Dose and Timing of the First Light Fraction in Two-fold Illumination Schemes for Topical ALA-mediated Photodynamic Therapy of Hairless Mouse Skin¶

Abstract

A fractionated illumination scheme in which a cumulative fluence of 100 J cm 22 is delivered in two equal light fractions separated by a dark interval of 2 h has been shown to considerably increase the efficacy of 5-aminolevulinic acid (ALA)-photodynamic therapy (PDT). The efficacy of such a scheme is further increased if the fluence of the first light fraction is reduced to 5 J cm 22 . We have investigated the relationship between the PDT response and the kinetics of protoporphyrin IX (PpIX) fluorescence in the SKH1 HR hairless mouse for first fraction fluences below 5 J cm 22 delivered 4 h after the application of ALA and 10 J cm 22 delivered 2 h after the application of ALA. Illumination is performed using 514 nm at a fluence rate of 50 mW cm 22 . Reducing the fluence of the first fraction to 2.5 J cm 22 does not result in significantly different visual skin damage. The PDT response, however, is significantly reduced if the fluence is lowered to 1 J cm 22 , but this illumination scheme (1 1 99 J cm 22 ) remains significantly more effective than a single illumination of 100 J cm 22 . A first light fraction of 10 J cm 22 can be delivered 2 h earlier, 2 h after the application of ALA, without significant reduction in the PDT response compared with 5 1 95 J cm 22 delivered 4 and 6 h after the application of ALA. The kinetics of PpIX fluorescence are consistent with those reported previously by us and do not explain the significant increase in PDT response with a twofold illumination scheme. Histological sections of the illuminated volume showed a trend toward increasing extent and depth of necrosis for the two-fold illumination scheme in which the first light fraction is 5 J cm 22 , compared with a single illumination scheme.

Topical Photodynamic Therapy Using Different Porphyrin Precursors Leads to Differences in Vascular Photosensitization and Vascular Damage in Normal Mouse Skin

“…In addition to enhanced tumor cell kill due to hypoxia from vascular damage, the vascular responses may also be part of the mechanism behind the success of light‐fractionated PDT. For ALA‐PDT, light fractionation has proven beneficial in both preclinical and clinical studies . We hypothesize that the vascular endothelium synthesizes a small but relevant amount of PpIX which makes it vulnerable to a second illumination.…”

Response of Bowen Disease to ALA-PDT Using a Single and a 2-Fold Illumination Scheme

“…Our research group has investigated the role of light fractionation in the response of tissues to ALA-PDT in animal 6,7 and clinical studies. 8,9 In a randomized comparative study of the response of superficial basal cell carcinoma (sBCC) to ALA-PDT, our group showed a significantly higher complete response rate at 1 year (n=476) (P = .002) using a 2-fold illumination scheme (20 ϩ 80 J/cm 2 ) with a 2-hour dark interval compared with a single illumination (75 J/cm 2 ).…”

“…Our group has shown that there is no difference in response of sBCC to ALA-PDT using these sources and light fractionation. 9 The rationale for choosing these illumination schemes-in particular the reason we used unequal total light fluences-is based on extensive work in preclinical models 6,7 and our group's demonstrated results in the treatment of sBCC. 8,9 These factors are discussed at length by de Haas et al 9 Patients were examined after 4 weeks and then at 3-month intervals.…”

Fractionated aminolevulinic acid–photodynamic therapy provides additional evidence for the use of PDT for non‐melanoma skin cancer

“…Results of these studies show that fractionated PDT results in significantly higher responses compared with PDT done with a single illumination 8,9 . Studies have also shown the importance of the time interval between ALA application and the first light fraction and its relation to the synthesis of PpIX 10 . Besides, the influence of the fluence (rate) of the individual light fractions 10,11 and, importantly, the time interval between light fractions has been shown to be critical 12 .…”