The effects of ultra low fluence rate single and repetitive photodynamic therapy on glioma spheroids

Abstract

Background and Objective Achieving local control of gliomas with photodynamic therapy (PDT) requires the delivery of adequate light fluences to depths of 1–2 cm in the resection margin where the majority of local recurrences originate. This is clinically impractical with current single-shot, intraoperative PDT treatments due to the length of time required to deliver adequate fluences. Multiple or extended treatment protocols would therefore seem to be required. The response of human glioma spheroids to 5-aminolevulinic acid (ALA)-mediated PDT using single or, repetitive light delivery protocols was investigated at both low and ultra low fluence rates. Study Design/Materials and Methods Human glioma spheroids (400 μm diameter) were subjected to sub-threshold light fluence (1.5, 3, or 6 J cm−2) ALA–PDT consisting of four light delivery schemes: single treatment given over either 1 or 24 hours, repetitive treatment given either as four 1 hour light treatments separated by a 4 day interval, or 24 hours light delivery, consisting of four 24 hours treatments separated by a 3 day interval. Treatment efficacy was evaluated using a growth assay. In some cases, confocal microscopy was used to image cell viability. Results The repetitive and single light treatment protocols were most effective when delivered at ultra low (μW cm−2) fluence rates. In all cases, growth inhibition was light dose-dependent. The repetitive ultra low fluence rate treatment (1.5 J cm−2; irradiance = 17 μW cm−2) light delivery protocol was the most effective resulting in total growth inhibition during the 2-week observation period. Conclusion Ultra low light fluence rate ALA–PDT results in significant spheroid growth inhibition. Repeated administration of ALA was required during repetitive and/or protracted single PDT treatment protocols. The existence of a lower fluence rate limit, below which the efficacy of threshold light fluences diminish was not found in these studies.

Photodynamic Therapy: Current Status and Future Directions

“…Instead of one, two light photons are absorbed and each photon accounts for only half of the excitation energy [142]. Metronomic PDT is based on the application of very low doses of PSs combined with low rates of irradiation lasting for extended periods of time [143]. As mentioned before, the outcome is cell death by apoptosis with minimal tissue necrosis.…”

Tumor Microenvironment as a Determinant of Photodynamic Therapy Resistance

“…Moreover, treatment with even lower fluence rates may also be effective. Recent studies establish the cytotoxic effects of ALA-PDT at ultralow (17 mW/cm 2 ) fluence rate when spheroids are exposed to either single or repetitive illumination of 24 h in duration [36]. Finally, the use of sunlight as the excitation source for methyl aminolevulinate-PDT is being studied in dermatology for treatment of actinic keratosis and basal cell carcinoma.…”

Efficacy of Multiple Low-dose Photodynamic TMPYP4 Therapy on Cervical Cancer Tumour Growth in Nude Mice

“…The mechanism of killing tumor cell by PDT depended on the photosensitizer concentration and the light fluence (Mathews et al, 2009). But the side effects of PDT were severe, even beyond 6 months out, they still had skin ulceration, seriously required multiple skin grafts (Gary et al, 2012).…”