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


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); microL/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 microL/min . 100 cm(3)), while exhibiting no measurable transendothelial leak (K(PS) = 0 microL/min . 100 cm(3)) in normal soft tissue microvessels allowing successful differentiation (P < 0.05) of cancers from normal muscle. PEG(12,000)-Gen4-(Gd-DOTA) leaked in tumors and in normal muscle (K(PS) = 51 +/- 26 and K(PS) = 21 +/- 18 microL/min . 100 cm(3), respectively). The smallest agent, PEG(12,000)-Gen3-(Gd-DOTA) also showed a measurable leak in both normal and malignant microvessels.


CONCLUSIONS
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.
Cyran
Clemens C
CC
Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, CA 94143-0628, USA.
Fu
Yanjun
Y
Raatschen
Hans-Juergen
HJ
Rogut
Victor
V
Chaopathomkul
Bundit
B
Shames
David M
DM
Wendland
Michael F
MF
Yeh
Benjamin M
BM
Brasch
Robert C
RC
D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis; D003287:Contrast Media; D004730:Endothelium, Vascular; D005260:Female; D005682:Gadolinium; D006571:Heterocyclic Compounds; D006801:Humans; D008279:Magnetic Resonance Imaging; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000175:diagnosis*; D009942:Organometallic Compounds; D051381:Rats; D011923:Rats, Nude; D014183:Transplantation, Heterologous
D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D005682:Gadolinium