Abstract
Bleomycin exhibits antiproliferative effects desirable for use in dermato-oncology but topical use is limited by its 1415 Da molar mass. Ablative fractional laser (AFL)-assisted drug delivery has been shown to enhance drug uptake in skin. The aim of this study was with AFL to deliver bleomycin into skin, quantify uptake, and visualize biodistribution with mass spectrometry. In a Franz diffusion cell study, pig skin samples (n = 66) were treated with AFL (λ = 10,600 nm), 5% density, and 0, 5, 20, or 80 mJ/microbeam (mb) pulse energies before exposure to bleomycin for 0.5, 4, or 24 h. Bleomycin was quantified in biopsy cryosections at depths of 100, 500, and 1500 µm using high-performance liquid chromatography-mass spectrometry (LC-MS), and drug biodistribution was visualized for 80 mJ/mb samples by matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The pulse energies 5, 20, and 80 mJ/mb resulted in microscopic ablation zones (MAZs) reaching superficial, mid, and deep dermis respectively. Bleomycin was successfully delivered into the skin and deeper MAZs and longer exposure time resulted in higher skin concentrations. After 24 h, AFL exposure resulted in significant amounts of bleomycin throughout all skin layers (≥510 µg/cm3, p ≤ .002). In comparison, concentrations in intact skin exposed to bleomycin remained below limit of quantification. MALDI-MSI supported the quantitative LC-MS results by visualizing bleomycin biodistribution and revealing high uptake around MAZs with delivery into surrounding skin tissue. In conclusion, topical drug delivery of the large and hydrophilic molecule bleomycin is feasible, promising, and should be explored in an in vivo setting.
Highlights
Pretreatment with ablative fractional lasers (AFL) shows promise to improve topical therapies by enhancing drug delivery through the skin (Haedersdal et al, 2016)
We aim to explore topical delivery of the large and hydrophilic drug bleomycin after Ablative fractional laser (AFL) delivery, quantify skin uptake with high-performance liquid chromatography-mass spectrometry (LC-MS), and visualize drug biodistribution in superficial (100 mm), mid (500 mm), and deep (1500 mm) dermis
Drug uptake depended on microscopic ablation zones (MAZs) depth and exposure time, resulting in higher bleomycin concentrations using deeper
Summary
Pretreatment with ablative fractional lasers (AFL) shows promise to improve topical therapies by enhancing drug delivery through the skin (Haedersdal et al, 2016). AFL targets water and in precise microbeams ablates tissue, resulting in laser channels termed microscopic ablation zones (MAZ), with surrounding vertical coagulation zones (CZ) of variable thickness (Hantash et al, 2007). Drug properties such as high molecular weight (>500 Da) and water solubility pose challenges to uptake through the lipid bilayers in the stratum corneum of intact skin (Morrow et al, 2007; Aulton, 2013). With chemical properties including molar masses of 1415–1426 Da and a predicted logP of À7.5 (Kim et al, 2016), bleomycin cannot cross the skin barrier unassisted to any significant degree
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