Inclusion complexes of melphalan with gemini-conjugated β-cyclodextrin: Physicochemical properties and chemotherapeutic efficacy in in-vitro tumor models

Abstract

Β-cyclodextrin (ΒCD) has been widely explored as an excipient for pharmaceuticals and nutraceuticals as it forms stable host-guest inclusion complexes and enhances the solubility of poorly soluble active agents. To enhance intracellular drug delivery, ΒCD was chemically conjugated to an 18-carbon chain cationic gemini surfactant which undergoes self-assembly to form nanoscale complexes. The novel gemini surfactant-modified ΒCD carrier host (hereafter referred to as 18:1ΒCDg) was designed to combine the solubilization and encapsulation capacity of the ΒCD macrocycle and the cell-penetrating ability of the gemini surfactant conjugate. Melphalan (Mel), a chemotherapeutic agent for melanoma, was selected as a model for a poorly soluble drug. Characterization of the 18:1ΒCDg-Mel host-guest complex was carried out using 1D/2D 1H NMR spectroscopy and dynamic light scattering (DLS). The 1D/2D NMR spectral results indicated the formation of stable and well-defined 18:1ΒCDg-Mel inclusion complexes at the 2:1 host-guest mole ratio; whereas, host-drug interaction was attenuated at greater 18:1ΒCDg mole ratio due to hydrophobic aggregation that accounts for the reduced Mel solubility. The in vitro evaluations were performed using monolayer, 3D spheroid, and Mel-resistant melanoma cell lines. The 18:1ΒCDg-Mel complex showed significant enhancement in the chemotherapeutic efficacy of Mel with 2-3-fold decrease in Mel half maximal inhibitory concentration (IC50) values. The findings demonstrate the potential applicability of the 18:1ΒCDg delivery system as a safe and efficient carrier for a poorly soluble chemotherapeutic in melanoma therapy.