TARGETING DENDRIMER-CHELATES TO TUMORS AND TUMOR-CELLS EXPRESSING THEHIGH-AFFINITY FOLATE RECEPTOR

RATIONALE AND OBJECTIVES, The authors developed a new method for deliv ering contrast agents to tumors and tumor cells, Gadolinium complexes of folate-conjugated dendrimer-chelates increased the longitudinal rel axation rate of tumor cells expressing the high-affinity folate recept or, hFR, The coupling of folate to polymeric chelates, composed of a d endrimer backbone, targets these chelates to endogenous folate binding proteins, These proteins exist in both the serum of patients with can cer and on the cell surface of many human cancers of epithelial origin , METHODS. The authors attached folic acid to a generation four ammoni a core polyamidoamine dendrimer, The folate-dendrimer was reacted with natobenzyl)-6-methyl-diethylenetriaminepentaacetic acid to form the p olymeric chelate f-PAMAM-TU-DTPA. For fluorescent studies, the generat ion four dendrimer was reacted with fluorescein-5-isothiocyanate and c arboxytetramethylrhodamine succinimidyl ester, followed by capping the remaining amines with succinic anhydride, RESULTS. The study results show that cells accumulate the folate-conjugated dendrimer in a recept or specific manner, Tumor cells expressing the high-affinity folate re ceptor showed a 650% increase in the mean fluorescence. This increase occurred with a rapid rise to 325%, followed by a slow increase to 650 %, It required both the expression of the hFR and the coupling of foli c acid to the dendrimer, Excess free folic acid inhibited the binding of the folate conjugated polymer, Fluorescent microscopic study showed that the folate-conjugated dendrimer binds to the cell surface and is accumulated within the cells, Treatment of tumor cells that express t he hFR with gadolinium complexes of the folate-conjugated polymeric ch elate increases the longitudinal relaxation rate by 110%, This increas e was inhibited by an excess of free folic acid. CONCLUSIONS. These da ta demonstrate that folate-conjugated magnetic resonance imaging contr ast agents represent a promising new approach to tumor targeting.