Yale Bulletin and Calendar

May 11, 2007|Volume 35, Number 28|Two-Week Issue

Using molecular 'nanosyringe,' researchers demonstrate how to 'tag' tumors

Research teams at Yale University and the University of Rhode Island have demonstrated a new way to target and potentially treat tumors using a short piece of protein that acts like a nanosyringe to deliver "tags" or therapy to cells, according to a report in the Proceedings of the National Academy of Sciences.

The researchers show that the protein fragment, called "pHLIP" -- for "pH (Low) Insertion Peptide" -- can be injected into the abdomen of a mouse, find its way into the blood and then specifically accumulate in tumors. Within 20 hours after injection of labeled pHLIP, the molecules had passed through the bloodstream and accumulated in mouse breast tumors grown to different "stages" on the leg of a mouse.

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, 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," says Donald Engelman, the Eugene Higgins Professor of Molecular Biophysics and Biochemistry (MB&B) at Yale, a co-author of the paper.

The paper's other co-authors -- Oleg Andreev, a research affiliate in MB&B at Yale, and Yana Reshetnyak, of the University of Rhode Island -- "have taken a recent discovery from our lab and we are pushing hard as a team to test possible applications," says 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 paper from the same groups shows that at low pH, Reshetnyak says, "pHLIP acts as a molecular nanosyringe, inserting itself into the cell membrane and injecting compounds into the cell. 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 tumors, pHLIP can also target other disease states that produce inflammation and cause tissue to be acidic. "Acidosis is a physiological marker of many diseases -- and pHLIP feels acidity," says Reshetnyak. "Therefore, pHLIP could also be used for monitoring of disease development and therapeutic outcomes. It might play a very important role in the study of arthritis, ischemia and stroke."

Andreev, the lead author, says, "We believe that a universal medical test to reveal many health problems at earlier stages may be developed based on pHLIP technology."

According to Engelman, this research is one example of why the National Institutes of Health (NIH) and the U.S. Department of Defense (DOD) support basic research. "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," says the Yale scientist.

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

Other authors are Allison D. Dupuy, Michael Segala, Srikanth Sandugu, David A. Serra and Clinton Chichester from Yale and the University of Rhode Island (URI). In addition to the NIH and the DOD, this work was supported by the URI Foundation and URI Research Council.

-- By Janet Rettig Emanuel

T H I SW E E K ' SS T O R I E S

Co-evolution of genitalia in waterfowl reveals 'war between the sexes'

Study of Galápagos tortoises' DNA may locate mate for 'Lonesome George'

Eighteen new Yale World Fellows named

Health clinic staff among the winners of Elm-Ivy Awards

Bringing a philosophical perspective to palliative care

University breaks ground for its 'most green building'

Child Study Center recognized for leadership in autism research

Yale senior Rebekah Emanuel wins Simon Fellowship for Noble Purpose

Using molecular 'nanosyringe,' researchers demonstrate . . .

Irish writer's play about Siamese twins wins Yale Drama Series award

When it comes to grades, giving is no easier than receiving, says panel

Talents of drama students showcased in Carlotta Festival

Biophysicist Steitz honored for ribosome research with Gairdner Award

CCL renovations on schedule; lawn to be used for Commencement

Project aims to improve financial services for those living in poverty

Pastoral leadership skills are focus of Center for Faith and Culture event

MacMillan Center honors the work of three Yale faculty members

Yale has highest number of sports teams honored . . .

WORKSPACE ENHANCEMENTS AT THE SCHOOL OF MEDICINE

Adding some sunshine to a windowless office

Creating a tranquil space for nursing mothers

Decking the hallways with quilted artworks