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Photochemistry and Photobiology 2005Characterization of the tissue light penetration in prostate photodynamic therapy (PDT) is important to plan the arrangement and weighting of light sources so that... (Clinical Trial)
Clinical Trial
Characterization of the tissue light penetration in prostate photodynamic therapy (PDT) is important to plan the arrangement and weighting of light sources so that sufficient light fluence is delivered to the treatment volume. The optical properties (absorption [mu(a)], transport scattering [mu(s)'] and effective attenuation [mu(eff)] coefficients) of 13 patients with locally recurrent prostate cancer were measured in situ using interstitial isotropic detectors. Measurements were made at 732 nm before and after motexafin lutetium (MLu)-mediated PDT in four quadrants. Optical properties were derived by applying the diffusion theory to the fluence rates measured at several distances (0.5-5 cm) from a point source. mu(a) and mu(s)' varied between 0.07 and 1.62 cm(-1) (mean 0.37 +/- 0.24 cm(-1)) and 1.1 and 44 cm(-1) (mean 14 +/- 11 cm(-1)), respectively. mu(a) was proportional to the concentration of MLu measured by an ex vivo fluorescence assay. We have observed, on average, a reduction of the MLu concentration after PDT, presumably due to the PDT consumption of MLu. mu(eff) varied between 0.91 and 6.7 cm(-1) (mean 2.9 +/- 0.7 cm(-1)), corresponding to an optical penetration depth (delta = 1/micro(eff)) of 0.1-1.1 cm (mean 0.4 +/- 0.1 cm). The mean penetration depth at 732 nm in human prostate is at least two times smaller than that found in normal canine prostates, which can be explained by a four times increase of the mean value of mu(s)' in human prostates. The mean light fluence rate per unit source strength at 0.5 cm from a point source was 1.5 +/- 1.1 cm(-2), excluding situations when bleeding occurs. The total number of measurements was N = 121 for all mean quantities listed above. This study showed significant inter- and intraprostatic differences in the optical properties, suggesting that a real-time dosimetry measurement and feedback system for monitoring light fluences during treatment should be considered for future PDT studies.
Topics: Humans; Male; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Prostate; Prostatic Neoplasms
PubMed: 15535736
DOI: 10.1562/2004-06-25-RA-216 -
Lasers in Surgery and Medicine 1999New photosensitizers proposed for photodynamic therapy (PDT) treatment of tumors need to be evaluated in animal models to determine the parameters needed for treatment.... (Comparative Study)
Comparative Study
BACKGROUND AND OBJECTIVE
New photosensitizers proposed for photodynamic therapy (PDT) treatment of tumors need to be evaluated in animal models to determine the parameters needed for treatment. They also need to be compared with existing photosensitizers for efficacy. We examined the PDT response to lutetium-texaphyrin (PCI-0123) in a mouse mammary adenocarcinoma model and compared it with the PDT response seen when using Photofrin.
STUDY DESIGN/MATERIALS AND METHODS
DBA/2 mice with SMT-F tumors were used to explore PCI-0123 toxicity, laser light dose, and drug dose effects on PDT response and to determine the most effective time for light application. The PDT response of PCI-0123-treated tumors was compared with that of Photofrin-treated tumors.
RESULTS
Treatment of tumors with 150 J/cm2 of 740 nm laser light 5-6 hr after PCI-0123 administration (40 mg/kg) resulted in a 100% response rate and a 55% cure rate. Tumors treated with 150 J/cm2 of 630 nm laser light 24 hr after Photofrin administration (10 mg/kg) resulted in a 67% response rate and a 16% cure rate.
CONCLUSION
PCI-0123 was found to be a more effective photosensitizer than Photofrin.
Topics: Adenocarcinoma; Animals; Dihematoporphyrin Ether; Female; Laser Therapy; Mammary Neoplasms, Animal; Metalloporphyrins; Mice; Mice, Inbred DBA; Photochemotherapy; Photosensitizing Agents; Tumor Cells, Cultured
PubMed: 10327046
DOI: 10.1002/(sici)1096-9101(1999)24:4<276::aid-lsm5>3.0.co;2-n -
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... Mar 2000We have investigated the pharmacokinetics (PK) of Lutetium Texaphyrin (Lu-Tex), a second-generation photosensitizer, in the Syrian hamster cheek pouch early cancer...
We have investigated the pharmacokinetics (PK) of Lutetium Texaphyrin (Lu-Tex), a second-generation photosensitizer, in the Syrian hamster cheek pouch early cancer model. Ten male hamsters, five with chemically induced early squamous cell cancer of the left cheek pouch, received an intracardiac injection of a 10 mg/ml Lu-Tex solution, resulting in a dose of 12 mg Lu-Tex per kg of bodyweight. The PK of the dye have been measured during the 24 h following the injection with an optical-fiber-based spectrofluorometer on the ventral skin, the healthy and the tumoral cheek-pouch mucosa. The Lu-Tex fluorescence is excited at 460 nm and detected around 740 nm. All the measurements yield very similar pharmacokinetic curves. The fluorescence intensity reaches a maximum between two and three hours after the injection and, at its maximum, it is consistently higher (up to 1.5 times) on the tumor than on the healthy mucosa. It remains smaller on the skin than on cheek-pouch mucosa. After 24 h, the Lu-Tex fluorescence is no longer detectable either on the skin, on the lesion or on the healthy mucosa. Moreover, Lu-Tex clearly displays a significant fluorescence selectivity between early carcinoma and healthy mucosa in this model. Furthermore, the inter-animal fluctuations of the fluorescence signal are small (+/-16% on the tumor-bearing mucosa). Eight-minute-long skin-irradiation tests have been performed 24 h after the injection of the Lu-Tex on the ventral skin of 16 additional animals with a solar simulator. No reaction is observed, either macroscopically or microscopically, which further demonstrates, as suggested by the fluorescence measurements, that this photosensitizer is significantly cleared from the skin after 24 h.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma in Situ; Carcinoma, Squamous Cell; Cricetinae; Male; Mesocricetus; Metalloporphyrins; Microscopy, Fluorescence; Mouth Mucosa; Mouth Neoplasms; Photosensitizing Agents; Skin; Sunlight
PubMed: 10877068
DOI: 10.1016/s1011-1344(00)00027-0 -
Photochemistry and Photobiology May 2004The use of near-infrared (NIR)-excited Fourier-transform (FT) Raman spectroscopy as a technique for evaluating the extent of photosensitizer localization in tumor (human...
The use of near-infrared (NIR)-excited Fourier-transform (FT) Raman spectroscopy as a technique for evaluating the extent of photosensitizer localization in tumor (human pancreatic adenocarcinomas)-bearing mice has been tested using lutetium(III) texaphyrin analogue Lu-T2B2Tex. The complex was injected subcutaneously in the form of three injections given during the course of 3 days. The kinetics of biodistribution were then followed over a time scale of 1-6 days. The NIR-FT-Raman spectra of tissue samples obtained from the xenographic tumor, muscle, heart, brain, liver, spleen, kidney and blood were recorded and used to identify the presence of Lu-T2B2Tex in these tissues. Five Raman sensitizer markers were used to estimate the relative content of Lu-T2B2Tex in tumor at various postinjection times. UV-Visible (Vis) absorption spectroscopic detection of this sensitizer in tissue extracts was applied as a conventional method. Both spectroscopic methods were in good agreement with each other and confirm that Lu-T2B2Tex localizes well in tumor tissue. Maximal drug content was observed 3 days after the final injection. This time delay seems to be optimal for tumor irradiation in photodynamic therapy.
Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Female; Humans; Metalloporphyrins; Mice; Mice, Inbred Strains; Mice, Nude; Models, Animal; Molecular Structure; Neoplasm Transplantation; Nitrates; Pancreatic Neoplasms; Photosensitizing Agents; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectroscopy, Near-Infrared; Spectrum Analysis, Raman; Tissue Distribution
PubMed: 15191055
DOI: 10.1562/he-03-05.1 -
Photochemistry and Photobiology Jul 2000Lutetium (III) texaphyrin photosensitizes postirradiation or "delayed" photohemolysis (DPH) of human and bovine red blood cells at 730 nm by a Type-2 pathway mediated by...
Lutetium (III) texaphyrin photosensitizes postirradiation or "delayed" photohemolysis (DPH) of human and bovine red blood cells at 730 nm by a Type-2 pathway mediated by singlet molecular oxygen. The DPH rate increases with increasing incubation temperature and with the second power of the incident fluence. The experimental DPH curves are in good agreement with a multi-hit kinetics model based on target theory.
Topics: Animals; Cattle; Erythrocytes; Hemolysis; Humans; In Vitro Techniques; Kinetics; Metalloporphyrins; Models, Biological; Photosensitizing Agents; Temperature
PubMed: 10911736
DOI: 10.1562/0031-8655(2000)072<0121:porbch>2.0.co;2 -
The Journal of Investigative Dermatology May 1998Photodynamic therapy (PDT) of pigmented melanoma has generally been unsuccessful because of insufficient light penetration in such tissues. In this study, the...
Photodynamic therapy (PDT) of pigmented melanoma has generally been unsuccessful because of insufficient light penetration in such tissues. In this study, the responsiveness of the heavily pigmented B16F10 murine melanoma to lutetium texaphyrin (PCI-0123), a water-soluble sensitizer with strong absorbance in the near infrared (700-760 nm), was examined. These studies were carried out in both normal and ApoE deficient C57BL/6 mice. The latter strain exhibits a lipoprotein profile more like humans (low density lipoprotein > high density lipoprotein) than rodents (high density lipoprotein >> low density lipoprotein). Under optimal conditions of drug dose, light dose, and interval between drug administration and irradiation--the median survival time of C57BL/6 tumor bearing mice was approximately doubled (29 d) compared with tumor bearing control animals (13 d). The life-span of the ApoE knockout mice was greater (33 d) than the C57BL/6 animals (23 d) when irradiation occurred 3 h after administration of a 10 micromol per kg drug dose. The greater efficacy of PDT in the ApoE deficient mice was associated with more rapid clearance of drug from the blood, greater accumulation of sensitizer in tumor tissue, and substantially greater drug binding to the very low density lipoprotein/low density lipoprotein plasma fraction. Confocal laser scanning microscopy showed that the predominant subcellular site of photosensitizer binding was to melanosomes; costaining was performed with Mel-5. Melanosomes are susceptible to oxidative stress. Photo-oxidation, mediated by PCI-0123 PDT, could potentially overload an already highly oxidized stressed state leading to cell death. The good tissue penetration depth achieved by PCI-0213 mediated PDT and the activation of melanosomes makes PDT of pigmented melanoma, for the first time, clinically relevant.
Topics: Animals; Apolipoproteins E; Apoptosis; Blood Proteins; Female; Longevity; Melanoma; Metalloporphyrins; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Transplantation; Photochemotherapy; Photosensitizing Agents; Tissue Distribution
PubMed: 9579539
DOI: 10.1046/j.1523-1747.1998.00182.x -
Proceedings of SPIE--the International... Apr 2005To deliver uniform photodynamic dose to the prostate gland, it is necessary to develop algorithms that optimize the location and strength (emitted power × illumination...
To deliver uniform photodynamic dose to the prostate gland, it is necessary to develop algorithms that optimize the location and strength (emitted power × illumination time) of each light source. Since tissue optical properties may change with time, rapid (almost real-time) optimization is desirable. We use the Cimmino algorithm because it is fast, linear, and always converges reliably. A phase I motexafin lutetium (MLu)-mediated photodynamic therapy (PDT) protocol is on-going at the University of Pennsylvania. The standard plan for the protocol uses equal source strength and equal spaced loading (1-cm). PDT for the prostate is performed with cylindrical diffusing fibers (CDF) of various lengths inserted to longitudinal coverage within the matrix of parallel catheters perpendicular to a base plate. We developed several search procedures to aid the user in choosing the positions, lengths, and intensities of the CDFs. The Cimmino algorithm is used in these procedures to optimize the strengths of the light catheters at each step of the iterative selection process. Maximum and minimum bounds on allowed doses to points in four volumes (prostate, urethra, rectum, and background) constrain the solutions for the strengths of the linear light sources. Uniform optical properties are assumed. To study how different opacities of the prostate would affect optimization, optical kernels of different light penetration were used. Another goal is to see whether the urethra and rectum can be spared, with minimal effect on PTV treatment delivery, by manipulating light illumination times of the sources. Importance weights are chosen beforehand for organ volumes, and normalized. Compared with the standard plan, our algorithm is shown to produce a plan that better spares the urethra and rectum and is very fast. Thus the combined selection of positions, lengths, and strengths of interstitial light sources improves outcome.
PubMed: 26136612
DOI: 10.1117/12.590343 -
Photochemistry and Photobiology Mar 1997Lutetium texaphyrin (PCI-0123) is a pure, water-soluble photodynamic therapy (PDT) agent that is activated by tissue-penetrating far red light. The sensitizer is highly...
Lutetium texaphyrin (PCI-0123) is a pure, water-soluble photodynamic therapy (PDT) agent that is activated by tissue-penetrating far red light. The sensitizer is highly fluorescent and exhibits a strong, broad emission signal at 750 nm. In vitro cellular uptake studies revealed an increase in sensitizer retention with incubation time. Confocal laser scanning microscopy demonstrated that the intracellular localization site of PCI-0123 is the lysosomes. Ensuing illumination of the EMT6 cells led to lysosomal breakup, extensive cytoplasmic blebbing and subsequent cell death. Noninvasive spectral imaging analysis of PCI-0123 fluorescence depicted selective drug uptake, compared to surrounding normal tissue, in EMT6 mammary sarcomas syngeneic to BALB/c mice. The PCI-0123 PDT was shown to effectively treat the EMT6 murine sarcoma. Irradiation (732 nm light) 3 h postintravenous injection of 10 mumol PCI-0123 per kg gave 100% cures (no evidence of cancer), whereas light exposure at 5 h resulted in 75% cures. Hematoxylin and eosin histologic examination of photoirradiated tumors indicated apoptosis of the EMT6 neoplasms at early times post-PDT progressing, with time, to extensive necrotic areas. Gel electrophoresis of extracted photoirradiated tumors showed the typical apoptotic DNA ladder pattern that increased in intensity following PDT treatment.
Topics: Animals; Mammary Neoplasms, Experimental; Metalloporphyrins; Mice; Microscopy, Confocal; Photochemotherapy; Photosensitizing Agents; Sarcoma, Experimental; Subcellular Fractions; Tumor Cells, Cultured
PubMed: 9077121
DOI: 10.1111/j.1751-1097.1997.tb08579.x -
Photochemistry and Photobiology 2006Photodynamic therapy (PDT) requires oxygen to cause cellular and vascular tumor damage. Tissue oxygen concentration, in turn, is influenced by blood flow and blood...
Photodynamic therapy (PDT) requires oxygen to cause cellular and vascular tumor damage. Tissue oxygen concentration, in turn, is influenced by blood flow and blood oxygenation. Real-time clinical measurement of these hemodynamic quantities, however, is rare. This paper reports the development and application of a probe, combining diffuse reflectance spectroscopy (DRS) for measurement of tumor blood oxygenation and diffuse correlation spectroscopy (DCS) for measurement of tumor blood flow. The instrument was adapted for clinical use during interstitial prostate PDT. Three patients with locally recurrent prostate cancer received 2 mg/ kg motexafin lutetium (MLu) 3 h before illumination and a total light dose of 100 J/cm(2) at 150 mW/cm. Prostrate blood oxygen saturation (StO2) decreased only slightly (approximately 3%) after treatment. On the other hand, prostate blood flow and total hemoglobin concentration over the course of PDT decreased by 50% and 15%, respectively, suggesting MLu-mediated PDT has an anti-vascular effect. While it is certainly impossible to draw definite conclusions from measurements of only three patients, the observed differences in tumor blood flow and blood oxygenation responses during PDT can, in principle, be used to choose among tissue oxygen consumption models and therefore emphasize the potential clinical value for simultaneous monitoring of both parameters.
Topics: Dose-Response Relationship, Radiation; Drug Monitoring; Humans; Kinetics; Light; Lighting; Male; Metalloporphyrins; Neoplasm Recurrence, Local; Phantoms, Imaging; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms
PubMed: 16696593
DOI: 10.1562/2005-10-19-RA-721