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.
Highlights
Melanoma, the malignant cancer of melanocytes, is the most aggressive form of skin cancer which causes the most skin-cancer related deaths [1]
Solution state NMR spectroscopy is a powerful tool for elucidating the molecular level structure and host/guest stoichiometry by analyzing the complexation-induced shifts (CIS)
In 2D ROESY NMR, the nuclear Överhauser effect (NOE ROE) is employed to elucidate the noncovalent interactions between nuclei that reside in close spatial proximity (~5 Å) [35,36]
Summary
The malignant cancer of melanocytes, is the most aggressive form of skin cancer which causes the most skin-cancer related deaths [1]. According to the World Health Organization (WHO), over 132,000 new cases of melanoma are diagnosed annually [2]. Melanoma can be treated by surgical incision with high survival rate. In the stage of in-transit metastases, in which the metastases are >2 cm from the primary lesion but within the nodal basin, the response to local and systemic therapeutic options is moderate with 5-year survival of 32.8% [3,4]. Advanced metastatic melanoma shows limited response to current therapeutic options with very low survival rate of less than 5% over 5 years [5]. Systemic chemotherapy is the first-line option for most patients with metastatic melanoma
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