Nanosyringe Peptide Technology Locates and Treats Tumors

The researchers, from Yale University (New Haven, CT, USA) and the University of Rhode Island (Kingston, RI, USA), have shown that the protein fragment, called pHLIP (pH [low] insertion peptide), can be injected into the abdomen of a mouse, find its way into the blood, and then exclusively accumulate in tumors. Within 20 hours after injection of labeled pHLIP, the molecules had passed through the bloodstream and gathered in engineered mouse breast tumors grown to different "stages” on the leg of a mouse. The study was published May 1, 2007, in the early online issue of the journal Proceedings of the [U.S.] National Academy of Sciences.

The researchers demonstrated that by attaching fluorescent probes to a pHLIP peptide, tumors could be detected. They expect that by attaching and delivering active agents with pHLIP, those tumors may be able to be treated. Targeting is based on the fact that most tumors, even very small ones, are acidic as a result of the way they grow. "Since the mechanism is general and since even very small tumors can be targeted, there is an exciting array of possible applications for pHLIP,” said Dr. Donald Engelman, a professor of molecular biophysics and biochemistry at Yale and a co-investigator of the study.

"Andreev and Reshetnyak [co-investigators of the study] have taken a recent discovery from our lab and we are pushing hard as a team to test possible applications,” said Dr. Engelman. "We are very excited by the possibilities for both imaging and treating tumors.”

The pHLIP molecule has three states: soluble in water, bound to the surface of a membrane, and inserted across the membrane as an alpha helix. Under normal tissue conditions of neutral pH, the water-soluble form is favored. At acidic pH, the transmembrane alpha helix predominates.

An earlier study from the same groups revealed that at low pH, pHLIP can move cell-impermeable molecules across a cell membrane, where they are released in the cytoplasm. "pHLIP acts as a molecular nanosyringe, inserting itself into the cell membrane and injecting compounds into cell,” said co-author Dr. Yana Reshetnyak, from the University of Rhode Island. "The transported molecules can be therapeutic or toxic to the cell, depending on the intended outcome--for treating cancer, the idea is to cause cell death.”

In addition to targeting tumors, other disease states that generate inflammation and cause tissue to be acidic are a target for pHLIP. "Acidosis is a physiological marker of many diseases--and pHLIP feels acidity,” said Dr. Reshetnyak. "Therefore, pHLIP could also be used for monitoring of disease development and therapeutic outcomes. It might play very important role in the study of arthritis, ischemia, and stroke.”

Lead investigator Dr. Oleg Andreev said, "We believe that universal medical tests to reveal many health problems at earlier stages may be developed based on pHLIP technology.”

Among the applications the team is actively pursuing are positron emission tomography (PET) imaging of tumors, treatment of breast cancer, and alternative designs using the principles they have already established.

"Our discovery is an example of the reason that the NIH [U.S. National Institutes of Health] and DOD [U.S. Department of Defense] support basic science--we were working on the principles of membrane protein folding, and made a discovery with important medical implications that wouldn't have happened without the ideas and approaches used in that work,” Dr. Engelman commented.


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Yale University
University of Rhode Island