Abstract
For topical treatment of skin cancer, the design of pH-responsive nanocarriers able to selectively release the drug in the tumor acidic microenvironment represents a reliable option for targeted delivery. In this context, a series of newly synthesized surface-active fatty acid-protic ionic liquids (FA-PILs), based on tetramethylguanidinium cation and different natural hydrophobic fatty acid carboxylates, have been investigated with the aim of developing a pH-sensitive nanostructured drug delivery system for cutaneous administration in the skin cancer therapy. The capability of FA-PILs to arrange in micelles when combined with each other and with the non-ionic surfactant d-α-Tocopherol polyethylene glycol succinate (vitamin E TPGS) as well as their ability to solubilize imiquimod, an immuno-stimulant drug used for the treatment of skin cancerous lesions, have been demonstrated. The FA-PILs-TPGS mixed micelles showed pH-sensitivity, suggesting that the acidic environment of cancer cells can trigger nanostructures’ swelling and collapse with consequent rapid release of imiquimod and drug cytotoxic potential enhancement. The in vitro permeation/penetration study showed that the micellar formulation produced effective imiquimod concentrations into the skin exposed to acid environment, representing a potential efficacious and selective drug delivery system able to trigger the drug release in the tumor tissues, at lower and less irritating drug concentrations.
Highlights
The incidence of skin cancer is on the rise worldwide and surgical removal or invasive procedures represent the most widely used treatments
The aim of the present work was to demonstrate the ability of a new set of fatty acid-protic ionic liquids (FA-protic ionic liquids (PILs)) (Figure 1) to behave as surfactants and originate micelles with nanometric dimensions
The FA-PILs structures were assessed by 1H and 13C-NMR analyses (Supplementary Figure S1–S4)
Summary
The incidence of skin cancer is on the rise worldwide and surgical removal or invasive procedures represent the most widely used treatments. In case of unresectable melanoma, in-transit metastatic melanoma, and lentigo maligna, non-surgical approaches can be pursued and include systemic agents, local radiation, and intralesional and topical therapies [8,9]. With advances in nano-technology and drug delivery systems, skin cancer treatment has been diversified and nanostructure-based formulations represent promising options, especially for topical delivery [10,11,12]. For the last few decades, the nanotechnologies have been studied to enhance drug bioavailability following topical application [10,14,15,16,17] and received increasing attention for the treatment of melanoma [2,7,18]. The field is open for the development of more potent and biocompatible topical formulations
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