Light Dose Fractionation to Enhance Photodynamic Therapy Using 5-Aminolevulinic Acid in the Normal Rat Colon

Abstract

5-Aminolevulinic acid (ALA) is an attractive photosensitizing agent for photodynamic therapy (PDT) as its photoactive derivative, protoporphyrin IX, is metabolized within 1-2 days, eliminating prolonged skin photosensitivity. However, at the maximum dose patients can tolerate by mouth, 60 mg/kg, only superficial effects are seen. This paper extends earlier studies on enhancing the effect by light fractionation. Experiments in the normal rat colon looked at the area of necrosis around a single light delivery fiber 3 days after PDT with a range of light-dose fractionation regimes. All animals were given 200 mg/kg ALA intravenously 2 h prior to light delivery (100 mW at 635 nm) and each interruption in illumination was for 150 s. The area of PDT necrosis (total dose 25 J) could be increased by a factor of 3 with a single interval after 5 J, compared with continuous illumination. Alternatively, with this single break, the total light dose could be reduced by 60% to achieve the same area of necrosis as with continuous illumination. This simple modification to PDT with ALA could markedly reduce current treatment times as well as increasing clinical efficacy.

The Hydroxypyridinone Iron Chelator CP94 Can Enhance PpIX‐induced PDT of Cultured Human Glioma Cells

“…Bearing in mind the median survival of patients with GBM is 15 months (18) it is recognized that further research to increase survival rates for these patients and improve quality of life is vitally important and various ways to try and enhance clinical PDT is currently under investigation. Research includes using different photosensitizers, adjusting the light dosimetry (total fluence and fluence rates) (19), light fractionation (20,21), manipulating oxygen levels (22), and as in this study, supplementing PpIX prodrugs with iron chelators (11,23). Normally, within cells via the heme biosynthesis pathway PpIX is converted to heme through the addition of ferrous iron.…”

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

“…The minimum interval between the application of ALA and the first light fraction is not known but would presumably be limited by the availability of PpIX at short time intervals after the application of ALA and by the increasing duration of the first light fraction. Another option to reduce the overall treatment time would be to reduce the length of the 2 h dark interval as investigated in a different animal model by Curnow et al (11). A manuscript is in preparation reporting the effect of the length of the dark interval between two light fractions in the model we have used in this study.…”

An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy

“…It is already known that poor penetration into the deeper skin layers can be improved clinically by employing more lipophilic ALA derivatives (e.g., MAL; Metvix, Galderma, UK) or nanoemulsion formulations (e.g., ALA; Ameluz, Spirit Healthcare, UK) and by performing skin pre‐treatments like the removal of the outer skin layer by tape stripping or scraping . In fact many adaptations to the standard treatment protocol have been considered to improve efficacy including skin pre‐treatment with the malignant cell differentiation potentiator dimethyl sulfoxide , light dose fractionation , low fluence rate light administration as well as combinations with other techniques (e.g., low dose Photofrin , hyperthermia , iontophoresis , and bioreductive drugs ). Concurrent administration of an iron chelator during PpIX‐PDT has also been demonstrated to increase cellular accumulation of PpIX .…”