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 (K-PS; mu L/min - 100 cm(3)) 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, PEG(20,000)Gen4-(Gd-DOTA), leaked in breast tumors (K-PS = 50 +/- 23 mu L/min - 100 CM3), while exhibiting no measurable transendothelial leak (K-PS = 0 mu L/min - 100 cm(3)) in normal soft tissue microvessels allowing successful differentiation (P < 0.05) of cancers from normal muscle. PEG(12,000)-Gen4-(GdDOTA) leaked in tumors and in normal muscle (K-PS = 51 26 and KPs = 21 +/- 18 mu L/min - 100 cm(3), respectively). The smallest agent, PEG I (12,000)-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.