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Biological Chemistry

Drug Delivery Hooked On Sugar

Cellular Delivery: Boronates home in on membrane sugars to ship proteins into cells

by Erika Gebel
February 15, 2012

Special Delivery
Credit: J. Am. Chem. Soc.
A protein decorated with benzoxaborole (red) reacts with cell-surface sugars (center) and can slide into the cell’s cytoplasm (right).
Credit: J. Am. Chem. Soc.
A protein decorated with benzoxaborole (red) reacts with cell-surface sugars (center) and can slide into the cell’s cytoplasm (right).

In an advance for drug delivery, researchers have demonstrated that they can slip large biological molecules inside cells by tagging them with small molecules called boronates (J. Am. Chem. Soc., DOI: 10.1021/ ja210719s). The boronates deliver molecular cargo by reacting with sugars on the cell surface. The researchers hope the new delivery method will aid the development of treatments for cancer and other diseases.

Scientists previously have relied on a variety of strategies for breaching the cellular membrane, including packaging drugs inside lipid particles or using positively charged chemicals to direct cargo to a cell’s negatively charged surface. But these approaches have their drawbacks, says Ronald Raines of the University of Wisconsin, Madison. Lipid particles “haven’t lived up to their potential,” he says, because drug molecules have difficulty escaping from them. Meanwhile, positively charged molecules deliver drugs to any and all cells. Once inside a cell the chemicals may interact with negatively charged molecules such as DNA instead of with the target, which can lead to harmful side effects.

Raines wondered if boronates could be more successful because they are uncharged and so are not attracted to the negatively charged molecules on or in all cells. Scientists already had shown that boronates bind to sugars on cell surfaces. He envisioned that the boronate and its attached cargo would reach a cell’s surface and then enter the cytoplasm through the cell’s normal process of pulling in sections of its membrane for recycling.

So Raines and his team designed a proof-of-principle experiment using a boronate called benzoxaborole. They chose it because of its high affinity for sialic acid, a sugar that is plentiful on the surface of cancer cells. The researchers used a simple condensation reaction to attach benzoxaborole to random carboxyl groups on the surface of RNase A, a protein that is toxic to cells once it reaches the cytoplasm. The researchers used mass spectrometry to determine that, on average, each protein bore about 7.5 boronates.

When they added the decorated protein to a sample of hamster cells, the researchers found that the molecules killed half the cells at a concentration of 4.1 µM. RNase A alone didn’t kill any of the cells, no matter how high the concentration. To confirm that the boronates were the key to helping RNase A get inside, the chemists showed they could protect the cells by adding fructose to the cell culture. The boronates reacted with the distracting fructose molecules instead of with the sugars on the cells.

Boronates represent “an exciting new paradigm for the targeted delivery of drugs, nucleic acids, or proteins,” says Theresa Reineke of the University of Minnesota, Twin Cities. Since the methods and materials are readily accessible, she says other groups easily could test the method in their own projects. Reineke would like researchers to test the boronates in animals, but Raines says that he first plans to optimize the condensation reaction so he can control the number and location of boronate attachments on proteins.



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