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Apr 22, 2011

Researchers Engineer Cells’ Own Vault Nanoparticles to Deliver Cytotoxic Drugs

  • Scientists have engineered cellular vault nanoparticles to carry cytotoxic drugs into cancer cells. The University of California Los Angeles (UCLA) team claims the achievement marks the first time that vaults have been successfully harnessed for drug delivery applications. Their research is published in the online edition of Small ahead of next month’s print issue, in a paper titled, “Vaults Engineered for Hydrophobic Drug Delivery.”

    The vault nanoparticle is one of the largest known ribonucleoprotein complexes in the sub-100 nm range, explains Daniel C. Buehler, Ph.D., at UCLA’s David Geffen School of Medicine, and colleagues. They are formed as a large nanocapsule with a barrel-shaped morphology surrounding a hollow interior. Electron microscopy and x-ray crystallographic studies by co-researcher Z. Hong Zhou, Ph.D., have also shown that both native and recombinant vaults have a thin protein shell enclosing a large internal volume of about 100,000 cubic nanometers, which the researchers claim in theory could hold hundreds to thousands of small molecule compunds. Moreover, vaults are highly conserved and almost ubiquitously expressed in eukaryotes. These properties make the structures  ideal candidates for development as drug delivery vehicles, the authors claim.  

    Recombinant vaults have been shown to be nonimmunogenic, and previous work has engineered the structure to enable cell surface receptor targeting and the encapsulation of a range of proteins. Dr. Buehler’s team’s strategy was to use engineered vaults as carriers for drug-loaded nanodisks comprising vault-binding lipopoprotein bilayers loaded with all-trans retinoic acid (ATRA).  

    Cryo-electron tomography (cryo-ET) reconstruction showed the vault-binding lipoprotein complex sequestered within the vault lumen, and ATRA-loaded vaults were found to demonstrate enhanced cytotoxicity against the HepG2 hepatocellular carcinoma cell line. "These vaults release therapeutics slowly, like a strainer, through tiny, tiny holes, which provides greater flexibility for drug delivery," comments co-author Leonard H. Rome, Ph.D.  “The ability to package therapeutic compounds into the vault is an important achievement toward their development into a viable and versatile platform for drug delivery,” the authors conclude.


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