Artificial switching of the metabolic processing pathway of an etiologic factor, β2-microglobulin, by a “navigator” molecule

• Published in: Journal of controlled release 2020-11, Vol.327, p.8-18
• Main Authors: Kambe, Yusuke, Koyashiki, Kento, Hirano, Yoshiaki, Harada-Shiba, Mariko, Yamaoka, Tetsuji
• Format: Article
• Language: English
• Subjects: Bodily distribution; Drug delivery system; Drug-navigated clearance system; Fusion protein; Metabolic disorder
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2020.07.041

Metabolic pathways in the body are highly specific. Dysfunction of a metabolic pathway triggers the accumulation of its target substance. For example, kidney failure results in increased β2-microglobulin blood levels, causing dialysis-related amyloidosis. Previously, we proposed a novel therapeutic concept, that is a removal of an etiologic factor of metabolic disease by artificial switching of its metabolic processing pathway, and tested this concept using in cultured cells. However, the feasibility of artificial metabolic switching in vivo remained unknown. Here, we show that a newly developed “navigator” molecule changes the metabolic processing pathway of β2-microglobulin from the kidney to the liver in mouse. The artificial metabolic switching is achieved by the capture of the etiologic factor by the navigator, which then steers the etiologic factor to hepatic lysosomes via low-density lipoprotein receptors. These findings demonstrate that navigator-based artificial metabolic switching can be a therapeutic strategy for various diseases caused by metabolic disorders. [Display omitted] •We developed a “navigator” that switches metabolic processing pathway in vivo.•β2-microglobulin (β2-m) was the target etiologic factor of the navigator.•The navigator caught β2-m and steered to LDL receptor on cells to reach lysosome.•The navigator switched β2-m accumulation from kidney to liver via LDL receptor.•Navigator-based artificial metabolic switching can be a new therapeutic strategy.