Ligand binding and kinetics of folate receptor recycling in vivo: impact on receptor-mediated drug delivery

Molecular Pharmacology
Chrystal M PaulosPhilip S Low

Abstract

Folate receptor-targeted cancer therapies constitute a promising treatment for the approximately one third of human cancers that overexpress the folate receptor (FR). However, the potencies of all folate-receptor targeted therapies depend on 1) the rate of folate-linked drug conjugate binding to the cancer cell surface, 2) the dose of folate conjugate that will saturate tumor cell surface FR in vivo, 3) the rate of FR internalization, unloading, and recycling back to the tumor cell surface for another round of conjugate uptake, and 4) the residence time of the folate conjugate before its metabolism or release from the cell. Because little information exists on any of these processes, we have undertaken to characterize them on both cancer cells in culture and solid tumors in live mice. We quantitate here the properties of FR saturation, internalization, recycling, and unloading in several cultured cancer cell lines and murine tumor models, and we describe the conditions that should maximize both the potencies and specificities of folate receptor-targeted therapies in vivo.

Associated Clinical Trials

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