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.

中文翻译：

---

通过 TPGS 胶束改善咪喹莫特增溶和皮肤保留：利用油酸的共溶作用

咪喹莫特 (IMQ) 是一种免疫刺激药物，批准用于局部治疗光化性角化病、外生殖器 - 肛周疣以及浅表基底细胞癌，用于治疗不同形式的皮肤癌，包括一些恶性黑色素细胞增生如恶性雀斑、非典型痣等原位黑色素瘤相关疾病。咪喹莫特的皮肤递送已被证明是一个真正的挑战，因为它的水溶性非常低，皮肤渗透能力降低。这项工作的目的是使用 d-α-生育酚聚乙二醇 1000 琥珀酸酯 (TPGS) 的胶束提高药物溶解度和皮肤保留率，TPGS 是一种水溶性维生素 E 衍生物，共包封各种具有潜在能力的亲脂性化合物提高咪喹莫特对胶束核的亲和力，从而将其加载到纳米载体中。制剂的特征在于粒度、zeta 电位和随时间推移的稳定性，并通过咪喹莫特在皮肤层中保留的量化和双光子显微镜对胶束负载荧光染料的可视化来评估胶束在皮肤上的性能。结果表明咪喹莫特的溶解度严格取决于共包封化合物的性质和浓度。基于 TPGS 和油酸的胶束配方在药物溶解度（从几微克/毫升增加到 1154.01 ± 112.78 微克/毫升）和胶束稳定性（从 6 个月开始评估）方面被认为是最有趣的。胶束制备）。