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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 -
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 -
AAPS PharmSci 2003Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) methods were developed and validated for...
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) methods were developed and validated for the evaluation of motexafin lutetium (MLu, lutetium texaphyrin, PCI-0123) pharmacokinetics in human plasma. The LC-MS/MS method was specific for MLu, whereas the ICP-AES method measured total elemental lutetium. Both methods were fast, simple, precise, and accurate. For the LC-MS/MS method, a closely related analogue (PCI-0353) was used as the internal standard (IS). MLu and the IS were extracted from plasma by protein precipitation and injected into an LC-MS/MS system configured with a C18 column and an electrospray interface. The lower limit of quantitation was 0.05 microg MLu mL(-1), with a signal-to-noise ratio of 15:1. The response was linear from 0.05 to 5.0 microg MLu mL(-1). For the ICP-AES method, indium was used as the IS. The sample was digested with nitric acid, diluted, filtered, and then injected into the ICP-AES system. Two standard curve ranges were validated to meet the expected range of sample concentrations: 0.5 to 50, and 0.1 to 10 microg Lu mL(-1). The LC-MS/MS and ICP-AES methods were validated to establish accuracy, precision, analyte stability, and assay robustness. Interday precision and accuracy of quality control samples were < or =6.3% coefficient of variation (CV) and within 2.2% relative error (RE) for the LC-MS/MS method, and < or =8.7% CV and within 4.9% RE for the ICP-AES method. Plasma samples from a subset of patients in a clinical study were analyzed using both methods. For a representative patient, over 90% of the elemental lutetium in plasma could be ascribed to intact MLu at early time points. This percentage decreased to 59% at 48 hours after dosing, suggesting that some degradation and/or metabolism of the drug may have occurred.
Topics: Chromatography, Liquid; Humans; Mass Spectrometry; Metalloporphyrins; Reproducibility of Results; Spectrophotometry, Atomic
PubMed: 14621958
DOI: 10.1208/ps050323 -
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 -
Proceedings of SPIE--the International... Apr 2005Among the challenges to the clinical implementation of photodynamic therapy (PDT) is the delivery of a uniform photodynamic dose to induce uniform damage to the target...
Among the challenges to the clinical implementation of photodynamic therapy (PDT) is the delivery of a uniform photodynamic dose to induce uniform damage to the target tissue. As the photodynamic dose depends on both the local sensitizer concentration and the local fluence rate of treatment light, knowledge of both of these factors is essential to the delivery of uniform dose. In this paper, we investigate the distribution and kinetics of the photosensitizer motexafin lutetium (MLu, Lutrin®) as revealed by its fluorescence emission. Our current prostate treatment protocol involves interstitial illumination of the organ cylindrical diffusing fibers (CDF's) inserted into the prostate though clear catheters. For planning and treatment purposes, the prostate is divided into 4 quadrants. We use one catheter in each quadrant to place an optical fiber-based fluorescence probe into the prostate. This fiber is terminated in a beveled tip, allowing it to deliver and collect light perpendicular to the fiber axis. Excitation light is provided by a 465 nm light emitting diode (LED) source coupled to a dichroic beamsplitter, which passes the collected fluorescence emission to a CCD spectrograph. Spectra are obtained before and after PDT treatment in each quadrant of the prostate and are analyzed a linear fitting algorithm to separate the MLu fluorescence from the background fluorescence originating in the plastic catheter. A computer-controlled step motor allows the excitation/detection fiber to be moved along the catheter, building up a linear profile of the fluorescence emission spectrum of the tissue as a function of position. We have analyzed spectral fluorescence profiles obtained in 4 patients before and after MLu-mediated PDT. We find significant variation both within individual prostates and among patients. Within a single quadrant, we have observed the fluorescence signal to change by as much as a factor of 3 over a distance of 2 cm. Comparisons of pre- and post-PDT spectra allow a quantification treatment-induced photobleaching. Like the drug distribution, the extent of photobleaching varies widely among patients. In two cases, we observed bleaching of approximately 50% of the drug, while others exhibited negligible photobleaching.
PubMed: 26136613
DOI: 10.1117/12.590709 -
Journal of Photochemistry and... Jun 2005It is desirable to quantify the distribution of the light fluence rate, the optical properties, the drug concentration, and the tissue oxygenation for photodynamic... (Clinical Trial)
Clinical Trial
Determination of the distribution of light, optical properties, drug concentration, and tissue oxygenation in-vivo in human prostate during motexafin lutetium-mediated photodynamic therapy.
It is desirable to quantify the distribution of the light fluence rate, the optical properties, the drug concentration, and the tissue oxygenation for photodynamic therapy (PDT) of prostate cancer. We have developed an integrated system to determine these quantities before and after PDT treatment using motorized probes. The optical properties (absorption (micro(a)), transport scattering (micro(s'), and effective attenuation (micro(eff)) coefficients) of cancerous human prostate were measured in-vivo using interstitial isotropic detectors. Measurements were made at 732 nm before and after motexafin lutetium (MLu) mediated PDT at different locations along each catheter. The light fluence rate distribution was also measured along the catheters during PDT. Diffuse absorption spectroscopy measurement using a white light source allows extrapolation of the distribution of oxygen saturation StO2, total blood volume ([Hb]t), and MLu concentration. The distribution of drug concentration was also studied using fluorescence from a single optical fiber, and was found to be in good agreement with the values determined by absorption spectroscopy. This study shows significant inter- and intra-prostatic variations in the tissue optical properties and MLu drug distribution, suggesting that a real-time dosimetry measurement and feedback system for monitoring these values during treatment should be considered in future PDT studies.
Topics: Dose-Response Relationship, Drug; Drug Monitoring; Humans; Light; Male; Metalloporphyrins; Optics and Photonics; Oxygen; Photochemotherapy; Prostatic Neoplasms; Spectrophotometry
PubMed: 15896650
DOI: 10.1016/j.jphotobiol.2004.09.013 -
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 -
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 -
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