Polymer mediated transport of the Hsp90 inhibitor LB76, a polar cyclic peptide, produces an Hsp90 cellular phenotype

Abstract

LB76 is a cyclic peptide that shows great promise as a selective heat shock protein 90 (Hsp90) inhibitor. However despite strong binding to and inhibition of Hsp90 in cell lysate its polar structure prevents it from crossing the cell membrane. We have developed a pH responsive polymer nanoparticle that effectively encapsulates LB76 from solution without need for purification. The nanoparticle releases the molecule upon crossing the cell membrane. Treatment of human colon cancer HCT116 cells with nanoparticles laden with LB76 produces the typical phenotype associated with Hsp90 inhibition, providing evidence of a therapeutically active payload.