Fractional laser-assisted topical delivery leads to enhanced, accelerated and deeper cutaneous 5-fluorouracil uptake.
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.



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.



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.



AFXL offers laser-channel depth-dependent, enhanced and accelerated 5-FU uptake, with increased deposition in deep skin layers.
a Department of Dermatology , Copenhagen University Hospital Bispebjerg , Copenhagen , Denmark.
Emily
E
Wenande
a Department of Dermatology , Copenhagen University Hospital Bispebjerg , Copenhagen , Denmark.
Uffe H
UH
Olesen
b Department of Drug Design and Pharmacology , University of Copenhagen , Copenhagen , Denmark.
Mette M B
MM
Nielsen
c Department of Pharmacy , University of Copenhagen , Copenhagen , Denmark.
Christian
C
Janfelt
c Department of Pharmacy , University of Copenhagen , Copenhagen , Denmark.
Steen Honoré
SH
Hansen
d Wellman Center for Photomedicine , Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
R Rox
RR
Anderson
a Department of Dermatology , Copenhagen University Hospital Bispebjerg , Copenhagen , Denmark.|d Wellman Center for Photomedicine , Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
Merete
M
Haedersdal
D000279:Administration, Cutaneous; D000818:Animals; D020405:Dermis / Q000378:metabolism; D016503:Drug Delivery Systems; D004817:Epidermis / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D054020:Lasers, Gas; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine; D014018:Tissue Distribution
D005472:Fluorouracil
5-Fluorouracil; Franz skin permeability diffusion cells; fractional ablative CO2 laser; high performance liquid chromatography; laser-assisted drug delivery; matrix-assisted laser desorption/ionization mass spectrometry imaging; non-melanoma skin cancer