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1.
Fetal Diagn Ther ; 33(2): 90-7, 2013.
Article in English | MEDLINE | ID: mdl-23306444

ABSTRACT

INTRODUCTION: Zinc coproporphyrin I (ZnCP-I) is a photosensitive molecule and a major component of meconium. Here, we examined the effects of ZnCP-I as a potential photosensitizer in photodynamic therapy for tumors. MATERIALS AND METHODS: (1) Aqueous ZnCP-I was irradiated with a pulsed YAG-SHG laser (wavelength: 532 nm)/YAG-SHG dye laser (wavelength: 566 nm). (2) HeLa cells were incubated in 200 mM ZnCP-I, and accumulation of ZnCP-I in HeLa cells was evaluated with ZnCP-I-specific fluorescence over 500 nm. (3) Aqueous ZnCP-I was administered intravenously to HeLa tumor-bearing mice at a dose of 10.2 mg/kg body weight. The tumors were irradiated with a filtered halogen lamp (wavelength: 580 nm) at 100 J/cm(2) 20 min after administration. RESULTS: (1) An intense near-infrared emission spectrum was observed at around 1,270 nm after irradiation. The emission intensity was proportional to the laser power between 10 and 80 mW and was completely inhibited by addition of NaN3, a singlet oxygen scavenger. (2) ZnCP-I-specific fluorescence was detected in the HeLa cell cytoplasm. (3) Irradiated tumors treated with ZnCP-I were mostly necrotized. CONCLUSION: ZnCP-I accumulated in tumor cells, produced singlet oxygen upon irradiation, and necrotized the tumor cells. These results suggest that ZnCP-I may be an effective photosensitizer.


Subject(s)
Antineoplastic Agents/therapeutic use , Coproporphyrins/therapeutic use , Meconium/chemistry , Neoplasms/drug therapy , Photochemotherapy , Photosensitizing Agents/therapeutic use , Singlet Oxygen/chemistry , Animals , Antineoplastic Agents/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Antineoplastic Agents/radiation effects , Biological Transport , Coproporphyrins/antagonists & inhibitors , Coproporphyrins/pharmacology , Coproporphyrins/radiation effects , Female , Free Radical Scavengers/pharmacology , HeLa Cells , Humans , Lasers, Dye/therapeutic use , Lasers, Solid-State/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Nude , Necrosis , Neoplasms/pathology , Oxidants/antagonists & inhibitors , Oxidants/pharmacology , Oxidants/radiation effects , Oxidants/therapeutic use , Photosensitizing Agents/antagonists & inhibitors , Photosensitizing Agents/pharmacology , Photosensitizing Agents/radiation effects , Xenograft Model Antitumor Assays , Zinc/chemistry , Zinc/pharmacology , Zinc/radiation effects , Zinc/therapeutic use
2.
Neuroimage ; 59(4): 3325-38, 2012 Feb 15.
Article in English | MEDLINE | ID: mdl-22166795

ABSTRACT

The neural-hemodynamic relationships may vary depending on cortical processing patterns. To investigate how cortical hemodynamics reflects neural activity involving different cortical processing patterns, we delivered electrical stimulation pulses to rat hindpaws, unilaterally or bilaterally, and simultaneously measured electrophysiological (local field potential, LFP < 100 Hz; multiunit activity, MUA>300 Hz) and optical intrinsic signals associated with changes in cerebral blood volume (CBV). Unilateral stimulation evoked neural and optical signals in bilateral primary somatosensory cortices. Ipsilateral optical responses indicating an increased CBV exhibited a peak magnitude of ~30% and mediocaudal shifts relative to contralateral responses. Correlation analyses revealed different scale factors between contralateral and ipsilateral responses in LFP-MUA and LFP-CBV relationships. Bilateral stimulation at varying time intervals evoked hemodynamic responses that were strongly suppressed at 40-ms intervals. This suppression quantitatively reflected suppressed LFP responses to contralateral testing stimulation and not linear summation, with slowly fluctuating LFP responses to ipsilateral conditioning stimulation. Consequently, in the overall responses to bilateral stimulation, CBV-related responses were more linearly correlated with MUA than with LFPs. When extracting high-frequency components (>30 Hz) from LFPs, we found similar scale factors between contralateral and ipsilateral responses in LFP-MUA and LFP-CBV relationships, resulting in significant linear relationships among these components, MUA, and cortical hemodynamics in overall responses to bilateral stimulation. The dependence of LFP-MUA-hemodynamic relationships on cortical processing patterns and the LFP temporal/spectral structure is important for interpreting hemodynamic signals in complex functional paradigms driving diverse cortical processing.


Subject(s)
Blood Volume , Brain/blood supply , Somatosensory Cortex/physiology , Animals , Electric Stimulation , Hemodynamics , Male , Rats , Rats, Sprague-Dawley
3.
Photodermatol Photoimmunol Photomed ; 25(5): 259-63, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19747245

ABSTRACT

BACKGROUND/PURPOSE: Photodynamic therapy (PDT) is a non-invasive cancer therapy that has a strong antitumor effect with intravenous administration of Photofrin. However, Photofrin causes light hypersensitivity that impairs the quality of life (QOL) of patients, and thus an improved method of administration is needed. Here, we report the antitumor effect of local administration of Photofrin in combination with a vasodilator, lidocaine hydrochloride. METHOD: The antitumor effect was investigated in nude mice transplanted with HeLa cells. An incision was made near the tumor and Photofrin dissolved in lidocaine jelly was applied directly to the tumor. The tumor was irradiated at 100 J/cm(2) with a yttrium aluminum garnet (YAG)-dye laser (630 nm) at 2 h after the direct application and the tumor volume was measured for 30 days after PDT to investigate the antitumor effect. In some mice, the tumor was excised 24 h after PDT and the depth of necrosis was measured in the excised specimen. RESULT: The tumor was mostly necrotized by PDT following direct application of 10 mg/ml Photofrin dissolved in lidocaine jelly and the effect was greater than with direct application of Photofrin alone. The increase in tumor volume observed in control mice was significantly inhibited in mice that received PDT after direct application of Photofrin in lidocaine jelly. CONCLUSION: PDT using direct application of Photofrin in lidocaine jelly has a strong antitumor effect in mice and this approach may avoid the adverse effects of systemic Photofrin administration.


Subject(s)
Dihematoporphyrin Ether/therapeutic use , Lidocaine , Neoplasms, Experimental/drug therapy , Photochemotherapy , Photosensitizing Agents/therapeutic use , Animals , Dihematoporphyrin Ether/chemistry , Dihematoporphyrin Ether/pharmacokinetics , Mice , Mice, Nude , Neoplasms, Experimental/pathology , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacokinetics , Solubility , Treatment Outcome
4.
Clin Rheumatol ; 27(6): 751-61, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18066613

ABSTRACT

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.


Subject(s)
Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Fibroblasts/drug effects , Photosensitizing Agents/pharmacology , Phototherapy/methods , Porphyrins/pharmacology , Animals , Arthritis, Experimental/diagnostic imaging , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/pathology , Cells, Cultured , Coloring Agents , Disease Models, Animal , Fibroblasts/pathology , Humans , Injections, Intra-Articular , Laser Therapy , Male , Mice , Mice, SCID , Photosensitizing Agents/pharmacokinetics , Porphyrins/pharmacokinetics , Radiography , Rats , Rats, Inbred Lew , Synovial Membrane/pathology , Tetrazolium Salts , Thiazoles , Transplantation, Heterologous
5.
Lasers Med Sci ; 23(4): 355-60, 2008 Oct.
Article in English | MEDLINE | ID: mdl-17885797

ABSTRACT

Although effectiveness of photodynamic therapy (PDT) after application of 5-aminolevulinic acid ointment to oral mucosal lesions has been reported, a consensus regarding recontact time of ALA applied to a lesion has been unreached. Hence, we determined the contact time of ALA required for protoporphyrin IX (PpIX) production efficient for full-blown PDT reaction. ALA ointment was topically applied to healthy rabbits' tongues for different periods and then washed out. On the surface of the tongue, 10-min contact of ALA maximized the PpIX-derived fluorescence. PpIX yield in a tissue specimen with 10-min contact of ALA reached 73% of that in a tissue specimen with 240-min contact. Histological observation showed that PpIX accumulation predominated in the basal layer, and the PDT effects were confined in the mucosal epithelium regardless of contact time. These results suggest that 5-aminolevulinic-acid-ointment-mediated PDT with short contact of ALA is potentially applicable for treating tongue epithelial lesions.


Subject(s)
Aminolevulinic Acid/pharmacology , Epithelium/drug effects , Mouth Mucosa/drug effects , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Protoporphyrins/biosynthesis , Tongue/drug effects , Aminolevulinic Acid/analogs & derivatives , Animals , Epithelium/radiation effects , Male , Models, Animal , Mouth Mucosa/radiation effects , Protoporphyrins/radiation effects , Rabbits , Time Factors , Tongue/radiation effects
6.
Clin Cancer Res ; 12(23): 7132-9, 2006 Dec 01.
Article in English | MEDLINE | ID: mdl-17145838

ABSTRACT

PURPOSE: Singlet oxygen ((1)O(2)) generated in photodynamic therapy (PDT) plays a very important role in killing tumor cells. Using a new near-IR photomultiplier tube system, we monitored the real-time production of (1)O(2) during PDT and thus investigated the relationship between the (1)O(2) production and photodynamic effects. EXPERIMENTAL DESIGN: We did PDT in 9L gliosarcoma cells in vitro and in an experimental tumor model in vivo using 5-aminolevulinic acid and nanosecond-pulsed dye laser. During this time, we monitored (1)O(2) using this system. Moreover, based on the (1)O(2) monitoring, we set the different conditions of laser exposure and investigated whether they could affect the tumor cell death. RESULTS: We could observe the temporal changes of (1)O(2) production during PDT in detail. At a low fluence rate the (1)O(2) signal gradually decreased with a low peak, whereas at a high fluence rate it decreased immediately with a high peak. Consequently, the cumulative (1)O(2) at a low fluence rate was higher, which thus induced a strong photodynamic effect. The proportion of apoptosis to necrosis might therefore be dependent on the peak and duration of the (1)O(2) signal. A low fluence rate tended to induce apoptotic change, whereas a high fluence rate tended to induce necrotic change. CONCLUSIONS: The results of this study suggested that the monitoring of (1)O(2) enables us to predict the photodynamic effect, allowing us to select the optimal laser conditions for each patient.


Subject(s)
Brain Neoplasms/drug therapy , Glioma/drug therapy , Photochemotherapy/methods , Photosensitizing Agents/therapeutic use , Singlet Oxygen/analysis , Animals , Brain Neoplasms/pathology , Cell Death/drug effects , Cell Line, Tumor , Disease Models, Animal , Drug Screening Assays, Antitumor , Glioma/pathology , Male , Photochemotherapy/instrumentation , Photosensitizing Agents/chemistry , Predictive Value of Tests , Rats , Rats, Inbred F344 , Singlet Oxygen/metabolism , Structure-Activity Relationship , Treatment Outcome
7.
J Med Chem ; 49(7): 2276-83, 2006 Apr 06.
Article in English | MEDLINE | ID: mdl-16570924

ABSTRACT

Two water-soluble porphyrin self-assemblies consisting of bisacetylene- and monoacetylene-linked conjugated bis(imidazolylporphyrin) have been synthesized. Two-photon absorption (2PA) cross section values in water were determined as 7500 GM for bisacetylene- and 7900 GM for monoacetylene-linked bisporphyrin by femtosecond open-aperture Z-scan measurement. These values were almost the same as those for the similar structure reported previously in CHCl(3). Therefore, the structure is suggested to be similar in CHCl(3) and aqueous solutions. Both compounds were found to efficiently generate singlet oxygen upon one-photon irradiation in a manner similar to protoporphyrin, as demonstrated by the time-resolved luminescence measurement at the characteristic band of 1270 nm. Photocytotoxicities for HeLa cancer cells were examined and found to be as high as those of hematoporphyrin, demonstrating that these newly prepared compounds are potential candidates as 2PA-photodynamic therapy agents.


Subject(s)
Imidazoles/chemical synthesis , Photochemotherapy , Photosensitizing Agents/chemical synthesis , Porphyrins/chemical synthesis , Acetylene/chemistry , HeLa Cells , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/chemistry , Porphyrins/pharmacology , Singlet Oxygen/metabolism , Solubility , Structure-Activity Relationship , Water
8.
Int J Oncol ; 27(5): 1207-13, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16211214

ABSTRACT

We investigated the feasibility of a novel photosensitizer, ATX-S10.Na (II), in photodynamic therapy (PDT) for glioma. First, PDT was performed in various brain tumor cell lines in vitro. Cytotoxicity depended upon both drug concentration and laser energy and the 50% inhibitory concentration ranged from 3.5 to 20 microg/ml. Next, PDT was performed in the subcutaneous and intracranial 9L tumor models in Fischer rats using ATX-S10.Na (II) and light from a 670-nm diode laser delivered by intratumoral insertion of an optical fiber. The effect of PDT on brain tumors was evaluated using magnetic resonance imaging. Sequential changes of the ATX-S10.Na (II) concentrations were also measured quantitatively by fluorospectrometry up to 12 h after intravenous administration in rats with intracranial and subcutaneous tumors. The concentration of ATX-S10.Na (II) in the brain tumor reached a maximum at 2 h after administration and the tumor/normal brain concentration ratio was as high as 131 at 8 h. Intratumoral PDT for intracranial tumors irradiated at this timing showed an obvious anti-tumor effect without severe side effects. The present study demonstrated the highly selective accumulation of ATX-S10.Na (II) in tumor tissue and its potent photodynamic effect in an experimental malignant glioma model.


Subject(s)
Brain Neoplasms/pathology , Glioma/pathology , Porphyrins/pharmacokinetics , Animals , Brain Neoplasms/veterinary , Glioma/veterinary , Magnetic Resonance Imaging/veterinary , Rats , Rats, Inbred F344 , Tissue Distribution , Tumor Cells, Cultured
10.
Lasers Med Sci ; 20(1): 1-5, 2005.
Article in English | MEDLINE | ID: mdl-15912266

ABSTRACT

Photodynamic therapy (PDT) is a useful strategy for treating various cancers. Details of the mechanisms of PDT have not been made clear yet. We intended to study the efficacy of PDT in relation to the cell cycle. HeLa S3 cells were synchronized by the thymidine block method. Cells in different cell cycle phases after release were treated with the water-soluble photosensitizer, ATX-S10(Na). The cellular viability after PDT was determined by the MTT assay. Intracellular levels of ATX-S10(Na) in different cell cycle phases were also determined. We found that cells in the S and G(2)/M phases were hypersensitive to PDT with ATX-S10(Na) in comparison with those in the G(1) phase, and that cellular levels of ATX-S10(Na) were increased in cells in the S and G(2)/M phases compared to those in the G(1) phase. We conclude that cellular ATX-S10(Na) levels differ among the different cell cycle phases, which is associated with the cell-cycle-dependent efficacy of PDT with ATX-S10(Na).


Subject(s)
Cell Cycle/drug effects , HeLa Cells/drug effects , Photochemotherapy/methods , Porphyrins/pharmacology , Analysis of Variance , Female , HeLa Cells/cytology , Humans , In Vitro Techniques , Probability , Sensitivity and Specificity , Tumor Cells, Cultured/cytology , Tumor Cells, Cultured/drug effects
11.
J Nucl Med ; 45(10): 1754-8, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15471845

ABSTRACT

UNLABELLED: 3'-Deoxy-3'-18F-fluorothymidine (18F-FLT) has been suggested as a new PET tracer for imaging tumor proliferation. We investigated the use of 18F-FLT to monitor the response of tumors to radiotherapy and photodynamic therapy (PDT) in mice. METHODS: C3H/He mice bearing an SCCVII tumor were treated with single-dose x-ray irradiation of 20 Gy. Tumor uptake was examined for 18F-FLT, 3H-thymidine (3H-Thd), 18F-FDG, and 14C-deoxyglucose (14C-DG) at 6 h, 12 h, 24 h, 3 d, and 7 d after radiotherapy. BALB/c nu/nu mice bearing a HeLa tumor were treated with PDT. Tumor uptake was examined for the 4 tracers at 24 h after PDT. Expression of proliferating cell nuclear antigen (PCNA) was determined in untreated and treated tumors. RESULTS: In the biodistribution study, considerable uptake of 18F-FLT was observed in both tumor types. Tumor volumes decreased to 39.3% +/- 22.4% at 7 d after radiotherapy. The PCNA labeling index was reduced in x-ray-irradiated tumors (control, 53.2% +/- 8.7%; 6 h, 38.5% +/- 5.3%; 24 h after radiotherapy, 36.8% +/- 5.3%). 18F-FLT uptake in tumor expressed as the percentage of the injected dose per gram of tumor (%ID/g) decreased significantly at 6 h and remained low until 3 d after radiotherapy (control, 9.7 +/- 1.2 %ID/g; 6 h, 5.9 +/- 0.4 %ID/g; 24 h, 6.1 +/- 1.3 %ID/g; 3 d after radiotherapy, 6.4 +/- 1.1 %ID/g). 18F-FDG uptake tended to gradually decrease but a significant decrease was found only at 3 d (control, 12.1 +/- 2.7 %ID/g; 6 h, 13.3 +/- 2.3 %ID/g; 24 h, 8.6 +/- 1.8 %ID/g; 3 d after radiotherapy, 6.9 +/- 1.2 %ID/g). PDT resulted in a reduction of the PCNA labeling index (control, 82.0% +/- 8.6%; 24 h after PDT, 13.5% +/- 12.7%). Tumor uptake of 18F-FLT decreased (control, 11.1 +/- 1.3 %ID/g; 24 h after PDT, 4.0 +/- 2.2 %ID/g), whereas 18F-FDG uptake did not decrease significantly after PDT (control, 3.5 +/- 0.6 %ID/g; 24 h after PDT, 2.3 +/- 1.1 %ID/g). Changes in the uptake of 18F-FLT and 18F-FDG were similar to those of 3H-Thd and 14C-DG, respectively. CONCLUSION: In our model system, changes in 18F-FLT uptake after radiotherapy and PDT were correlated with those of 3H-Thd and the PCNA labeling index. The decrease in 18F-FLT uptake after treatments was more rapid or pronounced than that of 18F-FDG. Therefore, 18F-FLT may be a feasible PET tracer for monitoring response to therapy in oncology.


Subject(s)
Carcinoma, Squamous Cell/diagnostic imaging , Carcinoma, Squamous Cell/therapy , Dideoxynucleosides , Animals , Carcinoma, Squamous Cell/metabolism , Cell Line, Tumor , Dideoxynucleosides/pharmacokinetics , Female , HeLa Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Nude , Organ Specificity , Photochemotherapy/methods , Positron-Emission Tomography , Prognosis , Radiopharmaceuticals/pharmacokinetics , Radiotherapy/methods , Tissue Distribution , Treatment Outcome
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