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Fractional laser-assisted topical delivery leads to enhanced,accelerated and deeper cutaneous 5-fluorouracil uptake |
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| Authors: | Emily Wenande Uffe H. Olesen Mette M. B. Nielsen Christian Janfelt Steen Honoré Hansen R. Rox Anderson |
| Affiliation: | 1. Department of Dermatology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark;2. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark;3. Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark;4. Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA |
| Abstract: | Background: Topical 5-Fluorouracil (5-FU) exhibits suboptimal efficacy for non-melanoma skin cancer, attributed to insufficient intracutaneous penetration. This study investigates the impact of ablative fractional laser (AFXL) at different laser-channel depths on cutaneous 5-FU pharmacokinetics and biodistribution. Methods: In vitro porcine skin underwent AFXL-exposure using a fractional 10,600 nm CO2-laser, generating microscopic ablation zones (MAZ) reaching the dermoepidermal junction (MAZ-ED), superficial-(MAZ-DS), or mid-dermis(MAZ-DM). 5-FU in AFXL-exposed and control skin was measured in Franz diffusion cells at 4 and 24 hours (n = 55). HPLC quantified 5-FU in full-thickness skin, specific skin depths of 100μm-1500μm, and transcutaneous receiver-compartments. Qualitative matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) visualized 5-FU in selected samples. Results: Overall, AFXL enhanced and accelerated 5-FU uptake versus unexposed controls, with increased accumulation in deep skin layers (p < 0.01). While total, 24-hour 5-FU uptake in control skin was 0.096 mg/cm3 (0.19% of applied concentration), AFXL delivered up to 4.707 mg/cm3 (MAZ-DM; 9.41% uptake, 49-fold enhancement) (p = 0.002; 24 hours). Indicating accelerated delivery, 5-FU in laser-exposed samples at 4 hours was at least 10-fold that of 24-hour controls (p = 0.002). Deeper laser-channels increased delivery throughout the skin (MAZ-ED vs. MAZ-DM; p<0.01). MALDI-MSI confirmed enhanced, accelerated, deeper and more uniform 5-FU distribution after AFXL versus controls. Conclusions: AFXL offers laser-channel depth-dependent, enhanced and accelerated 5-FU uptake, with increased deposition in deep skin layers. |
| Keywords: | 5-Fluorouracil fractional ablative CO2 laser Franz skin permeability diffusion cells high performance liquid chromatography laser-assisted drug delivery matrix-assisted laser desorption/ionization mass spectrometry imaging non-melanoma skin cancer |