Pharmacokinetics of a High-Generation Dendrimer–Gd-DOTA

Abstract

Dendrimers are three-dimensional branching polymers that have received much attention as transfection agents (1), drug delivery agents (2), and magnetic resonance (MR) contrast agents (3–5). To be used as MR contrast agents, dendrimers have been conjugated with paramagnetic metal ion complexes. The large number of paramagnetic metal ion complexes that can be covalently attached per dendrimer molecule, which depends on the dendrimer generation, has resulted in a new class of macromolecular MR contrast agents. Unlike other macromolecular-based MR contrast agents such as albumin, dextran, and poly-l-lysine, dendrimers are discrete reagents with well-defined sizes and shapes. The paramagnetic metal ion complexes have included gadolinium chelated to the derivatized acyclic ligand of diethylenetriaminepentaacetic acid (DTPA) and the derivatized macrocylic ligands of 1,4,7,10-tetra-azacyclododecane-1,4,7-triacetic acid (DO3A) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In addition to these complexes, which primarily affect T1 relaxation, the dysprosium chelate of the derivatized macrocyclic ligand DOTA has been studied to develop a T2 selective contrast agent (6). These macromolecular MR contrast agents are expected to have high relaxivities compared to the monomeric chelates through longer rotational correlation times (7,8).