Abstract
The discovery of the pH Low Insertion Peptides (pHLIPs®) provides an opportunity to develop imaging and drug delivery agents targeting extracellular acidity. Extracellular acidity is associated with many pathological states, such as those in cancer, ischemic stroke, neurotrauma, infection, lacerations, and others. The metabolism of cells in injured or diseased tissues often results in the acidification of the extracellular environment, so acidosis might be useful as a general marker for the imaging and treatment of diseased states if an effective targeting method can be developed. The molecular mechanism of a pHLIP peptide is based on pH-dependent membrane-associated folding. pHLIPs, being moderately hydrophobic peptides, have high affinities for cellular membranes at normal pH, but fold and insert across membranes at low pH, allowing them to sense pH at the surfaces of cells in diseased tissues, where it is the lowest. Here we discuss the main principles of pHLIP interactions with membrane lipid bilayers at neutral and low pHs, the possibility of tuning the folding and insertion pH by peptide sequence variation, and potential applications of pHLIPs for imaging, therapy and image-guided interventions.
Highlights
Many diseases such as cancer, ischemia, stroke, infection and others lead to the development of local hypoxia and acidosis
We have been developing a novel class of pHsensitive delivery agents, pHLIP® s, which are moderately hydrophobic peptides that can insert into membranes at mild acidic pHs, and which locate themselves at cell surfaces where the pH is lowest (Andreev et al, 2009, 2010a)
Since the surface bound peptide is located at an intermediate zone between polar and non-polar environments, the pK for the protonation of Asp and Glu residues is significantly shifted to higher pH values (Harris and Turner, 2002), and the apparent pK of pHLIP insertion can vary from 4.5 to 6.5 (Reshetnyak et al, 2007; Musial-Siwek et al, 2010; Barrera et al, 2011; Weerakkody et al, 2013)
Summary
Many diseases such as cancer (solid tumors), ischemia, stroke, infection and others lead to the development of local hypoxia and acidosis. We have been developing a novel class of pHsensitive delivery agents, pHLIP® s (pH Low Insertion Peptides), which are moderately hydrophobic peptides that can insert into membranes at mild acidic pHs, and which locate themselves at cell surfaces where the pH is lowest (Andreev et al, 2009, 2010a).
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