Tarak D. Mody

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.

Pharmaceutical development and medical applications of porphyrin‐type macrocycles

The current state of pharmaceutical development of porphyrin-type macrocycles in medicine is highlighted. Currently, several porphyrinoid-based drugs are under various stages of development as phototherapeutic agents, X-ray radiation enhancers and boron neutron capture agents. These compounds represent a burgeoning class of pharmacological agents that are potentially useful in an array of treatment areas.

Actinide expanded porphyrin complexes

Abstract In this article the uranyl cation (UO22+) coordination chemistry of several prototypic expanded porphyrins is reviewed. The ability of certain expanded porphyrins, large polypyrrolic ligands, to stabilize complexes containing the uranyl cation is contrasted to that of the porphyrins. These latter systems, well-recognized for their ability to stabilize a range of transition metal complexes, among others, have hitherto been shown to form structurally characterized complexes with only uranium(IV) and thorium(IV) cations among cations of the actinide series. Possible reasons for these differences in cation complexation behavior are discussed.

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.

THE TEMPLATE SYNTHESIS AND X-RAY CHARACTERIZATION OF PYRROLE-DERIVED HEXADENTATE URANYL(VI) SCHIFF-BASE MACROCYCLIC COMPLEXES

The template condensation of 3,4-diethyl-2,5-dicarbaldehyde with ethylenediamine and 1,3-propanediamine in the presence of UO2(NO3)2 gave neutral complexes of formulae UO2(C24H32N6) ([UO2(bi-pyen)], 2) and UO2(C26H36N6) ([UO2(bi-pytmd)], 3), respectively. X-Ray diffraction quality single crystals were obtained from chloroform/methanol. In the case of 2, these were monoclinic, space group C2/c, with a = 30.549(5), b = 8.251(1), c= 21.969(4) A, β = 114.47(1)°, V = 5040(1)A3, Z = 8, ϱcalc, = 1.78 g cm−3. Crystals of 3 were also monoclinic, space group C2/c, with a = 26.946(7), b = 9.436(2), c = 10.862(2)A, β = 105.04(2)°, V = 2667(1)A3, Z = 4, ϱcalc = 1.75 g cm−3. In the X-ray structure of 3, the complex lies on a crystallographic twofold axis. For 2, the final R = 0.0335, wR = 0.0371 for 297 parameters and 4475 reflections [F ⩾ 4(σ(Foo))], while for 3, the final R = 0.0223, wR = 0.0265 for 213 parameters and 2810 reflections [F ⩾4 (σ(Fo))]. In each complex, the uranyl(VI) cation is bound to all six nitrogen atoms such that the metal center, with its two apical oxygen atoms, lies in a distorted hexagonal bipyramidal environment. The change in overall macrocycle size that results in going from 2 to 3 does not affect the UN bond lengths. Rather, the principal difference between 2 and 3 is the exten tent of the twist between the two nearly planar halves of the macrocycle. In 2, the imine-pyrrole-imine dihedral angle is 17.5(1)° while in 3 it is 35.7(1)°. On the other hand, it is near 0° in an earlier reported complex, 1, derived from o-phenylenediamine [J.L. Sessler, T.D. Mody and V. Lynch, Inorg. Chem., 31 (1992) 531]. Complex 1 displays two reversible oxidations at +0.82 V and +1.09 V versus FcFc+ in CH2Cl2 containing TBAPF6, while complexes 2 and 3 display irreversible oxidation waves at +1.22 V, +1.46 V and +1.22 V and +1.47 V versus FcFc+, respectively. Complexes 1, 2, and 3 also display quasi-reversible uranyl-centered reductions at −0.85 V, −1.02 V, and −0.96 V versus FcFc+, respectively.

Capillary electrophoresis separation and native laser-induced fluorescence detection of metallotexaphyrins

Methods based on capillary zone electrophoresis (CZE) and electrokinetic chromatography (EKC) are developed for the separation of motexafin gadolinium (MGd, Xcytrin®), a novel redox-active drug, under development for cancer therapy, and two closely related metallotexaphyrin impurities, called PCI-0400 and PCI-0430. The three metallotexaphyrins are baseline resolved using EKC in a separation solution containing 400-mM cetyltrimethyl ammonium bromide, 50-mM phosphoric acid, and 20% methanol. Detection is achieved using native laser-induced fluorescence (LIF) by exciting at 488 nm and collecting emission at 750 nm. Analysis of a representative clinical batch of MGd using EKC combined with native LIF allowed for the detection of PCI-0400 and PCI-0430 along with nine other possible MGd impurities, each of which is present at approximately 0.1% (total weight of the sample).

Reaction chemistry of metallotexaphyrins: the synthesis and characterization of the first meso-oxotexaphlorin.

Ring-oxygenation of metallotexaphyrins, promoted by strong bases, produces oxotexaphlorin, the first example of a meso-oxo functionalized texaphyrin derivative.