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News

Targeted drug delivery now possible with pHLIP peptide

Yale University : 02 April, 2007  (Technical Article)
Scientists at Yale and the University of Rhode Island report the development of a peptide that can specifically and directly deliver molecules to the inside of cells like a nanosyringe, creating a new tool for drug delivery, gene control and imaging of diseased tissues.
Their “cargo carrier” peptide called pHLIP, for pH (Low) Insertion Peptide, accumulates in the membranes of cells in acidic environments and spontaneously transfers attached molecules across the membrane. The cargo is then released by cleavage of a sulfur-sulfur bond that is only unstable if it is inside the cell. The study, published early online in the Proceedings of the National Academy of Sciences, was led by Donald M. Engelman, professor of molecular biophysics and biochemistry at Yale.

“Our system offers a new technology for the fast and efficient delivery of drugs, imaging probes, or cell and gene regulation agents into living cells,” said Engelman. “pHLIP may provide a new approach for imaging, diagnosis and treatment of diseases with naturally occurring or artificially created low-pH extracellular environments, such as tumors, infarcts, stroke-afflicted tissue, atherosclerotic lesions, sites of inflammation or infection, or damaged tissue resulting from trauma.”

The study shows that pHLIP entry into the cell membrane and the translocation of molecules into cells are not mediated by the usual entry pathways, endocytosis, interactions with cell receptors, or by formation of pores in cell membranes.

“By translocating a molecule into a cell and releasing it in the cytoplasm, pHLIP functions, in effect, as a nanosyringe,” according to Engelman. “The peptide does not exhibit any of this structure in solution or on the cell membrane at neutral pH. However, at low pH it becomes rigid like a syringe needle, inserts into a cell membrane, and injects molecules into cells.

Drug or dye molecules can be linked by sulfur-sulfur bonds to pHLIP. This paper demonstrates the effectiveness of pHLIP with a cargo of fluorescently tagged phalloidin, a toxin from the deadly Amanita phalloides mushroom that normally cannot enter cells. Inside the cells phalloidin binds to actin molecules and “freezes” the cellular skeleton giving a distinct visual pattern under the microscope.

First authors of the paper Yana K. Reshetnyak and her husband Oleg A. Andreev are assistant professors of physics at the University of Rhode Island and research affiliates at Yale; author Ursula Lehnart was a post-doctoral fellow at Yale. Reshetnyak pioneered work with this mechanism of molecule delivery as a post-doctoral fellow in membrane biophysics at Yale with Engelman.

This research was supported in part by grants from the National Institute of General Medical Sciences, the Department of Defense, the National Center for Research Resources, and a Research Development Grant from the Council for Research, University of Rhode Island. The Yale Office of Cooperative research manages intellectual assets created at Yale and a patent application covering this subject matter has been filed. Further information is available through ocr@yale.edu or at http://www.yale.edu/ocr/
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