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August 31, 2011
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Forensic Chemistry: A new method could increase the number of explosives detected by airport screeners.
Trade: U.S. companies complain of market dumping by China.
Layoffs follow similar moves by Amgen, AstraZeneca.
Environment: Ban to halt export of hazardous waste to developing world.
Penrose (Parney) Albright will direct DOE national lab.
Toxic Exposure: Mercury isotopes in human hair illuminate dietary and industrial sources.
Cancer Biochemistry: Mass spectrometry follows the metabolism of very long fatty acids in cancer cells.
A new polymeric drug delivery system inspired by bacterial toxins could aid medical use of RNA drugs, which often get inactivated shortly after they are introduced into cells.
Cationic polymers have been used as nucleic acid delivery vehicles for more than a decade, but many of them don’t work well enough for medical applications. After entering cells, the polymers and their payloads often get trapped within endosomes and lysosomes, where they are rendered inactive.
Now, a team at the University of Washington has developed copolymer micelles with domains that are neutral or negatively charged under ambient conditions. If those particles get caught inside endosomes and lysosomes after entering a cell, the acidic environment of the organelles causes them to change their conformations and break free.
The new drug delivery concept was modeled on diphtheria toxin and other pathogen molecules, which have an uncanny ability to enter cells and then remain free from entrapment. “We wanted to see if we could mimic this in a nonbiological polymer,” said bioengineering professor Patrick S. Stayton of the University of Washington, who spoke at a Division of Medicinal Chemistry session on small interfering RNA (siRNA) therapeutics at the American Chemical Society national meeting in Denver.
Stayton described his group’s progress toward developing copolymers that can target cells selectively, pull large drugs through their membranes, and then assist those medications in remaining free from entrapment in cell compartments.
The work “addresses one of the critical aspects of siRNA delivery,” says Peter Senter, a chemist from Seattle Genetics, namely keeping drug molecules out of cell endosomes and lysosomes.
Each polymer has a mix of monomers with amine, alkane, and carboxylic acid side chains; an outer domain that can bind to RNA payloads; and an inner domain that associates with other inner domains to form the core of micelles. At standard physiological pH, 7.4, carboxylic acid groups in the polymers have a negative charge. Endosomes and lysosomes have acidic interiors that can protonate these groups. Once they have been protonated, the polymers adopt a new conformation that disrupts the structure of the compartments, releasing their cargo.
The new polymers “have domains that go from anionic to neutral in the endosome, which is a fundamentally different mechanism [from that of] cationic lipids or cationic polymers,” says Stephanie Gratton-Barrett, of Merck & Co., who organized the session.
Stayton and coworkers use reversible addition-fragmentation chain transfer, a living polymerization technique, to make the cationic polymers. They favor the technique because it has proven quite reproducible and scalable. Also, it allows them to affix targeting agents, such as antibodies, to the ends of each polymer via biotin linkers.
Recently, they have used polymer-antibody conjugates to deliver siRNA into lymphoma and ovarian cancer cells. Those conjugates achieved respectable gene knockdown efficiencies and selectivities in vitro. But so far they have not been studied in vivo, nor have they been tailored for optimal biodegradability. Their activity is being further explored by PhaseRx, a start-up company founded by Stayton and his colleagues.
“Those are exciting developments, but it would be nice to see the in vivo fate of these constructs,” says Muthiah Manoharan, a vice president at Alnylam Pharmaceuticals, which is at the forefront of RNA interference therapies. He went on to suggest that Stayton should expand upon his drug delivery concept by switching to polymers with a backbone that is inherently biodegradable.
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