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National Institute of Environmental Health Sciences

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Publication Detail

Title: Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide.

Authors: Svoronos, Alexander A; Bahal, Raman; Pereira, Mohan C; Barrera, Francisco N; Deacon, John C; Bosenberg, Marcus; DiMaio, Daniel; Glazer, Peter M; Engelman, Donald M

Published In Mol Pharm, (2020 02 03)

Abstract: Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, "drug-like" molecules. Here, we explore the ability of a tumor-targeted delivery system centered on the use of a pH-low insertion peptide (pHLIP) to directly deliver moderately polar, multi-kDa molecules into tumor cells. A pHLIP is a short, pH-responsive peptide capable of inserting across a cell membrane to form a transmembrane helix at acidic pH. pHLIPs target the acidic tumor microenvironment with high specificity, and a drug attached to the inserting end of a pHLIP can be translocated across the cell membrane during the insertion process. We investigate the ability of wildtype pHLIP to deliver peptide nucleic acid (PNA) cargoes of varying sizes across lipid membranes. We find that pHLIP effectively delivers PNAs up to ∼7 kDa into cells in a pH-dependent manner. In addition, pHLIP retains its tumor-targeting capabilities when linked to cargoes of this size, although the amount delivered is reduced for PNA cargoes greater than ∼6 kDa. As drug-like molecules are traditionally restricted to sizes of ∼500 Da, this constitutes an order-of-magnitude expansion in the size range of deliverable drug candidates.

PubMed ID: 31855437 Exiting the NIEHS site

MeSH Terms: A549 Cells; Animals; Cell Membrane Permeability/drug effects; Cell Membrane/metabolism; Cytoplasm/drug effects*; Disease Models, Animal; Drug Delivery Systems/methods*; Humans; Hydrogen-Ion Concentration; Lipid Bilayers/metabolism; Melanoma/drug therapy*; Melanoma/pathology; Membrane Proteins/metabolism*; Membrane Proteins/pharmacology; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy/methods; Peptide Nucleic Acids/administration & dosage*; Skin Neoplasms/drug therapy*; Skin Neoplasms/pathology; Treatment Outcome; Tumor Microenvironment/drug effects

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