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Nanopolymer Boasts Special Delivery

Originally Published MDDI June 2005 R&D DIGEST Nanopolymer Boasts Special Delivery

Originally Published MDDI June 2005

R&D DIGEST

Nanopolymer Boasts Special Delivery

Heather Thompson

After four weeks, mice (above) that were given the nanocompound had significantly limited tumor growth. The cyclodextrin allows siRNA to travel to targeted cells (below). Previous attempts to deliver to the tumors proved problematic (click to enlarge).

Nanoparticles designed to silence genes may help stop a form of cancer that has to date had few successful treatment options.
Researchers from the Children's Hospital of Los Angeles and the California Institute of Technology (CalTech; Pasadena, CA) conducted studies that delivered short-interfering RNA (siRNA) to mice grafted with Ewing sarcoma tumors.

For the experiment, chemical engineers bound the siRNA to a nanosized polymer and a protein molecule. “Ewing sarcoma was a good test subject because the protein provides a molecular target,” explains Mark Davis, PhD, head researcher for the project at CalTech. “There are usually several types of tumors in various parts of the body, so we were able to deliver the RNA to multiple sites.”

SiRNA has been shown in previous experiments to arrest Ewing sarcoma tumors. The issue many researchers are struggling with is how to deliver the siRNA. Caltech chemists designed a unique polymer that provided a delivery mechanism for the siRNA.

The polymer is formed from a sugar-based monomer called cyclodextrin. “We built the polymer from scratch,” Davis says. “It was designed and constructed for this particular application.”

Positive ions in the polymer bind to and condense the negatively charged siRNA, forming a protective shield. The resulting combination is then tied to a protein called transferrin, which normally delivers iron into cells. Transferrin carries the polymer and siRNA through the bloodstream to a receptor on the surface of a cell. The transferrin binds with the receptor and is surrounded by a small vesicle. As the vessels are acidified, the nanoparticles release the siRNA.

Following the protein's natural pathway gave the nanoparticles access to a growth-promoting gene that is active only in Ewing sarcoma tumors.

Previous attempts to deliver the RNA encased in lipids or other methods were problematic. Researchers found that other methods elicited immune response or degradation. “We don't really understand the mechanism, but we know that the polymer doesn't elicit the same response,” Davis says. He explains that one theory is that the polymer is hydrophilic, and so may not travel into the same sections as lipid-bound molecules.

Size was also an issue the researchers needed to tackle, since traveling through the blood stream can be a tricky process. Once made, the polymer, siRNA, and protein measure about 50 nm across. “It is truly a nanosized process,” Davis explains. “The molecule has to be about that size to circulate effectively. If it's 100 nm, that's too big, and if it's only 10 nm, that is too small.”

The team was encouraged by the polymer's results. Twice-weekly injections for up to four weeks markedly inhibited tumor growth, according to Siwen Hu, a postdoctoral fellow at Children's Hospital and one of the team's head researchers.

As to future uses for the polymer, Davis says, “We still have to perform preclinical testing, and then we have to make sure the quality is appropriate for humans.” He estimates it will take at least two more years to have a polymer ready for human clinical trials. “This is a whole new composition of matter.”

Copyright ©2005 Medical Device & Diagnostic Industry

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