Oxygen Consumption and Diffusion Effects in Photodynamic Therapy

Abstract

Effects of oxygen consumption in photodynamic therapy (PDT) are considered theoretically and experimentally. A mathematical model of the Type II mechanism of photooxidation is used to compute estimates of the rate of therapy-dependent in vivo oxygen depletion resulting from reactions of singlet oxygen (1O2) with intracellular substrate. Calculations indicate that PDT carried out at incident light intensities of 50 mW/cm2 may consume 3O2 at rates as high as 6-9 microM s-1. An approximate model of oxygen diffusion shows that these consumption rates are large enough to decrease the radius of oxygenated cells around an isolated capillary. Thus, during photoirradiation, cells sufficiently remote from the capillary wall may reside at oxygen tensions that are low enough to preclude or minimize 1O2-mediated damage. This effect is more pronounced at higher power densities and accounts for an enhanced therapeutic response in tumors treated with 360 J/cm2 delivered at 50 mW/cm2 compared to the same light dose delivered at 200 mW/cm2. The analysis further suggests that the oxygen depletion could be partially overcome by fractionating the light delivery. In a transplanted mammary tumor model, a regimen of 30-s exposures followed by 30-s dark periods produced significantly longer delays in tumor growth when compared to the continuous delivery of the same total fluence.

Response of Photofrin®-sensitised mesothelioma xenografts to photodynamic therapy with 514 nm light

“…This finding is consistent with previously reported results obtained with Photofringsensitised mesothelioma xenografts and 630 nm irradiation, where relatively lower fluence rates were found to be more effective (Gibson et al, 1994). Our interpretation of these data is that rapid photochemical oxygen consumption at higher irradiation fluence rates creates regions of transient hypoxia within which singlet oxygen formation is reduced (Foster et al, 1991). We are encouraged by the similar responses of the mesothelioma xenografts to the 20:28 green and the 50 mW cm-2 red light protocols, however, our approach to the design of the stepped irradiation schemes at the shorter wavelength was somewhat empirical, and more work needs to be done in order to develop treatment strategies that are based on real knowledge of tumour optical properties in vivo.…”

The sensitivity of normal brain and intracranially implanted VX2 tumour to interstitial photodynamic therapy

“…The arterial pao2 measured in our experiments during PDT was close to four times lower than reported in the human study. Hence, very poorly oxygenated regions could be present in the VX2 tumour despite a good vascular supply, resulting in reduced sensitivity to photodynamic therapy (Foster et al, 1991).…”

The influence of hypoxia and pH on aminolaevulinic acid-induced photodynamic therapy in bladder cancer cells in vitro

“…In addition to intrinsic tumour hypoxia, the process of PDT itself induces hypoxia, as the generation of reactive oxygen species is an oxygen-consuming process (Foster et al, 1991). PDT also damages the microcirculation causing hypoxia within minutes of treatment commencing (Star et al, 1986;Reed et al, 1989).…”