Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells

Abstract

PurposeThe 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.MethodsAnticancer 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.ResultsPtx-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.ConclusionMDR 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.

Application of Solid Lipid Nanoparticles to Improve the Efficiency of Anticancer Drugs

“…All in all, there are many drugs that have been incorporated in SLNs with positive results [30,59,60,61,62,63,64], as well as tumors in which their action has been verified [58,63,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80]. These are the main supports for the advance in research on the use of SLNs in tumor treatments.…”

“…The evaluation of concentration-dependent cytotoxicity indicated that SLNs with paclitaxel notably improved the IC 50 concentration in drug-resistant cells. Besides, these nanocarriers provided an enhanced cellular uptake in relation to the other formulations especially in drug-resistant cells, proving that SLNs are effective in avoiding multidrug resistance mechanisms in breast cancer cells [66].…”

Formulation and Characterization of Phytostanol Ester Solid Lipid Nanoparticles for the Management of Hypercholesterolemia: An ex vivo Study

“… 98 Likewise, Rhodamine 123-loaded SLNPs (average diameter 224 nm) were taken up by multidrug-resistant breast cancer cells by endocytosis. 99 The nano-scaled size, generally spherical shape and negative surface charge might have contributed to the internalization of SLNPs. 100 …”

Drug Resistance in Metastatic Breast Cancer: Tumor Targeted Nanomedicine to the Rescue

“…Xu et al significantly enhanced the anti-cancer activity of PTX by incorporating it into solid lipid nanoparticles in MCF7 and MCF7/ADR cell lines. Encapsulation of PTX into solid lipid nanoparticles successfully reversed the multidrug resistance by evading the efflux pumps in drug-resistant cells [ 179 ]. In addition to these formulations, co-encapsulation of PTX with other drugs into nano-formulations significantly enhanced the anti-cancer activity of the compounds in metastatic/multidrug-resistant breast cancer cells.…”