New macromolecular polymeric MRI contrast agents for application in the differentiation of cancer from benign soft tissues

Purpose To compare three new macromolecular polyethylene glycol (PEG) ‐core dendrimeric gadolinium(Gd)‐based MRI contrast agents for their applicability in quantitative assays of endothelial leakiness and tissue vascular density for the differentiation of cancer from normal soft tissues. Materials and Methods Thirty‐two athymic rats with human breast cancer xenografts (MDA‐MB‐435) were imaged by dynamic MRI following enhancement with one of three new (Gd‐DOTA)‐conjugated PEG‐core dendrimer contrast agents (effective molecular weights 161 to 323 kDa). Results were compared with a prototype macromolecular contrast agent, albumin (Gd‐DTPA). Assays of permeabilities (KPS; μL/min · 100 cm3) and tumor fractional plasma volumes (%) based on a two‐compartment kinetic model were performed for skeletal muscle and tumors. Results The largest PEG‐core contrast agent, PEG20,000‐Gen4‐(Gd‐DOTA), leaked in breast tumors (KPS = 50 ± 23 μL/min · 100 cm3), while exhibiting no measurable transendothelial leak (KPS = 0 μL/min · 100 cm3) in normal soft tissue microvessels allowing successful differentiation (P < 0.05) of cancers from normal muscle. PEG12,000‐Gen4‐(Gd‐DOTA) leaked in tumors and in normal muscle (KPS = 51 ± 26 and KPS = 21 ± 18μL/min · 100 cm3, respectively). The smallest agent, PEG12,000‐Gen3‐(Gd‐DOTA) also showed a measurable leak in both normal and malignant microvessels. Conclusion MRI assays of vascular endothelial leakiness using new PEG‐core, (Gd‐DOTA)‐conjugated macromolecular contrast agents proved applicable for the differentiation of human breast cancer from normal soft tissue. The apparent threshold in effective molecular weight for a clear differentiation of cancer from normal muscle with no measurable leak in the muscle is between 194 and 323 kDa. J. Magn. Reson. Imaging 2008. © 2008 Wiley‐Liss, Inc.