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Catheterization and Cardiovascular... Nov 2002Photodynamic therapy (PDT) has been approved as a tissue-specific light-activated cytotoxic therapy for many diseases. The ability of PDT to destroy target tissues... (Review)
Review
Photodynamic therapy (PDT) has been approved as a tissue-specific light-activated cytotoxic therapy for many diseases. The ability of PDT to destroy target tissues selectively is especially appealing for atherosclerotic plaque. Biotechnology has developed a new generation of selective photosensitizers and catheter-based technological advances in light delivery have allowed the introduction of PDT into the vasculature. The largest experience to date is with motexafin lutetium (MLu, Antrin), an expanded porphyrin (texaphyrin) that accumulates in plaque. The combination of the motexafin lutetium and endovascular illumination, or Antrin phototherapy, has been shown to reduce plaque in animal models. Antrin phototherapy generates cytotoxic singlet oxygen that has been shown to induce apoptosis in macrophages and smooth muscle cells. The safety, tolerability, and preliminary efficacy of Antrin phototherapy has been assessed in a phase 1 dose-ranging clinical trial in subjects with peripheral artery disease and is currently being examined in a phase 1 study in subjects with lesions of the native coronary arteries undergoing stent implantation. The preliminary results suggest that Antrin phototherapy is safe, well tolerated, and nontraumatic.
Topics: Animals; Coronary Artery Disease; Graft Occlusion, Vascular; Humans; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Treatment Outcome
PubMed: 12410519
DOI: 10.1002/ccd.10336 -
Retina (Philadelphia, Pa.) Aug 2002To review the biophysical basis and current state of therapy for photodynamic closure of subfoveal choroidal neovascularization in the eye. (Review)
Review
PURPOSE
To review the biophysical basis and current state of therapy for photodynamic closure of subfoveal choroidal neovascularization in the eye.
METHODS
A review of the literature is included, which encompasses the chemical structure, biophysical mechanism of action, range of available agents, status of clinical trials, clinical indications, results of treatments, complications, and future directions.
RESULTS
Photodynamic therapy has been shown to be effective in closing both experimental choroidal neovascularization in animal models as well as subfoveal choroidal neovascularization in humans. The therapy results in temporary closure of choroidal new vessels for a period of approximately 1 to 4 weeks. By 12 weeks, most patients have reperfusion or reproliferation of choroidal new vessels resulting in the need for retreatment to achieve continued closure and visual stabilization. Differences exist in the quantum yield, clinical efficiency, and light and sensitizer dose requirements between different classes of agents. Further clinical trials will be required to determine the optimal form of therapy, with verteporfin (Visudyne) as the only currently approved agent. Other agents, including tin etiopurpurin (Purlytin) and motexafin lutetium (Optrin), are currently undergoing phase III, and phase II trials, respectively.
CONCLUSIONS
Photodynamic therapy is a promising treatment modality shown to be effective in achieving closure and stabilization of vision loss compared with placebo control in eyes with subfoveal choroidal neovascularization.
Topics: Choroidal Neovascularization; Clinical Trials as Topic; Humans; Macular Degeneration; Myopia; Photochemotherapy; Photosensitizing Agents
PubMed: 12172104
DOI: 10.1097/00006982-200208000-00001 -
Physics in Medicine and Biology Mar 2002Motexafin lutetium (MLu) is a second-generation photosensitizer for photodynamic therapy (PDT) of cancer. We have developed and applied a diffuse optical reflectance...
Motexafin lutetium (MLu) is a second-generation photosensitizer for photodynamic therapy (PDT) of cancer. We have developed and applied a diffuse optical reflectance spectrometer for in vivo measurement of MLu uptake, optical properties, haemoglobin concentration and haemoglobin oxygen saturation in normal canine large bowels, kidneys and prostates. The probe consists of a broadband fibre-optic-coupled light source and detector fibres placed at various distances from the source fibre to collect reflected light. An analysis based on the diffusion approximation of the photon transport equation was used to recover tissue optical properties from the reflectance measurements. The instrumentation and analysis methods were validated using measurements from homogeneous, highly scattering phantoms with known MLu concentrations. The same techniques were then used to estimate chromophore concentrations of normal canine large bowels, kidneys and prostates. We estimated (mean (standard deviation)) total haemoglobin concentrations of 119 (25), 340 (92) and 51 (11) microM in the large bowels, kidneys and prostates of four dogs, respectively; tissue blood oxygen saturations in these same organs were 75 (15), 76 (21) and 74 (16) per cent, respectively. Tissue MLu concentrations (mg l(-1)) were estimated from data taken 3.5 h after injection of a 2 mg kg(-1) injected dose; data from three dogs gave concentrations of 2.4 (0.4) in large bowels, 6.8 (1.3) in kidneys and 2.2 (1.1) in prostates. The reduced scattering coefficients, mu's, estimated for large bowels, kidneys and prostates at 730 nm were, respectively: 10.1 (1.3), 19.6 (4.0) and 12.7 (0.6) cm(-1). We observed significant variability in MLu uptake, tissue scattering and haemoglobin concentration between organs and even between the same organ in different dogs. This class of in situ optical property measurement may be desirable to individualize PDT drug and light delivery.
Topics: Algorithms; Animals; Dogs; Dose-Response Relationship, Drug; Hemoglobins; Intestine, Large; Kidney; Male; Metalloporphyrins; Models, Statistical; Oxygen; Phantoms, Imaging; Photochemotherapy; Photosensitizing Agents; Prostate; Spectrophotometry
PubMed: 11936174
DOI: No ID Found -
Advanced Drug Delivery Reviews Oct 2001The present review examines the importance of improving photosensitizer delivery for choroidal neovascularization (CNV) in light of the clinical impact of photodynamic... (Review)
Review
The present review examines the importance of improving photosensitizer delivery for choroidal neovascularization (CNV) in light of the clinical impact of photodynamic therapy (PDT) for CNV. An overview of the classes of available photosensitizers is provided and the properties governing photosensitizer uptake and circulation in serum are discussed. Current delivery systems, for example liposomal formulations as well as the use of the promising strategy of antibody targeted delivery as a strategy to improve PDT selectivity and efficiency for CNV treatment are described. A summary of the work using Verteporfin, tin ethyl purpurin and Lu-Tex--photosensitizers currently in clinical trials for CNV--is given.
Topics: Choroidal Neovascularization; Clinical Trials as Topic; Humans; Liposomes; Metalloporphyrins; Photochemotherapy; Photolysis; Photosensitizing Agents; Porphyrins; Verteporfin
PubMed: 11672876
DOI: 10.1016/s0169-409x(01)00195-8 -
Transplantation Jun 2001Motexafin lutetium (Lu-Tex) is a photodynamic therapy (PDT) agent that localizes in atheromatous plaque in which it can be activated by far-red light. Lu-Tex...
BACKGROUND
Motexafin lutetium (Lu-Tex) is a photodynamic therapy (PDT) agent that localizes in atheromatous plaque in which it can be activated by far-red light. Lu-Tex biolocalization was examined in graft coronary artery disease (GCAD) with a rodent allograft model. After photoactivation, the effect on intimal proliferation was assessed.
METHODS
A PVG to ACI rat heterotopic heart transplantation model was used. Lu-Tex (10 mg/kg) was intravenously administered 90 days after transplantation. Photoactivation was performed 24 hr after Lu-Tex administration. A light-emitting diode, central wavelength of 742 nm, was used to illuminate the intraperitoneally placed allografts via a laparotomy (light fluence of 75 J/cm2 at a power density of 75 mW/cm2). Animals were divided into four groups according to postoperative treatments: PDT with Lu-Tex injection and light illumination (n=21), Lu-Tex injection and laparotomy (n=14), laparotomy with light only (n=14), and laparotomy only (n=16). GCAD was quantitatively assessed 14 days after treatments.
RESULTS
Lu-Tex localized in atherosclerotic plaque in vessels with GCAD. PDT significantly reduced both the percent of affected vessels and intimal proliferation compared to all other control study groups. alpha-Smooth muscle cell actin and anti-rat macrophage antibody-positive areas were significantly reduced within the neointima in allografts treated with PDT compared to all other study groups.
CONCLUSIONS
PDT significantly reduced atherosclerotic lesions of GCAD. Lu-Tex-mediated PDT may, therefore, be a potential method for treating accelerated atherosclerosis associated with transplantation.
Topics: Actins; Animals; Coronary Artery Disease; Coronary Vessels; Heart Transplantation; Male; Metalloporphyrins; Myocardium; Photochemotherapy; Photosensitizing Agents; Rats; Rats, Inbred ACI; Rats, Inbred Strains; Tissue Distribution; Tunica Intima
PubMed: 11435960
DOI: 10.1097/00007890-200106150-00008 -
Current Opinion in Ophthalmology Jun 2001Photodynamic therapy uses a photoactivating agent to selectively treat choroidal neovascularization. In April 2000, the United States Food and Drug Administration... (Review)
Review
Photodynamic therapy uses a photoactivating agent to selectively treat choroidal neovascularization. In April 2000, the United States Food and Drug Administration approved verteporfin photodynamic therapy for the treatment of subfoveal, predominately classic, choroidal neovascularization caused by age-related macular degeneration. The treatment of choroidal neovascularization from other causes such as myopia, angioid streaks, and idiopathy, and presumed ocular histoplasmosis syndrome is still under investigation. Other photoactivating agents are being evaluated. Photodynamic therapy has been shown to halt the progression of visual loss in patients with age-related macular degeneration who have subfoveal predominately classic choroidal neovascularization. The socio-economic impact of verteporfin approval has yet to be determined.
Topics: Choroidal Neovascularization; Humans; Macular Degeneration; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Porphyrins; Verteporfin
PubMed: 11389347
DOI: 10.1097/00055735-200106000-00010 -
Arteriosclerosis, Thrombosis, and... May 2001Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The...
Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium-loaded cells with 732-nm light (2 J/cm(2)) impaired cellular viability and growth (IC(50) 5 to 20 micromol/L). Depletion of intracellular glutathione potentiated (P=0.035) and the addition of antioxidant N-acetylcysteine attenuated (P=0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7+/-2% to 34+/-3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.
Topics: Animals; Apoptosis; Arteriosclerosis; Cell Division; Cell Line; Cell Survival; Cells, Cultured; Cytochrome c Group; Humans; Macrophages; Membrane Potentials; Metalloporphyrins; Mice; Mitochondria; Muscle, Smooth, Vascular; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents
PubMed: 11348871
DOI: 10.1161/01.atv.21.5.759 -
The Journal of Pharmacology and... Jun 2001Motexafin gadolinium (MGd) is a unique therapeutic agent that localizes in cancer cells and increases tumor response to ionizing radiation and certain chemotherapeutics....
Motexafin gadolinium (MGd) is a unique therapeutic agent that localizes in cancer cells and increases tumor response to ionizing radiation and certain chemotherapeutics. The in vitro intracellular localization, accumulation, and retention of MGd in murine EMT6 mammary sarcoma and Rif-1 fibrosarcoma cell lines were studied using interferometric Fourier fluorescence microscopy. MGd cellular uptake was semiquantified using its characteristic fluorescence emission band centered at 758 nm. Colocalization studies were performed using mitochondrial, endoplasmic reticulum, Golgi apparatus, nuclear, and lysosomal fluorescent organelle probes, and verified using interferometric Fourier spectroscopy. Cellular uptake was gradual and increased significantly with incubation time. MGd localized primarily within the lysosomes and endoplasmic reticulum, and to a lesser extent within the Golgi apparatus and mitochondria. Mitochondrial staining was increased in media without serum. No nuclear uptake was detected in the Rif-1 cells, but after 48 h nuclear uptake was observed in 15% of EMT6 cells. These results indicated that MGd accumulates within cytoplasmic compartments. The sustained intracellular localization of MGd may, in part, account for its unique radiation and chemotherapy enhancement properties. Interferometric Fourier fluorescence microscopy is a potentially powerful tool in delineating and verifying localization sites of therapeutic agents.
Topics: Animals; Biological Transport; Cell Nucleus; Cell Survival; Culture Media, Serum-Free; Endoplasmic Reticulum; Fluorescent Dyes; Golgi Apparatus; Lysosomes; Metalloporphyrins; Mice; Microscopy, Fluorescence; Microscopy, Interference; Mitochondria; Neoplasm Transplantation; Neoplasms, Experimental; Photochemistry; Radiation-Sensitizing Agents; Sarcoma; Spectrometry, Fluorescence; Tumor Cells, Cultured
PubMed: 11356908
DOI: No ID Found -
Clinical Cancer Research : An Official... Mar 2001Our purpose was to determine the feasibility of comprehensive treatment of the canine prostate with photodynamic therapy (PDT) using motexafin lutetium (Lu-Tex) and to...
Our purpose was to determine the feasibility of comprehensive treatment of the canine prostate with photodynamic therapy (PDT) using motexafin lutetium (Lu-Tex) and to evaluate the toxicity and tissue effects associated with this treatment. Twenty-five adult male beagles with normal prostate glands were given an i.v. injection of the second-generation photosensitizer Lu-Tex (2-6 mg/kg). An additional two dogs were used as controls and did not receive any photosensitizing drug. All 27 dogs underwent laparotomy to expose the prostate. Three hours postinjection, a total dose of 75-150 J/cm of 732 nm laser light was delivered interstitially and/or transurethrally to the prostate via cylindrical diffusing fibers. Dogs were euthanized between 2 days and 3 months after PDT. All subjects were monitored for clinical evidence of toxicity. Specimens were examined macroscopically and microscopically to characterize the tissue reaction and assess extent of tissue effect as a result of treatment. Interstitial and/or transurethral PDT were successfully delivered in all dogs with no perioperative complications. No clinical evidence of acute urinary obstruction or rectal bleeding was noted. At all dose levels, macroscopic and microscopic evaluation revealed a prostatic tissue reaction characterized initially (within 48 h) by inflammation and necrosis followed by fibrosis and glandular epithelial atrophy. Comprehensive treatment of the entire prostate could be achieved using the interstitial alone approach or combined transurethral and interstitial approach. The transurethral alone approach did not result in complete coverage of the prostate. Dogs receiving transurethral or combined interstitial and transurethral treatment developed erythema and urethral epithelial disruption at all dose levels. Those receiving combined treatment at the highest dose level (Lu-Tex 6 mg/kg, 150 J/cm light) developed urethral fistulae and peritonitis. Dogs treated with the interstitial alone approach were found to have the least amount of urethral damage. Comprehensive treatment of the canine prostate with Lu-Tex PDT is feasible using an interstitial alone or combined interstitial and transurethral approach. The interstitial alone technique results in the least amount of toxicity. The prostatic tissue reaction to treatment is characterized by initial inflammation and necrosis followed by fibrosis and glandular epithelial atrophy.
Topics: Animals; Dogs; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Endoscopy; Light; Male; Metalloporphyrins; Necrosis; Photosensitizing Agents; Phototherapy; Prostate; Prostatic Neoplasms; Time Factors; Urinary Bladder
PubMed: 11297261
DOI: No ID Found -
International Journal of Radiation... Apr 2001Experiments were undertaken to determine if metabolic changes induced by Motexafin gadolinium (Gd-Tex(+2), XCYTRIN) predict time intervals between drug and radiation...
PURPOSE
Experiments were undertaken to determine if metabolic changes induced by Motexafin gadolinium (Gd-Tex(+2), XCYTRIN) predict time intervals between drug and radiation wherein there is enhancement of radiation efficacy.
METHODS AND MATERIALS
We evaluated the effect of Gd-Tex(+2) on tumor metabolism and on tumor growth using a mouse mammary carcinoma model and (31)P nuclear magnetic resonance (NMR) experiments. Response to therapy was evaluated based on time for the tumor to regrow to pretreatment size and also tumor doubling time.
RESULTS
(31)P NMR experiments indicated that Gd-Tex(+2) effected tumor energy metabolism during the first 24 hours postadministration. A decrease in phosphocreatine was noted at 2 (p < 0.04), 6 (p < 0.006), and 24 (p < 0.001) hours post Gd-Tex(+2). A decrease in nucleoside triphosphates was noted only at 2 hours (p < 0.02), with subsequent recovery at 6 hours. Phosphocreatine in control (saline treated) tumors showed a significant decrease only at 24 hours (p < 0.01). Irradiation at 2 and 6 hours post Gd-Tex(+2) induced an enhanced effect compared to radiation alone as measured by analyzing the growth curves, maximum tumor volumes, and the time for the tumors to regrow to their initial volumes. Irradiation at 24 hours post Gd-Tex(+2) induced a modest enhancement in tumor growth delay compared to radiation alone.
DISCUSSION
NMR spectroscopy may be useful for monitoring tumor metabolism after treatment with Gd-Tex(+2) and administering radiation during the time of maximal efficacy of Gd-Tex(+2).
Topics: Animals; Energy Metabolism; Magnetic Resonance Spectroscopy; Male; Mammary Neoplasms, Animal; Metalloporphyrins; Mice; Mice, Inbred C3H; Phosphorus; Photosensitizing Agents; Radiation Tolerance; Radiobiology; Time Factors
PubMed: 11286846
DOI: 10.1016/s0360-3016(00)01566-2