Pretreatment with ablative fractional laser changes kinetics and biodistribution of topical 5‐aminolevulinic acid (ALA) and methyl aminolevulinate (MAL)

Abstract

Background and Objectives: 5-Aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) are porphyrin precursors used topically for photodynamic therapy (PDT). Previous studies have established that ablative fractional laser (AFXL) increases topical drug uptake. We evaluated kinetics and biodistribution of ALA-and MAL-induced porphyrins on intact and disrupted skin due to AFXL. Materials and Methods: Two Yorkshire swine were exposed to CO 2 AFXL (10.6 mm, 1,850 mm ablation depth) and subsequent topical application of ALA and MAL cream formulations (20%, weight/weight). Porphyrin fluorescence was quantified by digital fluorescence photography (30, 90, and 180 minutes) and fluorescence microscopy at specific skin depths (180 minutes). Results: Porphyrins gradually formed over time, differently on intact and AFXL-disrupted skin. On intact skin (no AFXL), fluorescence photography showed that MAL initially induced higher fluorescence than ALA (t ¼ 30 minutes MAL 21.1 vs. ALA 7.7 au, t ¼ 90 minutes MAL 39.0 vs. ALA 26.6 (P < 0.009)) but reached similar intensities for long-term applications (t ¼ 180 minutes MAL 56.6 vs. ALA 52 au, P ¼ ns). AFXL considerably enhanced porphyrin fluorescence from both photosensitizers (P < 0.05). On AFXL-exposed skin, MAL expressed higher fluorescence than ALA for short-term application (t ¼ 30 minutes, AFXL-MAL 26.4 vs. AFXL-ALA 14.1 au, P < 0.001), whereas ALA over time overcame MAL and induced the highest fluorescence intensities obtained (t ¼ 180 minutes, AFXL-MAL 98.6 vs. AFXL-ALA 112.0 au, P < 0.001). In deep skin layers, fluorescence microscopy showed higher fluorescence in hair follicle epithelium for ALA than MAL (t ¼ 180 minutes, 1.8 mm, AFXL-MAL 35.3 vs. AFXL-ALA 46.7 au, P < 0.05). Conclusions: AFXL changes kinetics and biodistribution of ALA and MAL. It appears that AFXL-ALA favors targeting deep structures.

Ablative fractional laser enhances MAL-induced PpIX accumulation: Impact of laser channel density, incubation time and drug concentration

“…Accelerated PpIX accumulation from AFL exposure has been reported in earlier experimental studies [3,23] and clinical studies on AFLmediated PDT have been conducted with reduced photosensitizer incubation times [8,9]. However, specific assessments on how PpIX accumulation is related to incubation time in AFL-assisted PDT have not yet been performed.…”

“…Limited information is available on pharmacokinetics for MAL uptake and biodistribution in AFL pretreated skin. Recent experimental studies indicate faster PpIX accumulation after AFL exposure [3,23] and clinical studies on AFL-mediated PDT for actinic keratosis and Bowen's disease have applied reduced incubation times of 70-90 min instead of conventional 180 min [8,9]. However, the optimal incubation time in AFLexposed skin remains to be clarified.…”

Laser-assisted drug delivery in dermatology: from animal models to clinical practice

“…In porcine skin, whilst AFXL pre-treatment increases fluorescence induced by MAL and ALA, ALA appears to induce greater fluorescence than MAL for deeper structures, putatively due to the smaller size and more hydrophilic nature of ALA [12]. 5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used in dermatology for treatment of NMSCs, including actinic keratoses (AKs), Bowen's disease and superficial basal cell carcinomas (BCCs).…”

Short incubation fractional CO2 laser‐assisted photodynamic therapy vs. conventional photodynamic therapy in field‐cancerized skin: 12‐month follow‐up results of a randomized intraindividual comparison study

“…The most frequently evaluated drugs in the field of AFXL‐assisted drug delivery according to preclinical and clinical studies are photosensitizers, especially methyl aminolevulinate (MAL) for photodynamic therapy (PDT) . PDT can be used as field therapy for actinic keratoses (AKs), when lesions become multiple, less well defined and more confluent in nature.…”