chlorophyll-a and Fibrosarcoma

Type II photodynamic therapy (PDT) is based on the photochemical reactions mediated through an interaction between a photosensitizer, ground-state oxygen ([(3)O2]), and light excitation at an appropriate wavelength, which results in production of reactive singlet oxygen ([(1)O2]rx). We use an empirical macroscopic model based on four photochemical parameters for the calculation of [(1)O2]rx threshold concentration ([(1)O2]rx,sh) causing tissue necrosis in tumors after PDT. For this reason, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-mediated PDT was performed interstitially on mice with radiation-induced fibrosarcoma (RIF) tumors. A linear light source at 665 nm with total energy released per unit length of 12 to 100  J/cm and source power per unit length (LS) of 12 to 150  mW/cm was used to induce different radii of necrosis. Then the amount of [(1)O2]rx calculated by the macroscopic model incorporating explicit PDT dosimetry of light fluence distribution, tissue optical properties, and HPPH concentration was correlated to the necrotic radius to obtain the model parameters and [(1)O2]rx,sh. We provide evidence that [(1)O2]rx is a better dosimetric quantity for predicting the treatment outcome than PDT dose, which is proportional to the time integral of the products of the photosensitizer concentration and light fluence rate.

Topics: Animals; Chlorophyll; Disease Models, Animal; Female; Fibrosarcoma; Light; Mice; Mice, Inbred C3H; Necrosis; Neoplasms; Photochemotherapy; Photosensitizing Agents; Radiometry; Singlet Oxygen

Liposomes are a potential system for more selective delivery of photosensitizers (PS) to tumors. Pheophorbides are one series of new PS under investigation for use in photodynamic therapy. The pharmacokinetics, anti-tumor response and normal tissue effects of methylpheophorbide-a-(hexyl-ether) (MPH) associated with negatively charged phospholipid vesicles composed of high and low transition temperature lipids were determined in mice. In some preparations monosialoganglioside, which is known to impart long circulation time to liposomes was also included. Normally water-insoluble MPH could be quantitatively incorporated in multilamellar liposomes up to at least 20 mol MPH/mol lipid% for most liposome compositions and sonicated to form clear suspensions. Evidence from electron microscopy and entrapment of aqueous space markers indicated that the particles formed by sonication were not standard liposomes. Anti-tumor responses to light treatment (135 J/cm2, 665 nm argon-dye laser) 24 h after MPH (0.4 mumol/kg) administration were slightly but significantly greater (P < 0.05) for lipid associated MPH compared to MPH solubilized in Tween 80. There were no major differences in tumor uptake and tumor cell photosensitization between lipid or Tween 80 formulations of MPH, whereas, dependent on lipid composition and time after MPH administration, the doses of light required to cause occlusive vascular damage were increased for the lipid formulations. Pharmacokinetic studies showed rapid dissociation between lipids and MPH in vivo. Lipid formulations are useful for solubilizing MPH and may improve the therapeutic effects of this PS.

Topics: Animals; Chlorophyll; Dose-Response Relationship, Radiation; Drug Carriers; Female; Fibrosarcoma; Liposomes; Mice; Mice, Inbred C3H; Microcirculation; Photochemotherapy; Photosensitizing Agents; Polysorbates; Skin; Skin Neoplasms; Tissue Distribution