Folate Receptor Targeting Agents

Folate receptor (FR) is overexpressed on a variety of human cancers, including those originating in ovary, lung, breast, endometrium and kidney.78-80 Folic acid (FA) is a vitamin that is transported into cells via FR mediated endocytosis. It has been well documented that the attachment of FA via its g-carboxylic function to other molecules does not alter its endocytosis by FR-expressing cells.81 FR targeting has been used successfully to deliver protein toxins, chemotherapeutic, radioimaging,

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therapeutic and MRI contrast agents, liposomes, gene transfer vectors, antisense oligonucleotides,85 ribozymes, and immunotherapeutic agents to FR-positive cancers.86 To deliver boron compounds, FA was conjugated to heavily boronated third generation PAMAM dendrimers containing polyethylene glycol (PEG).87 PEG was introduced into the bioconjugate to reduce its uptake by the reticuloendothelial system (RES), and more specifically, the liver and spleen. It was observed that folate linked to third generation PAMAM dendrimers containing 12-15 decaborate clusters and 1-1.5 PEG2000 units had the lowest hepatic uptake in C57Bl/6 mice (7.2-7.7% injected dose [I.D.]/g liver). In vitro studies using FR (+) KB cells demonstrated receptor-dependent uptake of the bioconjugate. Biodistribution studies with this conjugate, carried out in C57Bl/6 mice bearing subcutaneous (s.c.) implants of the FR ( + ) murine sarcoma 24JK-FBP, demonstrated selective tumor uptake (6.0% I.D./g tumor), but there was high hepatic (38.8% I.D./g) and renal (62.8% I.D./g) uptake.87

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