Folate Receptor-Mediated Drug Targeting: A Possible Strategy for Nonfunctioning Pituitary Adenomas?

Abstract

Clinically nonfunctioning pituitary adenomas (NFPAs) mostly arise from gonadotroph cells and account for about one-third of all pituitary tumors. Because they are not associated with hormone hypersecretion, these tumors are often diagnosed late when they are large and locally invasive. Consequently, the complete surgical removal of NFPAs is hard to achieve and they tend to recur. Medical treatment of NFPAs is still challenging because they are usually resistant to mainstay peptide receptor therapy with somatostatin (SRIF) analogs (octreotide and lanreotide) or dopamine agonists (bromocriptine and cabergoline). Indeed, although these agents may be useful in some cases to prevent residual tumor growth (1), their efficacy has not been confirmed in larger studies. Recently, SOM230 (pasireotide), a broad-range SRIF analog with affinity for SRIF receptor subtypes 1 to 3 and 5 (2) and BIM-23A760 (dopastatin), a chimeric agent interacting with both SRIF receptor and dopamine receptors were developed (3). However, NFPAs only partially respond to these compounds, at least in vitro (4, 5). After the discovery that NFPAs display overactivation of phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin pathway (6, 7), compounds inhibiting this signaling cascade at various levels have been tested against these tumors. The results are very promising, especially for dual inhibitors such as BEZ235 and XL765, which inhibit both mammalian target of rapamycin and the upstream phosphatidylinositol 3-kinase and exert a potent antiproliferative activity against primary human NFPA cells (8), rodent pituitary cell lines (9), and primary rat gonadotroph adenoma cells in vitro (10). In vivo studies are now required to prove or disprove the efficacy of these agents. Conventional chemotherapy has been one of the major medical advances of the last decades, but it is usually associated with poor specificity for the cancer cells and high toxicity to the normal cells. To overcome these limitations, it would be ideal to identify ways to deliver a biologically effective concentration of anticancer agents to the tumor tissues with very high specificity. To reach this ultimate goal, extensive efforts have been undertaken to develop tumor-selective drugs by conjugating therapeutic agents to hormones, antibodies, and vitamin derivatives. Among them, folic acid holds great promise as a tumor-homing agent (11). Folate (or folic acid) is an essential B vitamin, which plays a pivotal role in cell survival by participating in the biosynthesis of nucleic and amino acids. Folate is internalized into the cells via a low-affinity reduced folate carrier protein or via high-affinity folate receptors. The best studied isoform of these receptors is folate receptor(FR ), a cell surface glycosyl phosphatidylinositol-anchored glycoprotein that can internalize bound folates and folate-conjugated compounds via receptor-mediated endocytosis (12). Whereas FR has a very restricted expression pattern in normal tissues, it is expressed at a high level in various human cancers, particularly epithelial carcinomas, including nonmucinous ovarian carcinoma, cervical carcinomas, and testicular choriocarcinomas, and less frequently in breast, endometrial colon, and renal cell carcinomas (13, 14). Due to its selective expression in tumor but not normal cells, FR has become one of the most investigated cellular surface antigens for targeted delivery of a variety of molecules, including imaging agents, chemotherapeutic agents, oligodeoxynucleotides, and macromolecules. Various types of drug carriers have been conjugated to folate such as liposomes, lipid nanoparticles, polymeric nanoparticles, polymers, and micelles filled with the molecule that needs to be delivered (11). FR -targeted liposomal