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Turning a tumor’s weapon against itself

Understanding the building blocks of biochemistry and structural biology, says Bryan Berger, can lead to creative solutions to medical mysteries.

Berger studies protein structure and molecular recognition and is particularly interested in how cell receptors switch on and off in relation to disease and how engineered peptides function in the body to combat disease.

He and Mark Snyder, both assistant professors chemical engineering, are developing nanoscale packages that, like smart bombs, release chemotherapy drugs at the site of a rapidly growing tumor while limiting the drugs’ toxic effects on healthy tissues.

Normally growing cells feed off oxygen delivered through tiny blood vessels in tissue. When a precancerous cell morphs into a cancerous state, it grows at a rate faster than the oxygen supply can support. It then adjusts its metabolism to consume sugars stored in the cells and grow anaerobically.

This anaerobic metabolism causes the tumor cells to secrete enzymes called proteases that devour adjoining tissue to make room for the cancer’s rapid proliferation. The process produces lactic acid, which lowers the pH around the tumor site.

Berger synthesizes peptides (sequences of amino acids) and programs them to use the tumor’s protease weapons against itself.

“My lab designs peptides that the protease secreted by a specific cancer act upon,” he says. Utilizing knowledge about the types of amino acid bonds that a specific protease will attack, and the size and shape of molecules that can penetrate the diseased tissue, Berger develops a peptide that will fold or change shape when it senses the tumor’s enzymes and lowered pH.

Snyder incorporates the peptide into a silica-based nanoparticle package that encapsulates a small amount of an effective anti-cancer drug. The package is designed so that in the low-pH tumor environment, the peptide unfolds and is cleaved by protease, which causes the nanopackage to release the drug where it is needed.

“Most cancer drugs are effective but toxic,” Berger says. “We want to keep them stable, shield them and release them at the right time.”

Other organic, polymer-based approaches to packaging chemotherapy drugs exist, he says, “but the polymers are much more susceptible to degradation and have shorter half-lives than silica, which is inorganic and much more resilient.”

Berger and Snyder have a grant from the Pennsylvania Department of Health’s Commonwealth Universal Research Enhancement (CURE) program. They collaborate with Ellen Puré, professor of molecular and cellular oncogenesis at the Wistar Institute, a cancer research center in Philadelphia.