Folatedrug

Folatedrug is a term used to describe drugs that are covalently linked to folic acid (folate) to enable targeted delivery to cells that overexpress the folate receptor. This targeting strategy aims to improve selectivity for tumor cells while limiting exposure of normal tissues.

Mechanism and targeting. Folate receptors, particularly folate receptor alpha, are frequently upregulated on various cancer cells. Folatedrugs bind to these receptors and are taken into cells by receptor-mediated endocytosis. Inside the cell, a linker connecting the folate to the therapeutic payload is designed to be cleaved under intracellular conditions, releasing the active drug or diagnostic agent. This approach can enhance uptake in tumors with high folate receptor expression and may reduce systemic toxicity relative to non-targeted therapies.

Composition and design. A folatedrug typically comprises three components: folate as the targeting ligand, a linker that remains stable in circulation but undergoes cleavage in target cells, and a payload, which may be a cytotoxic drug or a diagnostic/imaging agent. Common payloads include cytotoxic agents such as derivatives of vinca alkaloids or other chemotherapeutics, or radiolabeled/fluorescent compounds used for imaging.

Representative examples and status. Vintafolide (EC-145) is a noted folatedrug in which folate is linked to a vinca alkaloid derivative and has undergone clinical testing. Etarfolatide is another folate-receptor–targeted agent used for imaging. Numerous folatedrugs have been investigated in preclinical and clinical studies, reflecting ongoing research into folate-mediated targeting.

Clinical considerations. Benefits of folatedrugs include potential tumor selectivity and reduced systemic toxicity, while challenges include variable folate receptor expression among tumors, possible competition with dietary folate, and safety concerns related to off-target receptor binding in normal tissues such as kidneys. Research continues to define their therapeutic and diagnostic potential.