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.
The delivery of fluorescent phalloidin into cells by pHLIP. (a) HeLa cells at pH 7.4 (Left) shows weak label localized at the cell membrane, and pH 6.5 (Right) shows fluorescent actin filaments inside cells. (b) HeLa (Left), breast cancer (Center), and prostate cancer (Right) cells show different and characteristic patterns of fluorescent actin filaments. Credit: Credit: Yale University
"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."
Normal cells are surrounded by an environment with a constant pH of about 7.4, while tumor cells and sites of inflammation actively pump protons out and create an acid extracellular pH of 5.5 to 6.5.
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.
During HIV infection, antibody can block B cells from fighting pathogens
14.08.2018 | NIH/National Institute of Allergy and Infectious Diseases
First study on physical properties of giant cancer cells may inform new treatments
14.08.2018 | Brown University
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur
What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...
The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.
Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...
08.08.2018 | Event News
27.07.2018 | Event News
25.07.2018 | Event News
14.08.2018 | Information Technology
14.08.2018 | Life Sciences
14.08.2018 | Life Sciences