Targeting Acidic Diseased Tissues by pH-Triggered Membrane-Associated Peptide Folding

Abstract

The advantages of targeted therapy have motivated many efforts to find distinguishing features between the molecular cell surface landscapes of diseased and normal cells. Typically, the features have been proteins, lipids or carbohydrates, but other approaches are emerging. In this discussion, we examine the use of cell surface acidity as a feature that can be exploited by using pH-sensitive peptide folding to target agents to diseased cell surfaces or cytoplasms.

pHLIP ICG for delineation of tumors and blood flow during fluorescence-guided surgery

“…1 c–e). pHLIP ICG is inserted into lipid bilayer of membrane and forms alpha helical structure at low pHs, as do all peptides of pHLIP family 3 , 22 . The midpoint of the transition for pHLIP ICG insertion in liposomes is at pH 6.3 as calculated from graph presented on Fig.…”

“…More than a decade ago, the first pH-Low Insertion Peptide (pHLIP) was introduced as an agent for targeting acidity at the surfaces of cellular membranes in vitro and in vivo 1 , 2 . The molecular mechanism of action of acidity targeting by peptides of the pHLIP family has been well-investigated and has been the subject of many publications (see review 3 and references within it). pHLIP is a water-soluble, moderately hydrophobic peptide containing several carboxyl groups in a sequence of hydrophobic and polar residues (Fig.…”

Selective Display of a Chemoattractant Agonist on Cancer Cells Activates the Formyl Peptide Receptor 1 on Immune Cells

“…This insertion topology can therefore be used to graft a variety of molecules onto cancer cell surfaces as long as they are conjugated to the N-terminus of pHLIP. [22,38,39] Here, we show that remodeling the surface of cancer cells with a FPR ligand using a pHLIPbased targeting strategy could selectively engage an immune response towards tumors by activating FPR1 on recruited immune cells (Figure 1).…”

“…This insertion topology can therefore be used to graft a variety of molecules onto cancer cell surfaces as long as they are conjugated to the N-terminus of pHLIP. [22,38,39]…”

Molecularly engineered tumor acidity-responsive plant toxin gelonin for safe and efficient cancer therapy

“…pH low insertion peptide (pHLIP) is a 36-amino acids peptide originated from bacteriorhodopsin C helix, which could form a transmembrane α-helix and translocate cell-impermeable cargoes that are conjugated to its C terminus across a cell membrane under acidic conditions [ 45 ]. pHLIP-mediated targeting strategy based on tumor acidic microenvironment is significantly superior to traditional passive and active targeting in many respects [ 46 ]. Thus, pHLIP has been tremendously utilized for delivery of a wide range of theranostic molecules to achieve specific tumor imaging or enhanced therapeutic index [ [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] ].…”