Stuart W. Young

Lutetium Texaphyrin (PCI-0123): A Near-Infrared, Water-Soluble Photosensitizer

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 μmol/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 ± 65 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 μmol/kg and 150 J/cm2 at 150 mW/cm2. The PDT efficacy was attributable to the selective uptakehetention of the texaphyrin photosensitizer in addition to the depth of light penetration achievable at the 732 nm laser irradiation.

Preclinical Evaluation of Gadolinium (iii) Texaphyrin Complex: A New Paramagnetic Contrast Agent for Magnetic Resonance Imaging

RATIONALE AND OBJECTIVES.Gadolinium III texaphyrin (Gd[III] texaphyrin) complex, a new magnetic resonance imaging contrast (MRI) agent, was evaluated. METHODS.In vitro relaxivity (1.5 T) and stability studies (5% dextrose) were conducted. Subchronic toxicity (8 males, 8 females; 2-20 (µmol Gd(III) texaphyrin complex/kg body weight; 3 times per week for 3 weeks). Biodistribution and excretion studies were conducted in Sprague-Dawley rats; MRI studies were conducted in normal and tumor-bearing rats and rabbits. RESULTS.Relaxivity values were as follows:1=19 (µmol/ L · sec)-1and r2=22 (µmol/L · sec)-1The 21-day subchronic toxicity study revealed no abnormalities. The compound is stable. Biodistribution demonstrated liver uptake. Magnetic resonance imaging in normal (n=34) and tumorbearing (n=4) rats and normal (n=8) and tumor-bearing (n=19) rabbits revealed: significant (P<.05) contrast enhancement of liver and kidney after 1-17 µmol/kg of Gd(III) texaphyrin complex. Gadolinium (III) texaphyrin complex (2.5 (µmol/kg) produced significant contrast enhancement of liver carcinomas in rabbits (n=8). Thigh V2 carcinomas (n=22) had selective (P<.05) enhancement, 5 µmol/kg. In rat fibro-sarcomas (n=4), 17 (µmol Gd(III) texaphyrin complex produced significant enhancement up to 24 hours. CONCLUSIONS.Gadolinium (III) texaphyrin complex appears to be an effective and safe MRI contrast agent.

LOCALIZATION AND EFFICACY ANALYSIS OF THE PHOTOTHERAPEUTIC LUTETIUM TEXAPHYRIN (PCI-0123) IN THE MURINE EMT6 SARCOMA MODEL

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.

Gelatin encapsulated nitrogen microbubbles as ultrasonic contrast agents.

Gelatin encapsulated nitrogen microbubbles were effective ultrasonic contrast agents in in vitro phantom and in vivo rabbit V2 carcinoma studies. Intra-arterial injection of 80-micrometer gelatin encapsulated nitrogen microbubbles appeared to improve tumor visualization by rim enhancement, which persisted for several minutes.

Magnetic susceptibility effects and their application in the development of new ferromagnetic catheters for magnetic resonance imaging.

Newly developed ferromagnetic catheters (Fe-Caths) are more conspicuous than conventional radiographic catheters (Rad-Caths) on magnetic resonance (MR) images because they produce recognizable ferromagnetic signal patterns (FSPs). To determine how MRI parameters influence these patterns, the imaging characteristics of nine Fe-Caths (ferromagnetic concentration 0.01 to 1.0 weight/weight %) were studied systematically and compared with three Rad-Caths. All catheters were studied in stationary and moving phantoms at mid-field (0.38 T) and high-field (1.5 T) strength using spin-echo and gradient-echo pulse sequences. Rad-Caths always produced a signal void. Fe-Caths produced FSPs, the size of which depended on the orientation of the catheter with respect to the main magnetic field, the concentration of ferromagnetic agent in the catheter, and the direction and strength of the frequency encoding gradient. When Fe-Caths were positioned perpendicular to the main magnetic field, they produced FSPs; however, when they were parallel to the main magnetic field, Fe-Caths produced no FSP, thus having a similar appearance to the Rad-Caths. Ferromagnetic catheters produce conspicuous patterns on MR images that depend on catheter orientation in the main magnetic field and vary predictably with the MRI parameters.

Safety and efficacy of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. multicenter phase III clinical trials (safety).

The short‐term1 safety of mangafodipir trisodium (MnDPDP) injection was studied in 546 adults with known or suspected focal liver lesions. An initial contrast‐enhanced computed tomography examination was followed by unenhanced magnetic resonance imaging (MRI), injection of MnDPDP (5 μmol/kg), and enhanced MRI. Adverse events were reported for 23% of the patients; most were mild to moderate in intensity, did not require treatment, and were not drug related. The most commonly reported adverse events were nausea (7%) and headache (4%). The incidence of serious adverse events was low (nine events in six patients) and not drug related. Injection‐associated discomfort was reported for 69% of the patients, and the most commonly reported discomforts included heat (49%) and flushing (33%). Changes in laboratory values and vital signs were generally transient, were not clinically significant, and did not require treatment. There were no clinically significant short‐term risks from exposure to MnDPDP. J. Magn. Reson. Imaging 2000;12:186–197.

Detection of tumors with 19F magnetic resonance imaging

Previous 19F magnetic resonance imaging studies showed that the reticuloendothelial system can be imaged with an emulsion of perfluorooctyl bromide (PFOB). Similar techniques can be used to detect previously implanted RIF-1 tumors in mice after intravenous PFOB administration. Accumulation of PFOB within these neoplasms is due to egress of the emulsion through tumor capillary fenestrations. This is the first report in which 19F MRI and PFOB are used to detect tumors. This technique may allow clinical detection of cancer with 19F MRI.

Detection of hepatic malignancies using Mn-DPDP (manganese dipyridoxal diphosphate) hepatobiliary MRI contrast agent.

A new hepatobiliary contrast agent (Mn-DPDP) was used in the detection of liver metastases in six rabbits with seven hepatic V2 carcinomas. This contrast agent is derived from pyridoxyl-5-phosphate which is biomimetically designed to be secreted by the hepatocyte. After Mn-DPDP administration, a 105% increase in liver signal to noise was obtained using a 200/20 (TR/TE) pulsing sequence, and a 62% decrease in intensity was observed using a 1200/60 pulsing sequence. Liver V2 carcinoma contrast enhancement increased 427% using the 200/20 pulsing sequence and 176% using the 1200/60 pulsing sequence. Four of seven V2 carcinomas were not detectable prior to the administration of Mn-DPDP (50 mumol/kg). Two neoplasms were only detectable in retrospect (after Mn-DPDP) on the 1200/60 sequence. The smallest neoplasms detected in this study were 1-4 mm. Mn-DPDP appears to be a promising MRI contrast agent.

Biomedical applications of lanthanide (III) texaphyrins Lutetium(III) texaphyrins as potential photodynamic therapy photosensitizers

Abstract The texaphyrins are a novel class of pentadentate, porphyrin-like aromatic macrocyclic ligands that form kinetically stable complexes with essentially all cations of the trivalent lanthanide series. This ability, combined with certain features inherent to the texaphyrin skeleton, gives rise to species that are of potential interest in a range of medical applications including diagnosis and therapy. In this paper, the biomedical utility of one particular metallotexaphyrin derivative, namely the lutetium(III) complex PCI-0123 (1), is highlighted. This system generates singlet oxygen in 11% quantum yield in water (20–30% in organic solvents) and is an effective sensitizer for photodynamic cancer therapy as judged from animal model studies. It is currently in Phase I human clinical trials.

Dynamic computed tomography time--density study of normal human tissue after intravenous contrast administration.

Dynamic sequential 3-second CT scans of human abdominal organs were obtained after an intravenous bolus injection of diatrizoate. Time--density curves obtained from the renal cortex and medulla were compared with similar curves obtained from the aorta, inferior vena cava, muscle, and normal liver. CT scans revealed the changes in density produced by the contrast agent reflecting the differential phases of blood flow in the aorta and inferior vena cava. Changes in density in the liver, muscle, and the cortex and medulla of the kidney undoubtedly were related to vascular and extravascular contrast agent. Renal cortical density increased rapidly after bolus administration and peaked approximately 6 seconds after the peak in aortic contrast and slowly declined over the observation period. Renal medullary density increased slowly and at first remained significantly below the cortex but was slightly above cortical values after 30 seconds. These studies indicate that dynamic CT scanning is an effective way of monitoring the contrast media pharmacokinetics within tissue and that human renal function can be monitored and evaluated by using this technique.