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:

• lipid nanoparticles
• anticancer agent
• drug resistance
• apoptosis
• spheroid
• zeta potential
• flow cytometry

Supplementary material

Figure S1 Flow cytometry plots.

Notes: (A) Untreated cells (1) forward vs side-scattering and (2) early apoptotic marker Annexin V vs late apoptotic/necrotic marker propidium iodide. (B) Cells treated with melphalan in acidified ethanol (1) forward vs side-scattering and (2) early apoptotic marker Annexin V vs late apoptotic/necrotic marker propidium iodide. (C) Cells treated with melphalan/CDgemini nanoparticles (1) forward vs side-scattering and (2) early apoptotic marker Annexin V vs late apoptotic/necrotic marker propidium iodide. (D) Cells treated with the CDgemini surfactant delivery agent alone (1) forward vs side-scattering and (2) early apoptotic marker Annexin V vs late apoptotic/necrotic marker propidium iodide. While the MTT assay and forward/side scattering plot (D1) of the cells treated with the CDgemini surfactant delivery system alone indicates no cellular death, similarly to untreated cells (A1), the plot for the apoptotic marker of the delivery agent (D2) shows a significant shift of the whole healthy population. This shift makes interpreting the cell death attributed to the Mel-CDgemini nanoparticles (C2) impossible.

Abbreviations: Au, arbitrary unit; Mel-NP, Melphalan/CDgemini nanoparticles.

Acknowledgments

This work was funded by the Natural Sciences and Engineering Research Council and the College of Pharmacy and Nutrition, University of Saskatchewan.

Disclosure

The authors report no conflicts of interest in this work.