The pH-low insertion peptide (pHLIP) holds great promise for diagnostic and therapeutic applications in diseases characterized by acidosis. Based on environmental factors, pHLIP can assume three different stable states: at neutral pH, pHLIP is unstructured in solution (State I), but in the presence of lipid bilayers it binds to the membrane surface (State II). Finally, a drop in pH causes pHLIP to insert across the membrane and fold into a transmembrane helix (State III). pHLIP has been shown to target different solid tumor types, and to translocate membrane-impermeable drugs across the plasma membrane into the cytoplasm of cancer cells
Reshetnyak YK, Andreev OA, Lehnert U, Engelman DM. Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6460-5.
Scott HL, Westerfield JM, Barrera FN. Determination of the Membrane Translocation pK of the pH-Low Insertion Peptide. Biophys J. 2017 Aug 22;113(4):869-879. doi: 10.1016/j.bpj.2017.06.065. PMID: 28834723; PMCID: PMC5567424.
Dhuri K, Duran T, Chaudhuri B, Slack FJ, Vikram A, Glazer PM, Bahal R. Head-to-head comparison of in vitro and in vivo efficacy of pHLIP-conjugated anti-seed gamma peptide nucleic acids. Cell Rep Phys Sci. 2023 Oct 18;4(10):101584.
Li X, Jian M, Sun Y, Zhu Q, Wang Z. The Peptide Functionalized Inorganic Nanoparticles for Cancer-Related Bioanalytical and Biomedical Applications. Molecules. 2021 May 27;26(11):3228.