Melanoma is a type of malignant tumor that emerges from the melanocytes [1] located in the basal layer of the epidermis [2]. Despite representing only 1–5% of skin cancers, it is responsible for over 80% of deaths associated with skin diseases [3]. Indeed, recent data reveals that melanoma caused more than 57,000 deaths worldwide in 2020 [4], [5].

Although significant progress has been made with more efficient modalities for the chemotherapy treatment of melanomas, local excision remains the primary clinical treatment option. However, excision is only feasible for patients diagnosed at early stages of the disease [6]. One of the advances in chemotherapy involves using protein kinase inhibitors as more selective drugs for certain tumors. Dabrafenib, for example, is a BRAF kinase inhibitor already used to treat melanomas. However, notwithstanding the positive results in reducing the tumors, some patients have developed drug resistance, relapse, and show disease progression, demanding combined therapies with immune checkpoint inhibitors [7], [8] that can lead to severe adverse reactions in a significant proportion of individuals undergoing treatment [9], [10].

Ibrutinib (IBR) is an inhibitor primarily targeting Bruton's tyrosine kinase (BTK), specifically at the amino acid Cys 481 in the ATP-binding domain. BTK is critical in the B-cell receptor (BCR) signaling pathway, influencing cell survival, proliferation, and differentiation [11], [12], [13]. IBR can also bind to other tyrosine kinase proteins with the same cysteine residue, which enables it to act on additional molecular targets. These targets include members of the TFK family (ITK, TEC, BMX, and RLK/TXK), kinases within the EGFR family (EGFR, ErbB2/HER2, and ErbB4/HER4), as well as BLK and JAK3 kinases [12], [14].

Despite the high effectiveness of oral IBR in cancer treatment, its toxicity can result in dose reduction or discontinuation of use [15]. The main adverse effects of IBR systemic usage include atrial fibrillation, hemorrhages, hypertension, myalgia, anemia, infections, and diarrhea, with some reactions persisting even after treatment discontinuation [16]. At the cutaneous level, approximately 30% of patients receiving such medication develop a rash, skin infection, neutrophilic dermatosis, peripheral edema, and fissures [16], [17], [18].

The oral administration of IBR also faces challenges. Classified as a BCS class II drug (low solubility and high permeability), its low solubility (approximately 0.002 mg/mL) and extensive first-pass effect contribute to its poor bioavailability of approximately 2.9%, which can be even lower depending on the patient's nutritional status [13], [19], [20], [21]. Consequently, oral drug products contain high doses of the drug, ranging from 420 to 840 mg per day, depending on the type of cancer being treated, which increases the occurrence of the aforementioned adverse effects [22], [23], [24].

In this work, we propose the topical application of IBR for melanoma treatment as an alternative to reduce the adverse reactions associated with oral administration. This approach has proven effective in delivering specific chemotherapeutic agents to skin tumors, particularly those more superficial [25]. In addition, topical administration offers the advantage of minimizing drug interactions and the required dosage, making the products more economically accessible.

The primary limitation to IBR topical effectiveness is the low percutaneous absorption in therapeutic levels to the sites where invasive tumors are located [26] – the basal epidermal layer in the case of melanomas. IBR is a lipophilic drug, which, upon topical application, must present difficulty in leaving the most superficial layer of the skin, the stratum corneum, which has high lipophilicity, to spread through the other layers of the skin towards the melanoma [27]. A lipid-based system to entrap IBR could overcome this issue in this context. Among lipid-based systems, nanostructured lipid carriers (NLCs) hold particular significance.

NLCs comprise a mixture of solid and liquid lipids dispersed in an aqueous phase and stabilized by surfactants. This configuration ensures a colloidal suspension of solid nanoparticles at room temperature, with dimensions ranging from 10 to 1000 nm, thereby enabling improved physicochemical stability of the formulation, high biocompatibility, and safety for topical application [28], [29]. Additionally, the lipids present in these nanosystems can interact with the combination of ceramides and fatty acids in the stratum corneum, generating an occlusive effect and increasing the fluidity of lipids, which, in turn, influences drug permeation across such superficial skin layer [27].

Thus, this study aimed to develop a formulation based on NLCs for topical IBR delivery to treat melanoma. First, the efficacy of IBR on melanoma proliferation was evaluated in vitro, considering that few studies report such an effect on human melanoma cells. Then, preformulation tests were performed to determine the physical compatibility between the drug and the components selected to prepare the NLCs. Next, NLCs with two lipid compositions were prepared, characterized, and subjected to in vitro release and skin permeation assays. Finally, an analysis of the interaction between the constituting lipids of the NLCs and the stratum corneum was carried out to explain the effect of NLCs composition on drug transport through the skin.