Folate receptor-β in activated macrophages: ligand binding and receptor recycling kinetics.
Activated macrophages overexpress a receptor for the vitamin folic acid termed the folate receptor β (FR-β). Because conjugation of folate to low molecular weight drugs, genes, liposomes, nanoparticles, and imaging agents has minor effects on FR binding, the vitamin can be exploited to target both therapeutic and imaging agents to activated macrophages without promoting their uptake by other healthy cells. In this paper, we characterize the binding, internalization, and recycling kinetics of FR-β on activated macrophages in inflamed tissues of rats with adjuvant-induced arthritis. Our results demonstrate that saturation of macrophage FR is achieved at injection doses of ∼150-300 nmol/kg, with more rapidly perfused tissues saturating at lower doses than inflamed appendages. After binding, FR-β internalizes and recycles back to the cell surface every ∼10-20 min, providing empty receptors for additional folate conjugate uptake. Because the half-life of low molecular weight folate conjugates in the vasculature is usually <1 h, these data suggest that targeting of folate conjugates to activated macrophages in vivo can be maximized by frequent dosing at conjugate concentrations that barely saturate FR (∼150 nmol/kg), thereby minimizing nonspecific binding to receptor-negative tissues and maximizing the probability that unoccupied cell surface receptors will be exposed to folate-drug conjugate.
['Varghese|Bindu|B|', 'Vlashi|Erina|E|', 'Xia|Wei|W|', 'Ayala Lopez|Wilfredo|W|', 'Paulos|Chrystal M|CM|', 'Reddy|Joseph|J|', 'Xu|Le-Cun|LC|', 'Low|Philip S|PS|']
D000818:Animals D001168:Arthritis D058976:Folate Receptor 2 D005492:Folic Acid D006801:Humans D007700:Kinetics D008264:Macrophages D051381:Rats
folate receptor recycling internalization arthritis endocytosis