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Arch Biochem Biophys. 2015 Jan 1;565:40-8. doi: 10.1016/ Epub 2014 Nov 18.

Targeting acidity in diseased tissues: mechanism and applications of the membrane-inserting peptide, pHLIP.

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Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA.
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA. Electronic address:


pHLIPs are a family of soluble ∼36 amino acid peptides, which bind to membrane surfaces. If the environment is acidic, a pHLIP folds and inserts across the membrane to form a stable transmembrane helix, thus preferentially locating itself in acidic tissues. Since tumors and other disease tissues are acidic, pHLIPs' low-pH targeting behavior leads to applications as carriers for diagnostic and surgical imaging agents. The energy of membrane insertion can also be used to promote the insertion of modestly polar, normally cell-impermeable cargos across the cell membrane into the cytosol of targeted cells, leading to applications in tumor-targeted delivery of therapeutic molecules. We review the biochemical and biophysical basis of pHLIPs' unique properties, diagnostic and therapeutic applications, and the principles upon which translational applications are being developed.


Membrane insertion; Transmembrane; Tumor microenvironment; Tumor targeting

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