Specific targeting of folate-dendrimer MRI contrast agents to the high affinity folate receptor expressed in ovarian tumor xenografts.
The need to develop target-specific MRI contrast agents to aid in disease characterization remains highly essential. In this study, we present a generation four polyamidoamine (PAMAM) folate-dendrimer that specifically targets the high affinity folate receptor (hFR) overexpressed on more than 80% of ovarian tumors. In vitro, mouse erythroleukemia cells expressing the hFR bind the radiolabeled folate-dendrimer chelate resulting in over 2700% increase in binding compared with untreated cells. The binding was inhibited by free folic acid to levels observed on folate-receptor-negative cells. In vivo, ovarian tumor xenografts resulted in a 33% contrast enhancement, following the folate-dendrimer chelate administration, that was significantly different compared with results obtained with a non-specific, extracellular fluid space agent, Gd-HP-DO3A. In addition, this contrast enhancement was absent in saline-treated animals, folate-receptor-negative tumors, and was inhibited by free folic acid. Results suggest that a macromolecular, dendrimeric MRI agent with high molecular relaxivities (1646 mM(-1) s(-1)) can be used in specifically targeting the hFR on tumor cells and ovarian tumors.
Konda
S D
SD
Biomedical Magnetic Resonance Laboratory, College of Medicine, University of Illinois, Urbana, IL 61801, USA.
Aref
M
M
Wang
S
S
Brechbiel
M
M
Wiener
E C
EC
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003287:Contrast Media; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000493:pharmacokinetics; D005682:Gadolinium / Q000493:pharmacokinetics; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D010051:Ovarian Neoplasms / Q000473:pathology*; D011869:Radioligand Assay; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D003287:Contrast Media; D058973:Folate Receptors, GPI-Anchored; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C062402:gadoteridol; D005492:Folic Acid; D005682:Gadolinium