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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 -
Photodiagnosis and Photodynamic Therapy Mar 2021This article is a review of approaches to treatment of low and high-grade prostate cancer including a discussion of active treatment vs. active surveillance for patients... (Review)
Review
This article is a review of approaches to treatment of low and high-grade prostate cancer including a discussion of active treatment vs. active surveillance for patients with low-grade prostate cancer. In particular, we will review PDT as an option for active treatment of low-grade prostate cancer considered in light of recent clinical trials. The mechanism and clinical methods of PDT application and the key points from clinical trials using PDT for prostate cancer with the photosensitizers m-tetrahydroxyphenyl chloride, protoporphyrin IX, motexafin lutetium, padoporfin, and padeliporfin between the years 2002 and 2017 are reviewed. Recently developed methodologies for photodynamic prostate cancer treatment that are in the experimental stage, photodynamic diagnosis, fluorescence guided resection, and PSMA-targeted PDT will also be discussed.
Topics: Humans; Male; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms
PubMed: 33352313
DOI: 10.1016/j.pdpdt.2020.102158 -
Biomaterials Research 2018Photodynamic therapy (PDT) is photo-treatment of malignant or benign diseases using photosensitizing agents, light, and oxygen which generates cytotoxic reactive oxygens... (Review)
Review
BACKGROUND
Photodynamic therapy (PDT) is photo-treatment of malignant or benign diseases using photosensitizing agents, light, and oxygen which generates cytotoxic reactive oxygens and induces tumour regressions. Several photodynamic treatments have been extensively studied and the photosensitizers (PS) are key to their biological efficacy, while laser and oxygen allow to appropriate and flexible delivery for treatment of diseases.
INTRODUCTION
In presence of oxygen and the specific light triggering, PS is activated from its ground state into an excited singlet state, generates reactive oxygen species (ROS) and induces apoptosis of cancer tissues. Those PS can be divided by its specific efficiency of ROS generation, absorption wavelength and chemical structure.
MAIN BODY
Up to dates, several PS were approved for clinical applications or under clinical trials. Photofrin® is the first clinically approved photosensitizer for the treatment of cancer. The second generation of PS, Porfimer sodium (Photofrin®), Temoporfin (Foscan®), Motexafin lutetium, Palladium bacteriopheophorbide, Purlytin®, Verteporfin (Visudyne®), Talaporfin (Laserphyrin®) are clinically approved or under-clinical trials. Now, third generation of PS, which can dramatically improve cancer-targeting efficiency by chemical modification, nano-delivery system or antibody conjugation, are extensively studied for clinical development.
CONCLUSION
Here, we discuss up-to-date information on FDA-approved photodynamic agents, the clinical benefits of these agents. However, PDT is still dearth for the treatment of diseases in specifically deep tissue cancer. Next generation PS will be addressed in the future for PDT. We also provide clinical unmet need for the design of new photosensitizers.
PubMed: 30275968
DOI: 10.1186/s40824-018-0140-z -
Oncotarget May 2017The search for new therapeutics for the treatment of prostate cancer is ongoing with a focus on the balance between the harms and benefits of treatment. New therapies... (Review)
Review
The search for new therapeutics for the treatment of prostate cancer is ongoing with a focus on the balance between the harms and benefits of treatment. New therapies are being constantly developed to offer treatments similar to radical therapies, with limited side effects. Photodynamic therapy (PDT) is a promising strategy in delivering focal treatment in primary as well as post radiotherapy prostate cancer. PDT involves activation of a photosensitizer (PS) by appropriate wavelength of light, generating transient levels of reactive oxygen species (ROS). Several photosensitizers have been developed with a focus on treating prostate cancer like mTHPC, motexafin lutetium, padoporfin and so on. This article will review newly developed photosensitizers under clinical trials for the treatment of prostate cancer, along with the potential advantages and disadvantages in delivering focal therapy.
Topics: Animals; Humans; Male; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms; Reactive Oxygen Species; Treatment Outcome
PubMed: 28430624
DOI: 10.18632/oncotarget.15496 -
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 -
Radiation Research Sep 2010Photodynamic therapy (PDT) with low light fluence rate has rarely been studied in protocols that use short drug-light intervals and thus deliver illumination while...
Photodynamic therapy (PDT) with low light fluence rate has rarely been studied in protocols that use short drug-light intervals and thus deliver illumination while plasma concentrations of photosensitizer are high, creating a prominent vascular response. In this study, the effects of light fluence rate on PDT response were investigated using motexafin lutetium (10 mg/kg) in combination with 730 nm light and a 180-min drug-light interval. At 180 min, the plasma level of photosensitizer was 5.7 ng/microl compared to 3.1 ng/mg in RIF tumor, and PDT-mediated vascular effects were confirmed by a spasmodic decrease in blood flow during illumination. Light delivery at 25 mW/cm(2) significantly improved long-term tumor responses over that at 75 mW/cm(2). This effect could not be attributed to oxygen conservation at low fluence rate, because 25 mW/cm(2) PDT provided little benefit to tumor hemoglobin oxygen saturation. However, 25 mW/cm(2) PDT did prolong the duration of ischemic insult during illumination and was correspondingly associated with greater decreases in perfusion immediately after PDT, followed by smaller increases in total hemoglobin concentration in the hours after PDT. Increases in blood volume suggest blood pooling from suboptimal vascular damage; thus the smaller increases after 25 mW/cm(2) PDT provide evidence of more widespread vascular damage, which was accompanied by greater decreases in clonogenic survival. Further study of low fluence rate as a means to improve responses to PDT under conditions designed to predominantly damage vasculature is warranted.
Topics: Blood Vessels; Humans; Metalloporphyrins; Neoplasms; Oxygen; Photochemotherapy; Photosensitizing Agents
PubMed: 20726728
DOI: 10.1667/RR2075.1 -
World Journal of Urology Oct 2010Although in early stages of clinical development, photodynamic therapy (PDT) shows promise in delivering focal treatment of both primary and post-radiotherapy prostate... (Review)
Review
Although in early stages of clinical development, photodynamic therapy (PDT) shows promise in delivering focal treatment of both primary and post-radiotherapy prostate cancer. This article will review the mechanism of action of PDT, previous research using PDT for treating prostate cancer including the development of newer vascular-acting photosensitizers, and the potential advantages and disadvantages of PDT in delivering focal therapy.
Topics: Dihematoporphyrin Ether; Humans; Male; Mesoporphyrins; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms; Treatment Outcome
PubMed: 20454966
DOI: 10.1007/s00345-010-0554-2 -
Clinical Cancer Research : An Official... Aug 2008The time course of serum prostate-specific antigen (PSA) response to photodynamic therapy (PDT) of prostate cancer was measured.
PURPOSE
The time course of serum prostate-specific antigen (PSA) response to photodynamic therapy (PDT) of prostate cancer was measured.
EXPERIMENTAL DESIGN
Seventeen patients were treated in a phase I trial of motexafin lutetium-PDT. PDT dose was calculated in each patient as the product of the ex vivo measured pre-PDT photosensitizer level and the in situ measured light dose. Serum PSA level was measured within 2 months before PDT (baseline), and at day 1; weeks 1 to 3; months 1, 2, and 3; months 4 to 6; and months 7 to 11 after PDT.
RESULTS
At 24 hours after PDT, serum PSA increased by 98% +/- 36% (mean +/- SE) relative to baseline levels (P = 0.007). When patients were dichotomized based on median PDT dose, those who received high PDT dose showed a 119% +/- 52% increase in PSA compared with a 54% +/- 27% increase in patients treated at low PDT dose. Patients treated with high versus low PDT dose showed a median biochemical delay of 82 versus 43 days (P = 0.024), with biochemical delay defined as the length of time between PDT and a nonreversible increase in PSA to a value greater than or equal to baseline.
CONCLUSIONS
Results show PDT to induce large, transient increases in serum PSA levels. Patients who experienced high PDT dose showed greater short-term increase in PSA and a significantly more durable PSA response (biochemical delay). These data strongly promote the need for individualized delivery of PDT dose and assessment of treatment effect in PDT of prostate cancer. Information gained from such patient-specific measurements could facilitate the introduction of multiple PDT sessions in patients who would benefit.
Topics: Dose-Response Relationship, Drug; Humans; Light; Male; Metalloporphyrins; Models, Biological; Photochemotherapy; Photosensitizing Agents; Prostate-Specific Antigen; Prostatic Neoplasms; Radiometry; Recurrence; Time Factors; Treatment Outcome
PubMed: 18676760
DOI: 10.1158/1078-0432.CCR-08-0317 -
Journal of Biomedical Optics 2007Near-infrared diffuse reflectance spectroscopy (DRS) has been used to noninvasively monitor optical properties during photodynamic therapy (PDT). This technique has been... (Comparative Study)
Comparative Study
Near-infrared diffuse reflectance spectroscopy (DRS) has been used to noninvasively monitor optical properties during photodynamic therapy (PDT). This technique has been extensively validated in tissue phantoms; however, validation in patients has been limited. This pilot study compares blood oxygenation and photosensitizer tissue uptake measured by multiwavelength DRS with ex vivo assays of the hypoxia marker, 2-(2-nitroimida-zol-1[H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5), and the photosensitizer (motexafin lutetium, MLu) from tissues at the same tumor site of three tumors in two patients with intra-abdominal cancers. Similar in vivo and ex vivo measurements of MLu concentration are carried out in murine radiation-induced fibrosarcoma (RIF) tumors (n=9). The selection of optimal DRS wavelength range and source-detector separations is discussed and implemented, and the association between in vivo and ex vivo measurements is examined. The results demonstrate a negative correlation between blood oxygen saturation (StO(2)) and EF5 binding, consistent with published relationships between EF5 binding and electrode measured pO(2), and between electrode measured pO(2) and StO(2). A tight correspondence is observed between in vivo DRS and ex vivo measured MLu concentration in the RIF tumors; similar data are positively correlated in the human intraperitoneal tumors. These results further demonstrate the potential of in vivo DRS measurements in clinical PDT.
Topics: Algorithms; Animals; Computer Simulation; Fibrosarcoma; Humans; Metalloporphyrins; Mice; Mice, Inbred C3H; Models, Biological; Oxygen; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Infrared
PubMed: 17614731
DOI: 10.1117/1.2743082 -
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