Basal cell carcinomas (BCCs) are the most prominent type of skin cancer in humans (Dika et al., 2020, Leiter et al., 2020, Roky et al., 2025). BCCs affect approximately 80% of the 2–3 million cases of non-melanoma skin cancer in the world. Every year, BCCs impact 2.8 million individuals in the United States. The incidence rate continues to rise (Eisemann et al., 2014, Kauvar et al., 2015). Smoothened, a membrane-spanning protein integral to Hedgehog signal transduction controlling the Hedgehog (Hh) pathway, contributes to basal cell carcinoma development and progression (Epstein, 2008). The majority of BCCs are treated with surgery, radiotherapy, or topical treatments (Cho et al., 2014). Alternative therapeutic options—including imiquimod, photodynamic therapy, cryosurgery, curettage, and radiation—may be explored based on histological subtype, tumor features, and patient health status (Marzuka and Book, 2015). However, a small proportion (approximately 1%) advances to metastatic or locally advanced basal cell carcinoma, a malignancy that disseminates systemically and becomes refractory to surgical excision or radiotherapy (Cowey, 2013). Surgical therapy in these situations would result in significant deformity or loss of function (Lear et al., 2014, Sekulic et al., 2013). Novel therapy approaches are in great need since surgery may be ineffective for complicated or recurrent cancers, and existing non-surgical topical techniques have lower therapeutic efficacy (Olesen et al., 2020).

Vismodegib (Hedgehog Antagonist GDC-0449) was approved by the US Food and Drug Administration in 2012 and by the European Medicines Agency in 2013 as the first orally bioavailable Smoothened receptor inhibitor for treating adult patients with metastatic or locally advanced basal cell carcinoma (Apalla et al., 2017, Cowey, 2013, Dreier et al., 2014, Macha et al., 2013). Vismodegib selectively blocks the Hh signaling cascade through Smoothened protein inhibition, thereby suppressing Gli-1/2 transcriptional activation and disrupting malignant cell proliferation and survival (Cowey, 2013). The medicine is currently available on the market as an orally administered Erivedge TM capsule 150 mg (Genentech). Till today, vismodegib remains a valuable option for the treatment of advanced BCC (Fife et al., 2017). However, the oral administration of vismodegib poses several drawbacks. The compound exhibits poor bioavailability. Furthermore, the oral use is limited by frequent and significant class-specific, systemic adverse effects (i.e., dysgeusia, muscle spasms, and alopecia), which could cause patient incompliance and treatment discontinuation for 12% of patients (Migden et al., 2015, Sekulic et al., 2012).

Therefore, topical delivery systems of vismodegib could enable a safe and effective treatment of BCCs with less systemic side effects, higher local drug concentrations, and improved patient compliance (Nastiti et al., 2017, Olesen et al., 2019). Recently, substantially enhanced skin absorption of vismodegib has been reported in vitro to deliver a higher plasma drug concentration than that achieved via the oral route (Olesen et al., 2019). Similarly, enhanced delivery of vismodegib has been obtained using microneedles (Nguyen and Banga, 2015a) and specialized drug formulations (Calienni et al., 2019, Kandekar et al., 2019). Vismodegib’s physicochemical properties (i.e., molecular weight 421.30 g/mol and lipophilicity log P = 2.7) make the drug particularly suitable for transdermal delivery.

Given the expansive skin surface area, the convenience of administration, patient acceptance, and therapeutic efficacy, transdermal delivery has long been recognized as a potential and appealing method for administering both small compounds and macromolecules. Therapeutic drugs are delivered transdermally, bypassing first-pass hepatic metabolism. As a result, this strategy is favored for (i) drugs with poor oral absorption, (ii) compounds degraded in gastric acidic conditions, (iii) compounds that irritate the gastrointestinal system, and (iv) medicines that require a targeted delivery rate (Bhat et al., 2025, Xu et al., 2025). However, transdermal transport is limited by the skin’s low permeability, which is caused by the stratum corneum layer of corneocytes trapped in a lipid-rich structure (Kolli and Banga, 2008). The stratum corneum serves as the principal barrier and is critical for controlling drug permeability via the skin. Traditionally, passive diffusion has been restricted to high-potency, low-molecular-weight compounds exhibiting moderate-to-high lipophilicity (Hampton, 2005). Transdermal delivery may be substantially improved through formulation optimization and various enhancement techniques. The primary challenge of these approaches is to prevent skin infection, irritation, and pain while sufficiently compromising barrier integrity to facilitate the transport of therapeutic agents (Bachhav et al., 2010).

The Precise Laser Epidermal System (P.L.E.A.S.E®, Pantec Biosolutions AG, Liechtenstein) employs a diode-pumped Erbium:yttrium-aluminum-garnet laser to produce a fractional ablative laser with an infrared wavelength (2940 nm). This wavelength is equivalent to the absorbance peak of the water molecules prevalent in skin tissue. When laser pulses deliver energy to skin tissue, water molecules absorb the laser’s loads of energy, vibrate, heat up, and quickly evaporate off the skin, forming aqueous micron-sized channels measuring 150 µm in diameter across a small skin regions that serve as transport pathway through the epidermis (Heinrich et al., 2011, Weiss et al., 2012, Yu et al., 2011). Due to the short duration of the energy exposure, heat transmission to the surrounding skin tissue is insignificant (Yu et al., 2011). Thus, the skin around the channels would likely be undamaged (Sklar et al., 2014). Each laser pulse may ablate a consistent quantity of skin tissue, allowing for the precise control of the pore depth and the generation of uniform micropore distributions (Nelson et al., 1991). Importantly, the channel diameters may be modified, controlled, and programmed by adjusting the system configuration, such as laser fluence, pore density, and ablated region (Haji Mohammadi et al., 2025, Parhi and Mandru, 2021). Numerous experiments have been conducted to evaluate the effects of varying laser parameters on the skin permeability of a variety of compounds (Taudorf et al., 2016, Taudorf et al., 2014). To obtain a safe, painless, and non-invasive ablation treatment, the pore depth must be monitored and limited to prevent damaging the delicate nerve endings located in the dermis layer. Ablative laser treatment has been shown to be tolerable in vivo (Kalia et al., 2008, Zech et al., 2011). In practice, the device can rapidly generate an array of several hundred micropores of a desired depth. As a result, ablative lasers may be used to deliver drugs transdermally in a controlled, reproducible, personalized, and targeted way (Nguyen, 2017).

The present investigation utilized fractional laser ablation for disrupting the physical skin integrity, enabling vismodegib diffusion through laser-generated micropores and thereby enhancing in vitro drug permeation through the skin. This study examined the effects of laser ablation on vismodegib penetration, investigating laser fluence, pore density, and drug concentration variables. We performed characterization of laser-treated human skin and investigation of laser-mediated transdermal delivery of vismodegib in vitro. Furthermore, we introduced a novel, reliable, and effective method to calculate the laser ablation volume in skin. We reported a strong linear correlation between this ablation volume and the drug delivery, i.e., cumulative delivery and steady-state plasma concentration. Also, we thoroughly investigated the permeability of vismodegib regarding cumulative drug permeability, lag time, flux, diffusion coefficient, permeability coefficient, and steady-state plasma concentration, total delivery, delivery efficiency, and topical selectivity.