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Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis.Proceedings of the National Academy of... Feb 2024Photon-controlled pyroptosis activation (PhotoPyro) is a promising technique for cancer immunotherapy due to its noninvasive nature, precise control, and ease of...
Photon-controlled pyroptosis activation (PhotoPyro) is a promising technique for cancer immunotherapy due to its noninvasive nature, precise control, and ease of operation. Here, we report that biomolecular photoredox catalysis in cells might be an important mechanism underlying PhotoPyro. Our findings reveal that the photocatalyst lutetium texaphyrin () facilitates rapid and direct photoredox oxidation of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and various amino acids, thereby triggering pyroptosis through the caspase 3/GSDME pathway. This mechanism is distinct from the well-established role of as a photodynamic therapy sensitizer in cells. Two analogs of , bearing different coordinated central metal cations, were also explored as controls. The first control, gadolinium texaphyrin (), is a weak photocatalyst but generates reactive oxygen species (ROS) efficiently. The second control, manganese texaphyrin (), is ineffective as both a photocatalyst and a ROS generator. Neither nor was found to trigger pyroptosis under the conditions where was active. Even in the presence of a ROS scavenger, treating MDA-MB-231 cells with at concentrations as low as 50 nM still allows for pyroptosis photo-activation. The present findings highlight how biomolecular photoredox catalysis could contribute to pyroptosis activation by mechanisms largely independent of ROS.
Topics: Pyroptosis; Reactive Oxygen Species; Metalloporphyrins
PubMed: 38381784
DOI: 10.1073/pnas.2314620121 -
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 -
Photochemistry and Photobiology 2006The in vivo fluorescence emission from human prostates was measured before and after motexafin lutetium (MLu)-mediated photodynamic therapy (PDT). A single side-firing...
The in vivo fluorescence emission from human prostates was measured before and after motexafin lutetium (MLu)-mediated photodynamic therapy (PDT). A single side-firing optical fiber was used for both the delivery of 465 nm light-emitting diode excitation light and the collection of emitted fluorescence. It was placed interstitially within the prostate via a closed transparent plastic catheter. Fitting of the collected fluorescence emission spectra using the known fluorescence spectrum of 1 mg/kg MLu in an intralipid phantom yields a quantitative measure of the local MLu concentration. We found that an additional correction factor is needed to account for the reduction of the MLu fluorescence intensity measured in vivo due to strong optical absorption in the prostate. We have adopted an empirical correction formula given by C = (3.1 cm(-1)/micro's) exp (microeff x 0.97 cm), which ranges from approximately 3 to 16, with a mean of 9.3 +/-4.8. Using a computer-controlled step motor to move the probe incrementally along parallel tracks within the prostate we can determine one-dimensional profiles of the MLu concentration. The absolute MLu concentration and the shape of its distribution are confirmed by ex vivo assay and by diffuse absorption measurements, respectively. We find significant heterogeneity in photosensitizer concentration within and among five patients. These variations occur over large enough spatial scales compared with the sampling volume of the fluorescence emission that mapping the distribution in three dimensions is possible.
Topics: Humans; Male; Metalloporphyrins; Phantoms, Imaging; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms; Spectrometry, Fluorescence
PubMed: 16808592
DOI: 10.1562/2005-10-04-RA-711 -
American Journal of Ophthalmology Mar 2000To investigate the suitability of lutetium texaphyrin (lu-tex) as a fluorescence imaging agent in the delineation of retinal vascular and choroidal vascular diseases....
PURPOSE
To investigate the suitability of lutetium texaphyrin (lu-tex) as a fluorescence imaging agent in the delineation of retinal vascular and choroidal vascular diseases. The utilization of an efficient fluorescent molecule that is also a photosensitizer represents a unique opportunity to couple diagnosis and therapy.
METHODS
Fundus fluorescence angiography comparing lu-tex (motexafin lutetium, Optrin, Pharmacyclics Inc, Sunnyvale, California) with the conventional angiographic dyes, sodium fluorescein, and indocynanine green (ICG), was performed on the eyes of normal and laser-injured New Zealand white rabbits. Plasma pharmacokinetic data and plasma protein binding were assessed in addition to light microscopy of the retina in both imaged and laser-injured eyes.
RESULTS
Normal retinal and choroidal vasculature was well delineated by lu-tex angiography. Experimentally induced choroidal and retinal vascular lesions were enhanced by lu-tex and demonstrated different staining patterns than fluorescein or ICG, particularly at the margins of the lesions. Lu-tex cleared rapidly from the plasma, with 39.7% bound to the high-density lipoprotein (HDL) fraction while 15.8% was bound to the low-density lipoprotein (LDL) fraction. No evidence of retinal toxicity after dye administration was observed by either ophthalmoscopy and fundus photography or by light microscopy.
CONCLUSION
Lu-tex angiography is a potentially valuable method for retinal vascular and choroidal vascular evaluation, and it has advantages over fluorescein and ICG angiography. The same agent could conceivably be used for both the identification of abnormal vasculature and subsequent photodynamic treatment.
Topics: Animals; Choroid; Choroidal Neovascularization; Disease Models, Animal; Fluorescein; Fluorescein Angiography; Fundus Oculi; Indocyanine Green; Lutetium; Male; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Rabbits; Retinal Neovascularization; Retinal Vessels
PubMed: 10704552
DOI: 10.1016/s0002-9394(99)00462-6 -
Methods and Findings in Experimental... Nov 2003Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abarelix, ABX-EGF, ademetionine, agomelatine, AMGN-0007, 9-aminocamptothecin, AN-9, anecortave acetate, anidulafungin, AOD-9604, apolizumab, apomate, L-arginine hydrochloride, arzoxifene hydrochloride; Bevacizumab, BP-897, BufferGel; Capravirine, carboxyamidotriazole, carnosine, CC-4047, CEP-701, cerivastatin sodium, clofarabine, conivaptan hydrochloride, CP-461, CS-003; Daptomycin, darifenacin, decitabine, deferasirox, duloxetine hydrochloride; Eberconazole, Ecyd, efalizumab, eglumegad hydrate, EMD-72000, (-)-epigallocatechin gallate, exatecan mesilate, exenatide; Fampridine, fenretinide, ferumoxtran-10; Gadofosveset sodium, garenoxacin mesilate, genistein, glutamine, GPI-15715; Hexyl insulin M2, human insulin, HYB-165; Indisulam, irofulven; KRN-5500, L-796568, laurocapram, lidocaine/prilocaine, lonafarnib, lotrafiban; Melagatran, melatonin, 2-methoxyestradiol, metreleptin, motexafin gadoliniu, motexafin lutetium; Natalizumab, nelarabine, NO-aspirin, NSC-683864; ONO-6126; Pemetrexed disodium, pexelizumab, pirfenidone, PncCRM9, polyglutamate paclitaxel, pramlintide acetate pregabalin, PRO-2000; Ragaglitazar, ramelteon, rasagiline mesilate, rDNA insulin, recombinant glucagon-like peptide-1 (7-36) amide, recombinant human parathyroid hormone (1-84), reolysin RG228, roflumilast, roxifiban acetate, RPI-4610, rubitecan; Safinamide mesilate, solifenacin succinate, SRL-172; T-138067, tafenoquine succinate, tecadenoson, TER-286, tesaglitazar, tetrathiomolybdate, tezosentan disodium, TheraCIM, tigecycline, tipifarnib, tolvaptan, trabectedin, tributyrin, trimegestone, troxacitabine; UCN-01, urokinase alfa; Vinflunine, viscum fraxini 2; Xcellerated T cells, ximelagatran.
Topics: Clinical Trials as Topic; Humans
PubMed: 14685303
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 -
Photochemistry and Photobiology Jun 1996Lutetium texaphyrin, PCI-0123, is a pure, water-soluble photosensitizer with a large broad absorption band centered at 732 nm. The compound was tested for photodynamic...
Lutetium texaphyrin, PCI-0123, is a pure, water-soluble photosensitizer with a large broad absorption band centered at 732 nm. The compound was tested for photodynamic therapy (PDT) effectiveness in a murine mammary cancer model. The texaphyrin macrocycle as illustrated by magnetic resonance imaging and 14C-radiolabeled texaphyrin studies was shown to be tumor selective; a tumor-to-muscle ratio of 10.55 was seen after 5 h. Lutetium texaphyrin, at a drug dose of 20 mumol/kg with irradiation 5 h postinjection at 150 J/cm2 and 150 mW/cm2, had significant efficacy (P < 0.0001) in treating neoplasms of moderate size (40 +/- 14 mm3) and also had significant efficacy (P < 0.0001) in treating larger neoplasms (147 +/- 68 mm3). The PDT efficacy was correlated with the time interval between PCI-0123 administration and light exposure. A 100% cure rate was achieved when photoirradiation took place 3 h postinjection compared to 50% for 5 h using 10 mumol/kg and 150 J/cm2 at 150 mW/cm2. The PDT efficacy was attributable to the selective uptake/retention of the texaphyrin photosensitizer in addition to the depth of light penetration achievable at the 732 nm laser irradiation.
Topics: Animals; Female; Infrared Rays; Magnetic Resonance Imaging; Mammary Neoplasms, Experimental; Metalloporphyrins; Mice; Mice, Inbred DBA; Photochemistry; Photochemotherapy; Photosensitizing Agents; Solubility; Water
PubMed: 8992510
DOI: 10.1111/j.1751-1097.1996.tb09647.x -
Biochemical Pharmacology Apr 2000The texaphyrins are quintessential metal-coordinating expanded porphyrins. They constitute a new series of synthetic porphyrin analogues that show promise as drugs for... (Review)
Review
The texaphyrins are quintessential metal-coordinating expanded porphyrins. They constitute a new series of synthetic porphyrin analogues that show promise as drugs for use in a range of medical therapies. Currently, two different water-solubilized lanthanide(III) texaphyrin complexes, namely the gadolinium(III) and lutetium(III) derivatives 1 and 2 (Gd-Tex and Lu-Tex, respectively), are being tested clinically. The first of these, XCYTRIN, is in a pivotal Phase III clinical trial as a potential enhancer of radiation therapy for patients with metastatic cancers to the brain receiving whole brain radiation therapy. The second, in various formulations, is being tested as a photosensitizer for use in: (i) the photodynamic treatment of recurrent breast cancer (LUTRIN; Phase II clinical trials complete), (ii) photoangioplastic reduction of atherosclerosis involving peripheral arteries (ANTRIN; now in Phase II testing), and (iii) light-based treatment of age-related macular degeneration (OPTRIN; currently in Phase I clinical trials), a vision-threatening disease of the retina. Taken in concert, these two metallotexaphyrins provide a powerful new class of experimental drugs whose diverse potential utility is abetted by a combination of well-optimized physical features, favorable tissue biolocalization characteristics, and novel mechanisms of action. Interestingly, these mechanisms may alter conventional wisdom regarding mechanisms of radiation therapy and the pathophysiology of atherosclerosis.
Topics: Arteriosclerosis; Clinical Trials as Topic; Humans; Macular Degeneration; Metalloporphyrins; Neoplasms; Photochemotherapy; Photosensitizing Agents; Radiation Tolerance
PubMed: 10718331
DOI: 10.1016/s0006-2952(99)00314-7 -
Proceedings of SPIE--the International... Jun 2014A continuing challenge in photodynamic therapy is the accurate determination of the optical properties of the tissue being treated. We have developed a method for...
A continuing challenge in photodynamic therapy is the accurate determination of the optical properties of the tissue being treated. We have developed a method for characterizing the absorption and scattering spectra of prostate tissue undergoing PDT treatment. Our current prostate treatment protocol involves interstitial illumination of the organ cylindrical diffusing optical fibers (CDFs) inserted into the prostate through clear catheters. We employ one of these catheters to insert an isotropic white light point source into the prostate. An isotropic detection fiber connected to a spectrograph is inserted into a second catheter a known distance away. The detector is moved along the catheter by a computer-controlled step motor, acquiring diffuse light spectra at 2 mm intervals along its path. We model the fluence rate as a function of wavelength and distance along the detector's path using an infinite medium diffusion theory model whose free parameters are the absorption coefficient µ at each wavelength and two variables A and b which characterize the reduced scattering spectrum of the form µ' = Aλ. We analyze our spectroscopic data using a nonlinear fitting algorithm to determine A, b, and µ at each wavelength independently; no prior knowledge of the absorption spectrum or of the sample's constituent absorbers is required. We have tested this method in tissue simulating phantoms composed of intralipid and the photosensitizer motexafin lutetium (MLu). The MLu absorption spectrum recovered from the phantoms agrees with that measured in clear solution, and µ at the MLu absorption peak varies linearly with concentration. The µ' spectrum reported by the fit is in agreement with the known scattering coefficient of intralipid. We have applied this algorithm to spectroscopic data from human patients sensitized with MLu (2 mg kg) acquired before and after PDT. Before PDT, the absorption spectra we measure include the characteristic MLu absorption peak. Using our phantom data as a calibration, we have determined the pre-treatment MLu concentration to be approximately 2 to 8 mg kg. After PDT, the concentration is reduced to 1 to 2.5 mg kg, an indication of photobleaching induced by irradiation. In addition, absorption features corresponding to the oxygenated and deoxygenated forms of hemoglobin indicate a reduction in tissue oxygenation during treatment.
PubMed: 26146442
DOI: 10.1117/12.528968 -
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