Abstract
BackgroundPhotodynamic therapy (PDT) involves excitation of sensitizer molecules by visible light in the presence of molecular oxygen, thereby generating reactive oxygen species (ROS) through electron/energy transfer processes. The ROS, thus produced can cause damage to both the structure and the function of the cellular constituents resulting in cell death. Our preliminary investigations of dose-response relationships in a human glioma cell line (BMG-1) showed that disulphonated aluminum phthalocyanine (AlPcS2) photodynamically induced loss of cell survival in a concentration dependent manner up to 1 μM, further increases in AlPcS2concentration (>1 μM) were, however, observed to decrease the photodynamic toxicity. Considering the fact that for most photosensitizers only monotonic dose-response (survival) relationships have been reported, this result was unexpected. The present studies were, therefore, undertaken to further investigate the concentration dependent photodynamic effects of AlPcS2.MethodsConcentration-dependent cellular uptake, sub-cellular localization, proliferation and photodynamic effects of AlPcS2 were investigated in BMG-1 cells by absorbance and fluorescence measurements, image analysis, cell counting and colony forming assays, flow cytometry and micronuclei formation respectively.ResultsThe cellular uptake as a function of extra-cellular AlPcS2 concentrations was observed to be biphasic. AlPcS2 was distributed throughout the cytoplasm with intense fluorescence in the perinuclear regions at a concentration of 1 μM, while a weak diffuse fluorescence was observed at higher concentrations. A concentration-dependent decrease in cell proliferation with accumulation of cells in G2+M phase was observed after PDT. The response of clonogenic survival after AlPcS2-PDT was non-monotonic with respect to AlPcS2 concentration.ConclusionsBased on the results we conclude that concentration-dependent changes in physico-chemical properties of sensitizer such as aggregation may influence intracellular transport and localization of photosensitizer. Consequent modifications in the photodynamic induction of lesions and their repair leading to different modes of cell death may contribute to the observed non-linear effects.
Highlights
Photodynamic therapy (PDT) involves excitation of sensitizer molecules by visible light in the presence of molecular oxygen, thereby generating reactive oxygen species (ROS) through electron/energy transfer processes
Type-I error rate was set to 5% but multiple comparison was handled by using Bonferroni correction in which type-I error rate for pairwise group comparisons was set to 1.66%
Cells were incubated with the sensitizer for 2 h in HBSS and observed under fluorescence microscope. 40-50 cells for each treatment group were analyzed from 2-3 different experiments
Summary
Photodynamic therapy (PDT) involves excitation of sensitizer molecules by visible light in the presence of molecular oxygen, thereby generating reactive oxygen species (ROS) through electron/energy transfer processes. Attempts have been made to overcome the limitations by the use of a) better sensitizers and b) strategies that target the sensitizer preferentially to the tumor and to the more sensitive intracellular sites Towards this end, second generation water soluble sensitizers such as phthalocyanine (Pc) derivatives are being widely investigated for their photodynamic effects [7,8]since these sensitizers are characterized by a more efficient absorption of therapeutically useful light wavelengths, especially in the 650-800 nm spectral range [9], permitting light penetration into tissues to almost twice the depth of that achieved using porphyrin PDT enabling photodynamic treatment of remote tissues [8,10,11]. The present studies were, undertaken to further investigate the concentration dependent photodynamic effects of AlPcS2 and to gain insight into the mechanisms underlying these effects
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