Comparison of Physical Pretreatment Regimens to Enhance Protoporphyrin IX Uptake in Photodynamic Therapy

Abstract

IMPORTANCE Skin pretreatment is recommended for adequate penetration of topical photosensitizing agents and subsequent protoporphyrin IX (PPIX) accumulation in photodynamic therapy (PDT).OBJECTIVE To compare the relative potential of different physical pretreatments to enhance PPIX fluorescence in normal skin. DESIGN, SETTING, AND PARTICIPANTSThis intraindividual, randomized clinical trial was performed from November 28 to December 20, 2014, at Bispebjerg Hospital, Copenhagen, Denmark, among 12 healthy volunteers 18 years or older. Analysis was based on intention to treat. All participants completed the study protocol.INTERVENTIONS Participants were each exposed to standardized skin preparation with curettage, microdermabrasion with abrasive pads, microneedling with dermarollers, ablative fractional laser (AFXL), non-AFXL, and no pretreatment, followed by 3 hours of methyl aminolevulinate hydrochloride incubation and subsequent red light illumination. MAIN OUTCOMES AND MEASURESThe primary outcome measure was methyl aminolevulinate-induced PPIX fluorescence accumulation. Secondary outcome measures were PPIX photobleaching and clinical local skin reactions, supported by noninvasive reflectance measurements of percentage of skin redness, transepidermal water loss, and participant-assessed pain.RESULTS Among the 12 healthy study participants (8 men; 4 women; mean [SD] age, 33 [15] years), histologic findings confirmed standardization of interventions with partial removal of the stratum corneum after curettage and microdermabrasion and similar vertical penetration depths for microneedling, AFXL, and non-AFXL (median, 125 μm). PPIX fluorescence reached highest intensities in skin pretreated with AFXL (median, 8661 arbitrary units [AU]) compared with microdermabrasion (median, 6731 AU), microneedling (median, 5609 AU), and curettage (median, 4765 AU) (P < .001), among which similar enhancement was shown. Comparatively lower fluorescence levels were demonstrated for skin pretreated with non-AFXL (median, 2898 AU), methyl aminolevulinate-treated controls (median, 2254 AU), and untreated controls (median, 239 AU) (P < .03). Increasing laser densities (2% vs 4% vs 6%) and the number of pretreatment passes (1, 2, and 3 passes) did not enhance PPIX fluorescence. Local skin reactions were most intensified in AFXL-pretreated skin and correlated with PPIX fluorescence and degree of PPIX photobleaching.CONCLUSIONS AND RELEVANCE Under standardized conditions, PPIX accumulation was most enhanced after AFXL pretreatment, followed by microdermabrasion, microneedling, and curettage. Increasing the number of pretreatment passes and laser densities did not further augment PPIX accumulation. These results may indicate relatively enhanced PDT response by AFXL pretreatment in diseased skin. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02372370

Challenges to laser‐assisted drug delivery: Applying theory to clinical practice

“…Using standardized settings with relatively comparable treatment depths, authors demonstrated that pre‐treatment with AFL, curettage, microneedling, and microdermabrasion all led to enhanced PDT reactions, whereas pre‐treatment with NAFL was comparable to MAL alone. Furthermore, AFL was found to offer more uniform MAL distribution through the skin, resulting in enhanced protoporphyrin IX formation followed by intense local skin reactions in comparison to the other modalities following PDT . Partly corroborated by the results of other studies , these findings give initial indication of the superiority of AFL as a cutaneous drug delivery technique.…”

European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 1: treatment delivery and established indications – actinic keratoses, Bowen's disease and basal cell carcinomas

“…In a comparison study of PDT (ALA and MAL) with or without debulking immediately pre‐photosensitizer application, residual nBCC was more often observed in lesions that were not debulked . Under standardized conditions in a randomized clinical trial, PpIX accumulation was most enhanced after ablative fractional laser pretreatment, followed by microdermabrasion, microneedling and curettage …”

“…10 Under standardized conditions in a randomized clinical trial, PpIX accumulation was most enhanced after ablative fractional laser pretreatment, followed by microdermabrasion, microneedling and curettage. 43 Practitioners typically cover treatment sites with light occlusive dressings, on the presumption that full exposure to ambient light during the incubation period will lead to increased activation of PpIX superficially reducing the opportunity for deeper photosensitizer penetration before photoactivation. PDT with occlusion is routine in conventional MAL and nanoemulsion ALA-PDT, but is not performed when using Levulan PDT and no occlusion is required for daylight PDT.…”

The more the better? An appraisal of combination therapies for actinic keratosis

“…The enrichment of PpIX in PDT was investigated comparatively after several physical pretreatments in an intra-individual trial. 21 It was highest with ablative fractional laser, followed by microdermabrasion, microneedling and curettage. However, the photosensitizer uptake does not necessarily reflect the effectiveness of PDT.…”

“…In addition to the evidence presented here, the experience of the practitioner's individual experience regarding specific combinations must also be taken into account. The enrichment of PpIX in PDT was investigated comparatively after several physical pretreatments in an intra‐individual trial . It was highest with ablative fractional laser, followed by microdermabrasion, microneedling and curettage.…”