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Nanocarriers Come Through

Tiny Trojan horses deliver a cancer drug to cell nuclei.
January 6, 2011

A new nanodelivery system is able to sneak cancer treatments past the defenses of drug-resistant tumor cells—offering hope to many cancer patients who benefit little from existing drug treatments.

Cell invader: Immediately after injection into live mice, micelles can be seen travelling through the bloodstream glowing green.

Researchers at the University of Tokyo designed small soapy clusters of molecules, called micelles, to carry drugs into tumor cells and release their cargo inside. The molecules harness the cell’s internal transport system to get close to their target—the cell’s DNA.

Releasing the drug close to a cancer cell’s nucleus appears to protect it from the cell’s self-defense mechanism. The approach slowed the growth of tumors in mice—even tumors that were completely resistant to the drug when it was administered normally. The work was published yesterday in the journal Science Translational Medicine.

“This addresses a key hurdle in cancer treatment by overcoming the limitations faced by free drugs—that is, development of resistance by cells,” says Samir Mitragotri, professor of chemical engineering at the University of California, Santa Barbara, who was not involved with the research.

Micelles were tested as a delivery system for the colorectal cancer drug oxaliplatin in mice with drug-resistant human colon cancer.

Ordinarily, oxaliplatin is injected into a patient’s bloodstream, and from there it enters the cytoplasm of tumor cells by way of small gaps or channels in the cell membrane. Only about 5 to 10 percent of the drug particles make it to the cell’s nucleus, but those that do attach themselves to the DNA and disrupt its function, eventually killing the cancer cell. Once colorectal cancer has begun to metastasize, however, within nine months it develops defense proteins in its cytoplasm that inactivate oxaliplatin.

The micelles penetrate the cell membrane in a different way, entering the cell through a process called endocytosis. Small sections of the cell membrane pinch off and form bubble-like vesicles that engulf the micelles. These membrane-enclosed sacks travel along the cell’s internal transport system until they approach the nucleus. As the micelles get closer to the cell nucleus the chemistry inside the vesicles gradually becomes more acidic, the better to digest their cargo into small nutrient particles.

As conditions become more acidic, the molecules of the micelles, which have self-assembled around the drug molecules, lose their ability to stick together and release the drug molecules.

“Micelles work as nanoscaled Trojan horses to efficiently deliver a drug into the nucleus of drug-resistant cancer cells,” says lead author Kazunori Kataoka, a professor in the Department of Materials Engineering and Bioengineering at the University of Tokyo.

This drug-delivery mechanism slowed tumor growth by approximately 75 percent compared with tumors treated with regular oxaliplatin.

By equipping each micelle component with a green fluorescent tag at the surface and a red fluorescent tag that faces the core, the researchers were able to track their progress through cells with fluorescent video microscopy and film when and where the micelles delivered their payload.

Katakoka’s colleague Nobuhiro Nishiyama, says the micelles are more responsive than any other known drug carrier to the chemical conditions at the target site inside a cell.

Omid Farokhzad of the Laboratory of Nanomedicine and Biomaterials at Harvard Medical School says that without this kind of subcellular targeting system, drugs delivered by nanocarriers are not necessarily more effective. “Nanocarrier engineering really needs to become more sophisticated, and people will look to this work as a landmark study for how you can engineer the system to target subcellular compartments,” Farokhzad says.

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