Evaluation of β-cyclodextrin-modified gemini surfactant-based delivery systems in melanoma models

Abstract

Novel drug delivery systems are developed to improve the biological behavior of poorly soluble drugs and to improve therapeutic outcomes. In melanoma therapy, the goal is efficient drug delivery and mitigation of drug resistance. Melphalan (Mel), a currently used therapeutic agent for melanoma, requires solvent system for solubilization, leading to poor chemical stability. Moreover, drug resistance often renders the drug inefficient in clinical setting. A novel β-cyclodextrin-modified gemini surfactant (CDgemini) delivery system was developed to incorporate Mel in order to improve its physicochemical and biological behavior. Melphalan nanoparticles (Mel-NP) showed optimal particle size in the 200-250 nm range for endocytosis and induced significantly higher cell death compared with Mel (50% of inhibitory concentration [IC₅₀] of 36 µM for the complexes vs 82 µM for Mel). The CDgemini delivery system did not alter the pathway of the cellular death triggered by Mel and caused no intrinsic toxicity to the cells. The Mel-NP complexes induced significant cell death in melanoma cells that were rendered resistant to Mel. These findings demonstrate in principle the applicability of the CDgemini delivery system as safe and efficient alternative to the current melanoma therapy, especially in chemoresistant cases.

Keywords: anticancer agent; apoptosis; drug resistance; flow cytometry; lipid nanoparticles; spheroid; zeta potential.

Figure 1

Photomicrographs of the cross-section of tumor spheroids showing a three-dimensional stratification. 200× Magnification.

Figure 2

Caspases 3/7, 8, 2 and 9 expression for Mel (A), Mel-NP (B) and CDgemini (C) treated cells. Notes: Results are presented for triplicate samples. Error bars are standard deviation. Abbreviations: Au, arbitrary unit; Mel-NP, drug/CDgemini nanoparticles; CDgemini, β-cyclodextrin-modified gemini; Mel, melphalan.

Figure 3

Evaluation of the efficiency of the Mel 20 and 40 µM and Mel-NP 20 and 40 µM concentrations on Mel-resistant melanoma cells. Notes: Bars represent standard deviation. *Statistical difference at P<0.05. Abbreviations: Mel-NP, drug/CDgemini nanoparticles; CDgemini, β-cyclodextrin-modified gemini; Mel, melphalan.