Tufts Engineer Wins NSF Award to Find New Ways to Deliver Drugs Directly into Cells

MEDFORD/SOMERVILLE, Mass. – Qiaobing Xu, Ph.D., an assistant professor of biomedical engineering in Tufts University School of Engineering, has received a $498,899 Faculty Early Career Development (CAREER) award from the National Science Foundation (NSF) to fund research into a new way to deliver protein-based cancer-fighting drugs and other therapeutics into cells.

Such an approach would enable drugs to destroy cancerous growth more effectively than existing treatments and target other diseases traditionally considered "undruggable."

Chemotherapy drugs attack all actively dividing cells—healthy and diseased alike—often causing significant side effects in the patients. New protein-based therapy, such as cytokines, monoclonal antibodies and growth factors, allow for highly targeted treatment. The problem is that, unlike compounds used in chemotherapy, proteins are too large to easily cross the cell membrane to penetrate into the cell cytoplasm. Instead, most of these protein therapies work by targeting specific receptors on the outside surface of diseased cells.

The NSF program supports junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education and research.

Xu is developing a method way to transport the protein inside the cell safely and efficiently by binding it with a nanoparticle that can cross the cell membrane and, when safely inside, release the protein. In his approach, the protein is first chemically altered to give it a negative charge and then bound to a positively charged nanoparticle composed of lipids. The lipids then pass through the cell membrane, which is naturally negatively charged.

Ferrying Drugs into Cells

"Think of it as a lipid-based transport. Think of the protein as cargo," says Xu. "Once it is bound with the nanoparticle, the protein is carried through the membrane into the cell. One advantage is the possibility to treat diseases at their roots and not their symptoms."

"There are a number of diseases, including genetic diseases and cancers, which have the potential to be treated through proteins with a target inside the cell," Xu adds. "We've found that we need to open a door so that these disease-fighting proteins can enter the cell interior. This could generate new therapies for a variety of diseases not traditionally viewed as treatable with drugs. "

Xu's work involves material science engineering, specifically nanoscience, and biomedical application, to develop new synthetic materials for the delivery of therapeutic biomacromolecules.

Findings published this past fall by Xu and his students in the leading chemistry journal Angewandte Chemie International Edition, (doi: 10.1002/anie.201407234)* show that Ribonuclease A (RNase A)—  a potential candidate for cancer therapy—could be safely delivered across the cell membrane and act only in the intracellular environment of unhealthy or cancerous cells.

"The beauty of this strategy is that the protein delivery vehicle is agnostic to its cargo," Xu says. "Other proteins or peptides that target diseases other than cancer could be loaded into the vehicle and delivered safely."

The NSF CAREER award will support further experiments to uncover the most efficient intracellular protein delivery vehicles.

Angew Chem Int Ed Engl. 2014 Dec 1;53(49):13444-8. doi: 10.1002/anie.201407234. Epub 2014 Oct 6.

"Reactive Oxygen Species (ROS)-responsive Protein Modification and Its Intracellular Delivery for Targeted Cancer Therapy," http://www.ncbi.nlm.nih.gov/pubmed/25287050

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