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.
There’s no question, drugs work in treating disease. But can they work better, and safer?
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.
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 —
including some that use dendrimers, liposomes or polyethylene glycol —
have won approval for clinical use, they have been hampered by size
limitations and ineffectiveness in accurately targeting tissues.
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.
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.
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 — 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.
vaults are nonimmunogenic and have undergone significant engineering,
including cell-surface receptor targeting and the encapsulation of a
wide variety of proteins.
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.”
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
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.
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
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
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.
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.
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