Skin Necrosis due to Photodynamic Action of Benzoporphyrin Depends on Circulating Rather than Tissue Drug Levels: Implications for Control of Photodynamic Therapy

In an ideal world, photodynamic therapy (PDT) of abnormal tissue would reliably spare the surrounding normal tissue. Normal tissue responses set the limits for light and drug dosimetry. The threshold fluence for necrosis (TFN) was measured in normal skin following intravenous infusion with a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA) Verteporfin as a function of drug dose (0.25-2.0 mg/kg), wavelength of irradiation (458 and 690 nm) and time interval (0–5h) between drug administration and irradiation. The BPD-MA levels were measured in plasma and skin tissue to elucidate the relationship between TFN, drug kinetics and biodistribution. The PDT response of normal skin was highly reproducible. The TFN for 458 and 690 nm wavelengths was nearly identical and the estimated quantum efficiency for skin response was equal at these two wavelengths. Skin phototoxicity, quantified in terms of 1/ TFN, closely correlated with the plasma pharmacokinetics rather than the tissue pharmacokinetics and was quadratically dependent on the plasma drug concentration regardless of the administered drug dose or time interval between drug and light exposure. This study strongly suggests that noninvasive measurements of the circulating drug level at the time of light treatment will be important for setting optimal light dosimetry for PDT with liposomal BPD-MA, a vascular photosensitizer.     

The phototoxicity of photodynamic therapy may be suppressed or enhanced by modulation of the cutaneous vasculature

In photodynamic therapy, the threshold for light induced toxicity depends on the drug concentration and the light dose. This study was aimed to show for vascular photosensitizers that the toxicity threshold on normal tissue may be predictably modified by modulation of the cutaneous vasculature. Albino rabbits were injected with 1.0 mg/kg of a vascular photosensitizer, benzoporphyrin derivative monoacid ring-A. The threshold light dose for toxicity to normal skin was determined at an absorption maximum of the drug (694 nm), 1 h after drug injection. The cutaneous vasculature was dilated by prior skin exposure to ultraviolet radiation or was constricted by iontophoretic application of epinephrine. Threshold toxicity was determined clinically and by assessing the effective concentration of hemoglobin in the skin by diffuse reflectance spectroscopy (DRS). Tissue samples that received threshold doses were investigated with light and electron microscopy. The toxicity threshold increased by 3.2+/-0.9 (mean+/-S.D.) following vasoconstriction and decreased by 3.6+/-0.8 following vasodilation, compared to control sites. Light and electron microscopy showed similar findings at threshold for both vasodilated and vasoconstricted sites. Therefore vascular modulation may be used to predictably enhance or suppress the level of phototoxicity of normal skin.