chlorophyll-a and Glioma

The photophysical, electrochemical and spectroscopic characteristics of a conjugate of 3-devinyl-3-(1'-hexyloxyethyl)pyropheophorbide-a (HPPH) and a cyanine dye have been investigated both as a linked conjugate and as individual components. A photoexcitation of the HPPH moiety of the conjugate results in electron transfer from the singlet excited state of HPPH (1HPPH*) to the cyanine dye as well as that from the cyanine dye to 1HPPH* and is followed in both cases by facile back electron transfer to the ground state as indicated by time-resolved fluorescence and transient absorption measurements. Intersystem crossing to the triplet excited state (3HPPH*) competes with the electron transfer and 3HPPH* is quenched by oxygen to produce singlet oxygen (1O2), leading to specific covalent cross-linking of the nonactivated signal transducer and activator of transcription (STAT-3). In contrast to excitation of the HPPH moiety, photoexcitation of the cyanine dye unit results in a strong emission at 875 nm, which can be used for efficient tumor imaging. Compared to HPPH alone, the presence of the cyanine dye moiety in the conjugate produces a significantly higher uptake in tumors than in skin. Thus, the HPPH-cyanine dye conjugate can be used as a dual tumor imaging and photodynamic therapy agent.

Topics: Animals; Carbocyanines; Chlorophyll; Cross-Linking Reagents; Electrochemistry; Fluorescence; Glioma; Mice; Mice, Nude; Molecular Structure; Neoplasm Transplantation; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Singlet Oxygen; STAT3 Transcription Factor

In this study, we evaluated 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha (HPPH or Photochlor) as a photosensitizer for the treatment of malignant gliomas by photodynamic therapy (PDT).. We performed in vivo reflection spectroscopy in athymic rats to measure the attenuation of light in normal brain tissue. We also studied HPPH pharmacokinetics and PDT effects in nude rats with brain tumors derived from stereotactically implanted U87 human glioma cells. Rats implanted with tumors were sacrificed at designated time points to determine the pharmacokinetics of HPPH in serum, tumor, normal brain, and brain adjacent to tumor (BAT). HPPH concentrations in normal brain, BAT and tumor were determined using fluorescence spectroscopy. Twenty-four hours after intravenous injection of HPPH, we administered interstitial PDT treatment at a wavelength of 665 nm. Light was given in doses of 3.5, 7.5 or 15 J/cm at the tumor site and at a rate of 50 mW/cm.. In vivo spectroscopy of normal brain tissue showed that the attenuation depth of 665 nm light is approximately 30% greater than that of 630 nm light used to activate Photofrin, which is currently being evaluated for PDT as an adjuvant to surgery for malignant gliomas. The t1/2 of disappearance of drug from serum and tumor was 25 and 30 hours, respectively.. Twenty-four hours after injection of 0.5 mg/kg HPPH, tumor-to-brain drug ratios ranged from 5:1 to 15:1. Enhanced survival was observed in each of the HPPH/PDT-treated animal groups. These data suggest that HPPH may be a useful adjuvant for the treatment of malignant gliomas.

Topics: Animals; Brain Neoplasms; Chlorophyll; Glioma; Humans; Male; Models, Animal; Photochemotherapy; Photosensitizing Agents; Rats; Rats, Nude; Rats, Sprague-Dawley; Spectrometry, Fluorescence; Survival Analysis

The authors describe a new photodynamic therapy (PDT) method for malignant brain tumors. Pheophorbide a (Ph-a), the photosensitizer, has low toxicity, causes no skin sensitization and is activated with an acoustic Q switched neodymium yttrium-argon-garnet (Nd:YAG) laser which achieves deep tissue penetration. The Ph-a distribution in Fisher 344 (F344) rats bearing rat T9 glioma at 24 hours after intravenous injection was very low in the normal brain tissue, but significantly higher in the T9 glioma giving a tumor to normal brain tissue concentration ratio of 7.5:1. The in vitro survival rate of T9 glioma cells pretreated with Ph-a was 68.8 +/- 5.4% after laser irradiation for 20 minutes, significantly lower than in the control groups. This indicates that Ph-a was activated with the acoustic Q switched Nd:YAG laser causing the photodynamic effect. The survival rate after Ph-a pretreatment and laser irradiation in a waterbath at 44.0 degrees C was further reduced to 15.8 +/- 3.3%. In vivo PDT studies using T9 glioma cells inoculated into the dorsal region of F344 rats showed tumor eradication in four of six rats. The combination of PDT and laser hyperthermia produced tumor eradication in all six rats. The combination of PDT and hyperthermia is a promising method for tumor treatment.

Topics: Animals; Brain Neoplasms; Chlorophyll; Glioma; Laser Therapy; Photochemotherapy; Radiation-Sensitizing Agents; Rats; Rats, Inbred F344; Survival Analysis; Tumor Cells, Cultured