Abstract
Imiquimod (IMQ) is an immunostimulant drug approved for the topical treatment of actinic keratosis, external genital-perianal warts as well as superficial basal cell carcinoma that is used off-label for the treatment of different forms of skin cancers, including some malignant melanocytic proliferations such as lentigo maligna, atypical nevi and other in situ melanoma-related diseases. Imiquimod skin delivery has proven to be a real challenge due to its very low water-solubility and reduced skin penetration capacity. The aim of the work was to improve the drug solubility and skin retention using micelles of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of vitamin E, co-encapsulating various lipophilic compounds with the potential ability to improve imiquimod affinity for the micellar core, and thus its loading into the nanocarrier. The formulations were characterized in terms of particle size, zeta potential and stability over time and micelles performance on the skin was evaluated through the quantification of imiquimod retention in the skin layers and the visualization of a micelle-loaded fluorescent dye by two-photon microscopy. The results showed that imiquimod solubility strictly depends on the nature and concentration of the co-encapsulated compounds. The micellar formulation based on TPGS and oleic acid was identified as the most interesting in terms of both drug solubility (which was increased from few µg/mL to 1154.01 ± 112.78 µg/mL) and micellar stability (which was evaluated up to 6 months from micelles preparation). The delivery efficiency after the application of this formulation alone or incorporated in hydrogels showed to be 42- and 25-folds higher than the one of the commercial creams.
Highlights
Actinic keratosis (AK) is a precancerous lesion caused by excessive exposure to light whose appearance is related to several mechanisms such as oxidative stress, immunosuppression, inflammation, altered proliferation and dysregulation of cell growth, impaired apoptosis, mutagenesis and papilloma virus (HPV) [1]
We evaluated the effect of different formulations on imiquimod solubility
As fatty acids have previously demonstrated good imiquimod solubilization properties [15,44], we studied their co-encapsulation into tocopheryl polyethylene glycol succinate (TPGS) micelles
Summary
Actinic keratosis (AK) is a precancerous lesion caused by excessive exposure to light whose appearance is related to several mechanisms such as oxidative stress, immunosuppression, inflammation, altered proliferation and dysregulation of cell growth, impaired apoptosis, mutagenesis and papilloma virus (HPV) [1]. As actinic keratosis is the most common precursor of cutaneous invasive squamous cell carcinomas, its treatment appears to be imperative. In this sense, imiquimod (IMQ), a synthetic drug belonging to the class of imidazoquinolones, has widely demonstrated its usefulness thanks to its immunostimulant activity mediated by the binding to the toll-like receptors 7 and 8. Imiquimod (IMQ), a synthetic drug belonging to the class of imidazoquinolones, has widely demonstrated its usefulness thanks to its immunostimulant activity mediated by the binding to the toll-like receptors 7 and 8 These receptors play a pivotal role in controlling innate immune system response as they induce the secretion of pro-inflammatory cytokines such as interferons (IFN-α, IFN-γ), tumor necrosis factor-alpha. Together with imiquimod indication for the treatment of actinic keratosis, other uses of the drug have been approved by the U.S
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