptx) incorporated into solid lipid nanoparticles (SLNs) and reveal reversal of multidrug resistance (MDR) by SLNs mediated by increased uptake through different entry mechanisms from that in drug-sensitive cells.Methods: Anticancer activity of Ptx incorporated in SLNs (Ptx-SLNs) was measured in the drug-sensitive human breast cancer cell line MCF7 and its MDR variant MCF7/ADR. Cellular uptake of cargo molecules in SLNs was compared using Ptx-SLNs and rhodamine 123-loaded SLNs (Rho-SLNs) in both cell lines. In addition, endocytic uptake was evaluated using genistein (Gen) and chlorpromazine (Cpz) as inhibitors of clathrin- and caveola-mediated endocytosis, respectively.Results: Ptx-SLNs showed remarkably enhanced anticancer activity in MCF7/ADR compared to Ptx delivered in dimethyl sulfoxide (DMSO) and Cremophor EL-based vehicles. SLNs significantly increased intracellular uptake of Ptx and Rho in MCF7/ADR. Western blotting demonstrated that clathrin was expressed in both cell lines, while caveolin 1 was expressed only in MCF7/ADR. In MCF7/ADR, uptake of Ptx-SLNs and Rho-SLNs was reduced by Gen, while there was no change by Cpz, suggesting the involvement of caveola-mediated endocytosis. Size reduction of Rho-SLNs through high-pressure homogenization (Rho-SLNs) appeared to cause a shift of the endocytosis mechanism from a clathrin-independent pathway to a clathrin-dependent one. In contrast to MCF7/ADR, the uptake of SLNs into MCF7 was not changed by Gen or Cpz, suggesting involvement of clathrin- and caveola-independent mechanism for the entry of SLNs.Conclusion: MDR was reversed by incorporating drug into SLNs, and the reversal was mediated by increased uptake of SLNs evading efflux pumps in MDR cells. The enhanced uptake could also be due to the use of different endocytosis pathways by SLNs in MDR cells from drug-sensitive cancer cells. Keywords: SLNs, MDR, paclitaxel, Pgp, breast cancer, endocytosis
