MRI tumor characterization using Gd‐GlyMe‐DOTA‐perfluorooctyl‐mannose‐conjugate (Gadofluorine M™), a protein‐avid contrast agent

Abstract

The rationale and objectives were to define the MRI tumor-characterizing potential of a new protein-avid contrast agent, Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg(-1), was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), 45-250 mg kg(-1). These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two-compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K(PS)) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff-Bloom-Richardson score) and location of necrosis. Eighteen tumor-bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K(PS) and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K(PS) and fEV* but not fPV were significantly lower in a group consisting of benign and low-grade malignant tumors compared with the group of less-differentiated high-grade tumors (1.61 +/- 0.64 vs 3.37 +/- 1.49, p < 0.01; 0.45 +/- 0.17 vs 0.78 +/- 0.24, p < 0.01; and 0.076 +/- 0.048 vs 0.121 +/- 0.088, p = 0.24, respectively). It is concluded that the protein-avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low-grade malignant lesions from high-grade cancers.

Transient Widespread Blood—Brain Barrier Alterations after Cerebral Photothrombosis as Revealed by Gadofluorine M-Enhanced Magnetic Resonance Imaging

“…After intravenous administration, Gf binds reversibly to plasma proteins leading to macromolecular Gf-protein complexes in the circulation. The plasma half-life T1/2b of these Gf complexes is 15.6 h (Raatschen et al, 2006). Gadofluorine M has a high T1 relaxivity in plasma (15.9 L/mmol per sec per Gd ion) and in water (15.8 L/mmol per sec; Misselwitz et al, 2004).…”

Magnetic resonance imaging of the pancreas in streptozotocin-induced diabetic rats: Gadofluorine P and Gd-DOTA

“…Gadofluorine agents are amphiphilic gadolinium complexes, synthesized by adding a perfluoroctyl chain to a gadoliniumcontaining macrocycle (Figure 2) [13] ; therefore, they form micelles in water. In blood or extracellular tissue, Gadofluorine agents strongly interact with hydrophobic proteins (e.g., albumin, extracellular matrix proteins), leading to a breakdown of the micelles [17,18] . After intravenous injection, Gadofluorine P also binds reversibly to plasma proteins and forms semistable, macromolecular Gadofluorine-protein complexes [19] .…”

Long-term assessment of contrast effects of gadofluorine M and gadofluorine P in magnetic resonance imaging of mice

“…It binds to plasma proteins and extracellular matrix proteins through hydrophobic interactions, leading to a breakdown of the micelles [5,6]. Gadofluorine M injected intravenously is retained in the blood for a long period, with a blood half-life of approximately in 10 h in rabbits [7], and acts as a blood pool-enhancing agent.…”