Reema Zeineldin, Ph.D.
Folate receptor alpha is a receptor for folic acid itself and not to its derivatives tetrahydrofolate or
dihydrofolate, which are usually referred to as folates. These other derivatives are transported into cells via
another receptor, which is the reduced folate carrier (RFC) that is ubiquitously present in all cells.
Nevertheless this carrier has a low affinity for folic acid (Km ~ 100-400 uM), whereas FRα has a high affinity
for folic acid (Kd ~ 1 nM). It has been reported that conjugates of folic acid to drugs are not transported by
RFC, but by FRα or FR beta which is useful for tissues of epithelial origins, with limited distribution to the
kidneys, lungs, choroid plexus, and placenta. The receptors in these tissues, except the placenta, are
localized in the apical membrane facing away from the blood (toward urine, and airway) (Figure below). This
makes FRα inaccessible to folate conjugates administered intravenously and intraperitoneally. However,
epithelial cancer cells that express FRα lose this polarity, so FRα becomes expressed all over the cell
surface, and at high levels, which make FRα accessible intravenously (Figure below). In addition, in the case
of ovarian cancers where cancer cells exist as clump or free floating cells in ascitic fluid in the peritoneal
cavity, the FRα on these cancer cells become accessible by intraperitoneal therapy. All this makes FRα an
ideal candidate for therapeutic targeting on cancer cells. It has been reported that activated macrophages
associated with ovarian and other cancers express high levels of macrophages can also be targeted with
folate conjugates in addition to cancer cells, which is useful in regulating the microenvironment of the tumor.
In fact folate conjugates have been used for drug delivery to target folate receptors on ovarian cancer cells
and their associated activated macrophages.”
Zeineldin, R. Carbon Nanotubes for Targeted Cancer Therapy. In Challa Kumar, Ed. of book series: Carbon
Nanomaterials for Life Sciences. 2011. Wiley-VCH, NJ.