In recent years, researchers have grappled with the challenge of administering therapeutics in a way that boosts their effectiveness by targeting specific cells in the body while minimizing their potential damage to healthy tissue.
The development of new methods that use engineered nanomaterials to transport drugs and release them directly into cells holds great potential in this area. And while several such drug-delivery systems â€" including some that use dendrimers, liposomes or polyethylene glycol â€" have won approval for clinical use, they have been hampered by size limitations and ineffectiveness in accurately targeting tissues.
Now, researchers at UCLA have developed a new and potentially far more effective means of targeted drug delivery using nanotechnology.
In a study to be published in the May 23 print issue of the journal Small (and currently available online), they demonstrate the ability to package drug-loaded "nanodisks" into vault nanoparticles, naturally occurring nanoscale capsules that have been engineered for therapeutic drug delivery. The study represents the first example of using vaults toward this goal.
Vaults: Vault containing nanodisk. The image shows a single-particle electron microscope tomography reconstruction, which reveals that a fully assembled drug-loaded nanodisk (red) can be packaged into the vault lumen (green) as a viable method for vault-mediated drug delivery. The electron micrograph in the background shows negatively stained vaults containing nanodisks.The UCLA research team was led by Leonard H. Rome and included his colleagues Daniel C. Buehler and Valerie Kickhoefer from the UCLA Department of Biological Chemistry; Daniel B. Toso and Z. Hong Zhou from the UCLA Department of Microbiology, Immunology and Molecular Genetics; and the California NanoSystems Institute (CNSI) at UCLA.
Vault nanoparticles are found in the cytoplasm of all mammalian cells and are one of the largest known ribonucleoprotein complexes in the sub-100-nanometer range. A vault is essentially barrel-shaped nanocapsule with a large, hollow interior â€" properties that make them ripe for engineering into a drug-delivery vehicles. The ability to encapsulate small-molecule therapeutic compounds into vaults is critical to their development for drug delivery.
Recombinant vaults are nonimmunogenic and have undergone significant engineering, including cell-surface receptor targeting and the encapsulation of a wide variety of proteins.
"A vault is a naturally occurring protein particle and so it causes no harm to the body," said Rome, CNSI associate director and a professor of biological chemistry.
"These vaults release therapeutics slowly, like a strainer, through tiny, tiny holes, which provides great flexibility for drug delivery."
The internal cavity of the recombinant vault nanoparticle is large enough to hold hundreds of drugs, and because vaults are the size of small microbes, a vault particle containing drugs can easily be taken up into targeted cells.
With the goal of creating a vault capable of encapsulating therapeutic compounds for drug delivery, UCLA doctoral student Daniel Buhler designed a strategy to package another nanoparticle, known as a nanodisk (ND), into the vault's inner cavity, or lumen.
"By packaging drug-loaded NDs into the vault lumen, the ND and its contents would be shielded from the external medium," Buehler said. "Moreover, given the large vault interior, it is conceivable that multiple NDs could be packaged, which would considerably increase the localized drug concentration."
According to researcher Zhou, a professor of microbiology, immunology and molecular genetics and director of the CNSI's Electron Imaging Center for NanoMachines, electron microscopy and X-ray crystallography studies have revealed that both endogenous and recombinant vaults have a thin protein shell enclosing a large internal volume of about 100,000 cubic nanometers, which could potentially hold hundreds to thousands of small-molecular-weight compounds.
"These features make recombinant vaults an attractive target for engineering as a platform for drug delivery," Zhou said. "Our study represents the first example of using vaults toward this goal."
"Vaults can have a broad nanosystems application as malleable nanocapsules," Rome added.
The recombinant vaults are engineered to encapsulate the highly insoluble and toxic hydrophobic compound all-trans retinoic acid (ATRA) using a vault-binding lipoprotein complex that forms a lipid bilayer nanodisk.
The research was supported by the UC Discovery Grant Program, in collaboration with the research team's corporate sponsor, Abraxis Biosciences Inc., and by the Mather's Charitable Foundation and an NIH/NIBIB Award.
The California NanoSystems Institute at UCLA is an integrated research facility located at UCLA and UC Santa Barbara. Its mission is to foster interdisciplinary collaborations in nanoscience and nanotechnology; to train a new generation of scientists, educators and technology leaders; to generate partnerships with industry; and to contribute to the economic development and the social well-being of California, the United States and the world. The CNSI was established in 2000 with $100 million from the state of California. An additional $850 million of support has come from federal research grants and industry funding. CNSI members are drawn from UCLA's College of Letters and Science, the David Geffen School of Medicine, the School of Dentistry, the School of Public Health and the Henry Samueli School of Engineering and Applied Science. They are engaged in measuring, modifying and manipulating atoms and molecules â€" the building blocks of our world. Their work is carried out in an integrated laboratory environment. This dynamic research setting has enhanced understanding of phenomena at the nanoscale and promises to produce important discoveries in health, energy, the environment and information technology.
Contact: Jennifer Marcus jmarcus@cnsi.ucla.edu 310-267-4839 University of California - Los Angeles
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