PEGylated nanoassemblies composed of edelfosine and fulvestrant drugs: In vitro antiproliferative effect against breast cancer cells

Abstract

Edelfosine (EDL) and Fulvestrant (FUL), proven anticancer agents, suffer significant limitations for low water solubility and poor bioavailability. FUL is an effective breast cancer endocrine therapy (ET) as a selective estrogen receptor α (ERα) antagonist. Resistance to ET results from ER ligand-independent transactivation via PI3K-AKT and/or MAPK/ERK survival pathways that are the main target for EDL. Thus, combination of both drugs in the same nanosystem, with high encapsulation efficiency, may enhance their effectiveness, overcome undesirable features, and may overcome ET resistance. In the current work, self-assembled nanostructures of both drugs were formulated utilizing the nanoprecipitation method as stable and monodisperse nanoassemblies in aqueous suspension. The selected drug-based nanostructures were fully characterized by dynamic light scattering, FTIR spectroscopy, and transmission electron microscopy. Different drugs ratios, drug contents, colloidal stability, and hemolysis experiments were investigated. The selected nanoassemblies were also evaluated for their cytotoxicity, cellular uptake, and cell penetration against human breast cancer cell lines, MCF-7 and MDA-MB-231. The current study provides, for the first time, a novel drug–based self nanoassemblies composed of EDL and FUL that enable a high encapsulation efficiency of 80 and 84% for two hydrophobic agents, FUL and EDL, respectively, with almost no or minimum amounts of auxiliary stabilizing lipids that may affect, counter interact, or retard their final approval. Both selected formulas, F2 NPs (FUL and EDL) and F2F NPs (FUL, EDL, cholesterol, and DSPE-PEG), provide ˂ 0.3 polydispersity index (PDI) with an average size of and 224.3 ± 1.8 nm and 247.3 ± 3.3 zeta potential of −17.3 ± 1.06 and −23.1 ± 3.51 mV, respectively. The PEGylated F2F NPs showed reasonable stability at 4 °C and in both physiological and acidic conditions at 37 °C in PBS buffer at pH 7.4 and pH 5.5. F2F NPs exhibited an evident cellular uptake and cell penetration with ameliorated antitumor activity and induced apoptosis, mainly against ER + Breast cancer cell line. Finally, the PEGylated F2F NPs can be a promising nanoplatform for delivering FUL and EDL combination that may improve therapeutic outcomes against breast cancer compared to free drugs.