Delivering hydrophilic peptide inhibitors of heat shock protein 70 into cancer cells

Abstract

Heat shock protein 70 (Hsp70) plays a major role in protein folding and has emerged as an attractive target in a wide range of cancers. Here we used a polymer nanogel to deliver two hydrophilic peptide inhibitors that block the interaction between the C-terminus of Hsp70 and heat shock organizing protein (HOP). The nanogels are able to load ∼200 wt% of the peptide inhibitors from solution via simple agitation at pH 7, and release them after cell uptake. Delivery of Hsp70 inhibitors to HCT116 cancer cells produced a clear Hsp70 inhibition phenotype: downregulation of client proteins glucocorticoid receptor (GR), immunophilins (FKBP51 and FKBP52), the protein kinase Akt-1, as well as the co-chaperone CHIP, and they induce cancer cell death. These results showcase the advantages of using versatile nanogels for delivery of hydrophilic cargo such as peptides and demonstrate the viability of these peptide inhibitors for targeting the Hsp70-HOP interaction in a cellular system.

Keywords: Heat shock protein 70; Nanogel delivery; Peptide inhibitors.