Micro‐MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: Reference to pharmacokinetic properties of dendrimer‐based MR contrast agents

Abstract

Pharmacokinetic characteristics of intravascular macromolecular magnetic resonance imaging (MRI) contrast agents with polyamidoamine dendrimer cores smaller than generation-7 were previously studied in the literature. To evaluate the effects of greater hepatic uptake on the pharmacokinetics of the larger generation dendrimers, the MRI contrast agents GxD-(1B4M-Gd) 2 x؉2 were synthesized with generation-7, -8, and -9 polyamidoamine dendrimers and 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M). Their pharmacokinetic characteristics in mice were compared with that of G6D-(1B4M-Gd) 256 . In biodistribution and dynamic micro-MRI studies, significantly less renal accumulation of G7D-(1B4M-Gd) 512 , G8D-(1B4M-Gd) 1024 , and G9D-(1B4M-Gd) 2048 was shown compared to G6D-(1B4M-Gd) 256 (P < 0.01). There was a significantly greater accumulation of G8D-(1B4M-Gd) 1024 and G9D-(1B4M-Gd) 2048 in the liver compared to G6D-(1B4M-Gd) 256 and G7D-(1B4M-Gd) 512 (P < 0.01). The highest blood retention of all dendrimer-based MRI contrast agents was exhibited by G7D-(1B4M-Gd) 512 (P < 0.01). The normal and intratumoral fine vessels of approximately 100 m diameter were visualized in normal or tumor-bearing mice by high resolution three-dimensional-micro-MR angiographs with G7D-(1B4M-Gd) 512 and G8D-(1B4M-Gd) 1024 with good vessel-to-soft tissue contrast. In summary, increased accumulation in the liver with concomitant decreased uptake in the kidney was caused by increased molecular sizes of the dendrimerbased MRI contrast agents.

Application of a Macromolecular Contrast Agent for Detection of Alterations of Tumor Vessel Permeability Induced by Radiation

“…The clearance rate of G8-Gd-D is considerably different from that of a standard magnetic resonance imaging contrast agent, for example, Gd-diethylenetriaminepentaacetic acid or "Magnevist." The blood half-life of the G8-Gd-D contrast agent is ϳ2 hours, and tissue half-life (wash-out) is ϳ6 hours (22). Execution of repeated dosing within the 48-hour time frame after study is impossible for the dynamic study, because significant levels of the initial dose of G8-Gd-D remain in the tumor tissue.…”

“…With respect to noninvasive approaches to assess tumor leakiness and permeability, a series of gadolinium-(Gd) labeled dendrimers of varying sizes has been synthesized recently (21)(22)(23). Dendrimers are a class of highly ordered spherical polymers of which there are a vast array of types, chemical structures, and functional groups.…”

“…The defined structure and large number of available surface amino groups of these dendrimers have promoted their use as substrates for the attachment of large numbers of chelating agents to a single antibody molecule (27-31). As noted above, three gadolinium-labeled polyamidoamine dendrimers (generation-4, -6, and -8; G4, G6, G8) ranging in size from 6 to 13 nm have been synthesized recently (21)(22)(23). Preliminary studies with these dendrimers indicated that the generation-8 polyamidoamine gadolinium dendrimer (G8-Gd-D; 13 nm), when injected into tumor-bearing animals and imaged using dynamic magnetic resonance imaging, exhibited enhancement associated with tumor vasculature, whereas the analogous, but smaller G6-Gd-D (10 nm) demonstrated greater evidence of tumor tissue delineation (23).…”

High‐resolution three‐dimensional MR angiography of rodent tumors: Morphologic characterization of intratumoral vasculature

“…Althogh the morphologic characterization of intratumoral neovasculature in experimental tumors might add important insights into the process of tumor angiogenesis, only a few studies have evaluated the potential of non-invasive, high-resolution MR angiography to visualize intratumoral blood vessels (23)(24)(25)(26). The major reason is the still substantially inferior spatial resolution of MRI compared to other imaging techniques.…”

“…Schwickert et al (26) report the use of high loaded gadolinium albumin (HSA-[Gd-DTPA] 30 ) with a molecular weight of 92 kDa. In more recent studies, Kobayashi et al (23)(24)(25) used polyamidoamine (PAMAM) dendrimer-based Gd chelates with molecular weights from 58 up to 467 kDa. Although compounds with a high molecular weight (owing to their longer intravascular distribution) promise favorable imaging characteristics, elimination may prove increasingly problematic as glomerular filtration is, depending on the charge of the molecule, only realized for drugs with a molecular weight below 70 kDa or a molecular size below 7 nm (24,29).…”