RESUMEN
The accurate mapping of the tumor blood volume (TBV) fraction (vb) is a highly desired imaging biometric goal. It is commonly thought that achieving this is difficult, if not impossible, when small molecule contrast reagents (CRs) are used for the T1-weighted (Dynamic-Contrast-Enhanced) DCE-MRI technique. This is because angiogenic malignant tumor vessels allow facile CR extravasation. Here, a three-site equilibrium water exchange model is applied to DCE-MRI data from the cerebrally-implanted rat brain U87 glioma, a tumor exhibiting rapid CR extravasation. Analyses of segments of the (and the entire) DCE data time-course with this "shutter-speed" pharmacokinetic model, which admits finite water exchange kinetics, allow TBV estimation from the first-pass segment. Pairwise parameter determinances were tested with grid searches of 2D parametric error surfaces. Tumor blood volume (vb), as well as ve (the extracellular, extravascular space volume fraction), and Ktrans (a CR extravasation rate measure) parametric maps are presented. The role of the Patlak Plot in DCE-MRI is also considered.
Asunto(s)
Determinación del Volumen Sanguíneo/métodos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Gadolinio DTPA/farmacocinética , Glioma/metabolismo , Glioma/patología , Animales , Volumen Sanguíneo , Línea Celular Tumoral , Simulación por Computador , Medios de Contraste/farmacocinética , Glioma/irrigación sanguínea , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética , Masculino , Tasa de Depuración Metabólica , Modelos Neurológicos , Ratas , Ratas DesnudasRESUMEN
A class of hybrid molecules which we term 'reversed chloroquines' (RCQs) was designed, and a prototype molecule, N'-(7-chloroquinolin-4-yl)-N-[3-(10,11-dihydrodibenzo[b,f]azepin-5-yl)propyl]-N-methylpropane-1,3-diamine (1), was synthesized and tested against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. An in vitro assay against the two strains indicated that 1 was effective at low-nM concentrations against both strains. A preliminary study in mice demonstrated oral efficacy against P. chabaudi and the absence of obvious toxicity. The RCQ approach therefore appears to be feasible.