(T1430-01-02) Enhanced Transdermal Delivery of Anticancer Agent: A Comprehensive Study on Fractional Ablative Laser

Purpose: Basal cell carcinomas─the most prominent type of skin cancer in humans─affect approximately 80% of non-melanoma skin cancer cases in the world and impact 2.8 million individuals in the US annually. Vismodegib was approved by the US Food and Drug Administration in 2012 as the first-in-class, orally bioavailable inhibitor of Smoothened receptor for use in adult patients with metastatic or locally advanced basal cell carcinoma. However, the oral administration of vismodegib poses several drawbacks, including low absolute bioavailability, frequent systemic adverse effects, and patient incompliance. Physical properties of vismodegib appear ideal for transdermal delivery, including a small molecular weight (421.30 g/mol), moderate lipophilicity (log P = 2.7), and high permeability. In this study, fractional ablative laser was employed to disrupt the skin barrier, delivering the drug through the ablated micropores in a controlled, reproducible, and targeted way. This investigation aims to study transdermal delivery of vismodegib in vitro into and across human skin ablated by fractional ablative laser.

Methods: Skin samples were exposed to varying laser fluence (11.4, 22.7, and 34.1 J/sq.cm), pore density (2, 6, and 10%), and drug concentration (2.74, 4.11, and 5.48 mg/mL) (The Precise Laser Epidermal System platform, P.L.E.A.S.E^® system). Successful skin microporation was demonstrated by histological sectioning, dye binding, pore uniformity, confocal laser scanning microscopy, and scanning electron microscopy studies. The volume of individual pores and the total volume of pores in the skin were calculated using the pores’ depth, surface area, and the number of pores. The skin barrier function was assessed by skin resistance and transepidermal water loss (TEWL) measurements. A permeation experiment was then conducted on Franz cells to assess the transdermal delivery of vismodegib.

Results: Laser ablation provided uniform micropores in skin. The change in pore density and laser energy levels had no significant impact on the shape and surface area of the individual pores (n=10, p >0.05). As the laser energy varied, only the pores’ depth was observed to change. The successful formation of microchannels was confirmed using methylene blue staining. The microscopic images of stained skin tissue revealed that only the disrupted area of skin ─ microchannels ─ could uptake the dye while the vicinity of the channels appeared unstained with undisturbed barrier function. When the pore density decreased from 10 to 6 and 2%, the pore-to-pore distance increased markedly (n=20, p< 0.05), and the number of pores in the treatment site decreased accordingly from 90 to 54 and 16 pores. The laser-ablated pores were distributed uniformly in the treatment area. When the pore density was kept constant, the laser fluence imposed no effects on the number of pores and pore-to-pore distance. Histological images of skin layers demonstrated that laser ablation disrupted localized areas of stratum corneum and epidermis layers, leaving the surrounding of the pores unaffected. Confocal laser scanning microscopy studies revealed that increasing laser fluence resulted in the ablation of deeper channels (n=10, p< 0.01). When we kept the laser fluence constant and changed the pore density, the pore depth in skin did not change significantly (p=0.84). The individual pore volume was comparable among laser groups with differing pore densities. Notably, when the laser fluence was reduced from 34.1 to 22.7 and 11.4 J/sq.cm, the individual pore volume dropped dramatically. Decreasing the pore density led to a significant reduction in the total pore volume (n=10, p< 0.05). Also, changes in the laser fluence had a marked impact on the total pore volume. A considerable increment in TEWL and a reduction in skin electrical resistance indicated a disruption in the skin barrier. Untreated skin had a significantly lower TEWL value as compared to the laser-treated groups (n=4, p=0.03) while varying laser parameters caused no considerable difference in TEWL values of skin (p=0.60). Untreated skin had a significantly greater electrical resistance than laser-treated skin (p < 0.01). Increasing pore density from 2 to 6 and 10% resulted in a substantial reduction in skin resistance. Similarly, increasing the laser fluence from 11.4 to 22.7 and 34.1 J/sq.cm led to a significant reduction in skin resistance values (n=4, p< 0.05). The permeation experiment indicated that laser ablation with all researched parameters led to markedly more drug delivered into the receptor fluid and skin tissue (n=4, p< 0.05). An increase in the laser energy (from 11.4 to 22.7, and 34.1 J/sq.cm), pore density (from 2 to 6 and 10%), and drug concentration in the formulation (from 2.74 to 4.11, and 5.48 mg/mL) resulted in a statistically significant enhancement in the drug permeation, flux, permeability coefficient, diffusion coefficient, and predicted steady-state plasma concentration, however, a marked decrease in the lag time (p < 0.05). Drug quantity in the skin layers (i.e., stratum corneum, epidermis, and dermis), total delivery, delivery efficiency, and topical selectivity were also measured and reported.

Conclusion: Skin ablation by fractional ablative laser significantly increased transdermal delivery of vismodegib in vitro. 

Acknowledgements: The authors do not have any conflicts of interest to report for this abstract

Graphic Abstract

Transdermal delivery, lag time, flux, diffusion coefficient, permeability coefficient, and steady-state plasma concentration, total delivery, delivery efficiency, and topical selectivity of in vitro permeation of vismodegib though dermatomed human cadaver skin

In vitro permeation of vismodegib through laser-treated dermatomed human skin