talaporfin and Disease-Models--Animal

Topics: Animals; Cattle; Cell Death; Disease Models, Animal; Dogs; Extracellular Fluid; Humans; Lasers, Semiconductor; Light; Myocardium; Photochemotherapy; Photosensitizing Agents; Porphyrins; Rats; Serum Albumin; Sus scrofa

Radiofrequency ablation has limitations, largely related to creation of lesions by heating. Here, we report the first nonthermal ablation by applying photodynamic therapy (PDT) to cardiac tissues using a custom-made deflectable laser catheter. The present study investigated the feasibility of PDT for cavotricuspid isthmus ablation in a canine model.. We evaluated the pharmacokinetic profiles of 17 canines after administration of a photosensitizer (talaporfin sodium) by various protocols. We succeeded in maintaining the photosensitizer concentration at a level in excess of the clinically effective dose for humans. Using a 4-polar 7-French deflectable laser catheter, we performed PDT-mediated cavotricuspid isthmus ablation in 8 canines. PDT caused oxidative injury only to the irradiated area and successfully produced a persistent electric conduction block. No acute, gross changes such as edematous degeneration, thrombus formation, steam pops, or traumatic injury were observed after irradiation. Hematoxylin and eosin staining of tissues samples also showed well-preserved endothelial layers. Testing of the blood samples taken before and after the procedure revealed no remarkable changes. Lesion size at 2 weeks after the procedure and the temperature data collected during irradiation were compared between the PDT and irrigated radiofrequency ablation procedures. A ventricular cross-section revealed a solid PDT lesion, which was as deep as a radiofrequency lesion. In addition, endocardial, surficial, and intramural temperature monitoring during the PDT irradiation clearly demonstrated the nonthermal nature of the ablation technique.. Nonthermal PDT-mediated catheter ablation is a potentially novel treatment for cardiac arrhythmias.

Topics: Animals; Atrial Flutter; Catheter Ablation; Disease Models, Animal; Dogs; Feasibility Studies; Fluoroscopy; Laser Therapy; Photochemotherapy; Porphyrins

Photodynamic therapy (PDT) may be a less invasive treatment for lung cancer. Our newly developed surface layer-preserving PDT (SPPDT) technique enables us to irradiate deep tumor while preserving the overlying tissue. The aim of this basic study was to verify that the SPPDT technique might be applied to lung cancer.. PDT with talaporfin sodium was performed using a pulsed laser with different pulse dose rates (PDRs, 2.5-20.0 mJ/cm(2) /pulse) in a mouse model of subcutaneous tumor. To mimic the tracheal wall structure and a thoracic tumor in the tracheobronchus, we also made a mouse model in which a piece of swine cartilage was placed between the dermis and the tumor, and PDT was carried out 2 weeks after implantation. In both experiments, the tissue samples were collected 48 hours after PDT and evaluated microscopically.. SPPDT using a high-PDR laser damaged the underlying tissue but left the superficial tissue intact in the mouse subcutaneous tumor model. In SPPDT, a higher PDR produced a thicker layer of intact superficial tissue than a lower PDR, while a lower PDR produced a deeper layer of damaged tissue than a higher PDR. SPPDT was also able to preserve the superficial tissue and to damage the tumor tissue beneath the cartilage implant.. SPPDT was able to damage tumor beneath the superficial normal tissue layer, which included tracheal cartilage in the mouse model. The thickness control of SPPDT was provided by controlling laser pulse intensity. SPPDT is a new technology, whose future potential is unknown. The initial clinical application of this technology could be endoscopic treatment (e.g., palliative therapy of thoracic malignancies via bronchoscopy).

Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Injections, Subcutaneous; Lasers; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Photochemotherapy; Photosensitizing Agents; Porphyrins; Skin; Subcutaneous Tissue

Photodynamic therapy (PDT) is a potential treatment for the peritoneal dissemination of gastric cancer, because its cytotoxicity is limited to superficial lesions. We examined the accumulation of talaporfin in peritoneal metastatic nodules and determined the optimal laser condition for these nodules. We also evaluated the pathological response after therapy. We created a peritoneal metastasis model in nude mice using the MKN-45 EGFP cell line. We evaluated the accumulation of talaporfin in peritoneal metastatic nodules and normal organs by spectrophotometric analysis 2-8 h after i.p. talaporfin. To determine optimal PDT conditions, we treated metastatic nodules and the small intestine using multiple laser doses (2, 5, and 10 J/cm2, respectively). Accumulation of talaporfin was detected in metastatic nodules in higher intensities than in the small intestine. The fluorescent intensity of the peritoneal metastatic nodules gradually decreased dependent on the time interval between the laser treatment and talaporfin administration. Fluorescent intensity in the small intestine decreased more than in the metastatic nodules. The pathological response rates by dose were 52.5% at 2 J/cm2, 43.2% at 5 J/cm2, and 64.4% at 10 J/cm2, respectively, when the laser treatment was used 2 h after talaporfin administration, whereas at 4 h, they were 20.8, 25.5, and 26.2%, respectively. Finally, the recommended treatment conditions were considered to be a 2 J/cm2 laser dose and a 4-h interval in terms of toxicity. Talaporfin-mediated PDT may be an effective treatment modality for patients with advanced gastric adenocarcinoma and metastatic peritoneal nodules.

Topics: Animals; Disease Models, Animal; Male; Mice; Mice, Nude; Peritoneal Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Stomach Neoplasms; Tissue Distribution

We investigated the efficacy of photodynamic therapy (PDT) using talaporfin sodium as a new method of synovectomy for rheumatoid arthritis (RA). We first used RA synovial membrane (RASM) for in vitro and in vivo study. The RASM was obtained from patients with RA during total knee replacement. In the in vitro study, RA fibroblast-like synoviocytes (RASCs) obtained from the RASM were examined by fluorescent microscopy to measure the intracellular localization of talaporfin sodium. The cells were then subjected to PDT, and their viability was examined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium inner salt assay. In the in vivo assay, RASM was obtained as described above, grafted onto severe combined immunodeficiency (SCID) mice and subjected to PDT. The damaged area of RASM was evaluated histologically at 1 day after PDT. Next, we performed a separate experiment using rats with collagen-induced arthritis (CIA). After intra-articular injection of talaporfin sodium, the concentration of talaporfin sodium accumulated in the CIA synovial membrane (CIASM) was compared with that in cartilage, periarticular muscle, and skin. We then performed PDT with intra-articular injection of talaporfin sodium and intra-articular irradiation. The damaged area of the CIASM was measured at 1 day after the PDT, and the articular histological and radiological changes of the ankle were observed at 56 days after the PDT. In RASM, talaporfin sodium accumulated in lysosomes in vitro, and the phototoxicity to RASCs in vitro and to RASM grafted onto SCID mice in vivo depended on the concentration of talaporfin sodium and the laser energy. In CIA rats, there was a greater accumulation of talaporfin sodium in the CIASM than in normal tissue. The CIASM was selectively damaged at 1 day after the PDT, and the bone and cartilage destruction were ameliorated at 56 days after the PDT. In conclusion, PDT using talaporfin sodium might be a new method for synovectomy in patients with RA.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cells, Cultured; Coloring Agents; Disease Models, Animal; Fibroblasts; Humans; Injections, Intra-Articular; Laser Therapy; Male; Mice; Mice, SCID; Photosensitizing Agents; Phototherapy; Porphyrins; Radiography; Rats; Rats, Inbred Lew; Synovial Membrane; Tetrazolium Salts; Thiazoles; Transplantation, Heterologous

We studied the detection of apoptosis of malignant human salivary gland tumor cells induced by photodynamic therapy (PDT) using the photosensitizer mono-L-aspartyl chlorin e6 (NPe6) in vitro and in vivo in mice receiving transplanted human salivary gland tumor (HSG) cells. An immunohistocytochemical method using a monoclonal antibody (MoAb), M30, which reacts with the product resulting from the cleavage of cytokeratin (CK) 18 by activated caspase, was applied to detect the apoptosis of HSG cells induced by PDT. Significant amounts of immunoreactive products were observed in the cytoplasm of HSG cells after PDT. In vitro, M30-positive cells increased from 2 h after PDT, increased rapidly from 8 h and reached a peak 24 h after PDT. In vivo, a peak of early apoptosis was confirmed two hours after PDT. In comparison with DNA fragmentation detected by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method, the destroyed tumor cells were observed sporadically 24 h after PDT. These results suggest that immunohistocytochemical staining with the MoAb M30 may be useful for detecting early apoptosis induced by PDT. Futhermore, PDT using NPe6 is effective in inducing apoptosis of HSG cells at an early stage, which suggests the possibility of the therapy being ideal for treatment of human malignant neoplasms.

Topics: Animals; Apoptosis; Cell Line, Tumor; Disease Models, Animal; DNA, Neoplasm; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Mice, Nude; Necrosis; Photochemotherapy; Photosensitizing Agents; Porphyrins; Salivary Gland Neoplasms

To demonstrate the selective localization of the hydrophilic photosensitizer mono-L-aspartyl chlorin e6 (NPe6) in experimental choroidal neovascularization in nonhuman primate eyes.. Sixty-seven experimental choroidal neovascular lesions (CNV) were created in the fundi of Macaca monkeys using the modified Ryan's model and documented by fluorescein and indocyanine green angiography. To determine the biodistribution of NPe6 and the optimal timing of laser irradiation after dye administration, NPe6 angiography and fluorescence microscopy with NPe6 were performed. Photodynamic therapy (PDT) was performed at various dye doses (0.5-10.0 mg/kg) and laser fluences (7.5-225.0 J/cm2) on the CNV and on 10 areas of normal retina and choroid. Treatment outcomes were assessed by fluorescein and indocyanine green angiography and confirmed by light and electron microscopy.. NPe6 fluorescence microscopy demonstrated intense fluorescence of CNV and retinal pigment epithelial cells. Choroidal vessel walls and outer retina adjacent to CNV fluoresced moderately; retinal vessel walls and microcapillaries had trace fluorescence. The fluorescence of CNV lesions on fluorescein angiography became stronger than that of retinal vessels 20-60 minutes after dye injection. Choroidal neovascular lesion closure was achieved with NPe6 PDT without significant damage to the sensory retina. Histology demonstrated necrosis of CNV endothelial cells with minimal damage to surrounding tissues.. NPe6 PDT selectively localizes to experimental CNV in nonhuman primates, resulting in occlusion of CNV with sparing of the neurosensory retina.

Topics: Animals; Choroid; Choroidal Neovascularization; Disease Models, Animal; Fluorescein Angiography; Indocyanine Green; Macaca fascicularis; Microscopy, Fluorescence; Photochemotherapy; Photosensitizing Agents; Pigment Epithelium of Eye; Porphyrins; Retinal Vessels; Treatment Outcome

Photodynamic therapy and photodynamic diagnosis using photosensitizers have yet to be clinically employed for hepatoma. Mono-L-aspartyl chlorin e6, a chlorin derivative with high tumor affinity developed as a second-generation photosensitizer, enables rapid tumor detection after administration, without light-shielding. This study examined the potential of photodynamic therapy, using this photosensitizer, for hepatoma in rabbits. VX2 tumor cells were transplanted into the liver of Japanese white rabbits, and the animals were administered 2.5 mg/kg of mono-L-aspartyl chlorin 36 1 week later. Accumulation of mono-L-aspartyl chlorin e6 in hepatoma was observed over time with an epifluorescence stereoscope, and the efficacy of continuous photodynamic therapy following photodynamic diagnosis was examined. A diode laser system was used for treatment, and efficacy was examined in a control group and four other groups that were irradiated at different times following administration. Efficacy in suppressing tumor growth, tumor necrosis rates, and efficacy in suppressing pulmonary metastasis were studied. For all these aspects, treatment was significantly more effective in the group irradiated 5 minutes after administration than in groups irradiated at later times. Liver function testing in all groups revealed no distinct disorders. Photodynamic therapy with mono-L-aspartyl chlorin e6 may be suitable for clinical use in therapy for hepatoma.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Fluorescence; Laser Therapy; Liver Neoplasms, Experimental; Photochemotherapy; Photosensitizing Agents; Porphyrins; Rabbits; Reference Values; Treatment Outcome

Despite their relatively localized nature, the therapy for surgically unresectable cholangiocarcinomas has been largely unsuccessful. Photodynamic therapy is a promising technique for both curative and palliative treatment of this malignancy. The effectiveness of a potential new photosensitizer, mono-l-aspartyl chlorin e6 (NPe6), was compared with that of a traditional drug, hematoporphyrin derivative (HpD), in photodynamic therapy administered to a human cholangiocarcinoma model.. An established cholangiocarcinoma cell line was inoculated subcutaneously in the left back of male nude mice age 8 weeks. After a predetermined tumor size was reached, the mice were randomly assigned to either a control group or an experimental group. Experimental tumor-bearing mice received either HpD (5 mg/kg or 10 mg/kg) or NPe6 (2 mg/kg, 5 mg/kg, or 8 mg/kg) followed by photoradiation. HpD and NPe6 were administered intraperitoneally at 24 and 2 hours, respectively, prior to light exposure. Photoradiation was conducted using a xenon-mercury arc lamp with a 405-650 nm filter at a light flux of 80 J/cm2. Tumor response was assessed by serial tumor volume measurements.. Control mice showed an estimated mean tumor volume doubling rate of 9.0 days. Triaxial tumor measurements correlated well with autopsy measurements (correlation coefficient = 0.9). Overall differences in tumor volume reduction were detected (P < 0.001) among the three groups: HpD, NPe6, and controls (photoradiation only, HpD only, or NPe6 only). The degree of tumor volume reduction was superior for dosages of NPe6 compared with all dosages of HpD (P < 0.05). Although a dose effect was detected (P < 0.05) for HpD and separately for NPe6, a consistent dose-response relationship was not observed for either. Inhibition of tumor regrowth was better for NPe6 compared with HpD. The depth of tissue injury was significantly increased (P < 0.05), by 67%, for 5-8 mg/kg of NPe6 compared with 5-10 mg/kg of HpD. The duration of cutaneous photosensitization was also decreased for NPe6 compared with HpD.. Photodynamic therapy with HpD or NPe6 was effective inducing tumor regression in the cholangiocarcinoma model in this study. At the dosages studied, NPe6 appeared to induce greater tumor regression than HpD, with decreased tumor regrowth and duration of cutaneous photosensitization.

Topics: Animals; Antineoplastic Agents; Cholangiocarcinoma; Disease Models, Animal; Hematoporphyrin Derivative; Hematoporphyrin Photoradiation; Humans; Injections, Intraperitoneal; Male; Mercury; Mice; Mice, Nude; Palliative Care; Photochemotherapy; Photosensitivity Disorders; Photosensitizing Agents; Porphyrins; Random Allocation; Remission Induction; Skin; Soft Tissue Neoplasms; Xenon

A mouse mammary tumor model was used to evaluate metabolic properties of the photosensitizer mono-L-aspartyl chlorin e6 (NPe6) and to determine the optimal time interval between drug administration and light treatment for effective photodynamic therapy (PDT). Photosensitizer metabolism was evaluated by comparing tissue distribution patterns of NPe6 having 14C atoms positioned on either the tetrapyrrole ring or on the aspartyl residue. High performance liquid chromatographic analysis of photosensitizer extracted from tumor tissue was also obtained as a function of time after drug administration. NPe6 distribution in tissue samples and pharmacological calculations of area under the curve were similar for both forms of [14]NPe6. Likewise, metabolic contaminants of NPe6 were not detected by high performance liquid chromatographic analysis following extraction of the photosensitizer from tumor tissue. Maximal in vivo PDT effectiveness was achieved when light treatments were started within 2 h of drug injection. PDT effectiveness was decreased by 50% when light treatments were initiated 6 h after drug injection and was abolished with a 12-h interval between NPe6 injection and light exposure. Responsiveness to NPe6-mediated PDT was correlated with photosensitizer levels in the plasma but not in tumor tissue. These results show that NPe6 was not metabolized following in vivo administration and that the responsiveness of NPe6 mediated PDT was associated with vascular clearance of the photosensitizer.

Topics: Animals; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Disease Models, Animal; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Photochemotherapy; Porphyrins; Radiation-Sensitizing Agents; Time Factors; Tissue Distribution