Targeting Using Folate Receptors

During the past few decades, there has been great interest in the utilization of folate receptors for the targeted delivery of therapeutic and imaging agents. A number of delivery systems have been utilized for this purpose, including drug conjugates,38-40 liposomes,41 micelles,42 viral vectors,43 and nanoparticles.

Folate (vitamin B-9) is essential for the synthesis of nucleotides and amino acids. Two main groups of molecules are responsible for transport of folate molecules in vivo. Most cells in the body express a folate anion transporter with micro-molar affinities for folates that participates in the transport of coenzyme 5-methyltetrahydrofolate, the physiologic circulating reduced form of folate. Folate receptors (FR), by contrast, are members of the glycosylphosphatidylinositol (GPI)-linked membrane glycoprotein family and have high affinity for folic acid, an oxidized form of folate, and 5-methyltetrahydrofolate, with binding affinities being in the nanomolar range (KD < 1X109 M) for the a isoform of FR.44-46 It has been observed with few exceptions that only cells involved in pathologic conditions, including cancer cells, express the high affinity folate receptors. These receptors are able to transport folic acid, folate-bound molecules, and even particles through receptor-mediated endocytosis. 7

FR are known to be overexpressed in various epithelial cancer cells, such as those of ovarian, mammary gland, colon, lung, prostate, and brain epithelial cancers, and in leukemic cells.49-61 Folate receptor overexpression has been correlated to poor prognosis. In addition, metastasized cancer cells have been found to overexpress the folate receptor to a larger degree than localized tumor cells.62 This finding is of great importance. The only nonpathological tissues where FR is expressed are choroid plexus, placenta, lungs, thyroid, and kidney.46,63 FR expression is limited to the apical (luminal) side of polarized epithelial cells, except for the cells of the proximal tubules in the kidney. As a consequence, FR is practically inaccessible to blood-borne folate-linked systems.44,45 These characteristics make folate receptors very advantageous for targeted delivery of nanoparticles with high payloads of therapeutic agents, imaging agents, and even genes for the treatment, detection, and monitoring of cancer. What is more, the macromolecular size of nanoparticles will prevent gromerular filtration and the consequent exposure of kidney tissue to folate-targeted nanoparticles.

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