Scientists engineer nanoscale vaults to encapsulate 'nanodisks' for drug delivery

There's no question, drugs work in treating disease. But can they work better, and safer? 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 -- 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.

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, 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.

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 -- 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.

Story Source:

The above story is reprinted (with editorial adaptation) from materials provided by University of California - Los Angeles.

Journal Reference:

Daniel C. Buehler, Daniel B. Toso, Valerie A. Kickhoefer, Z. Hong Zhou, Leonard H. Rome. Vaults Engineered for Hydrophobic Drug Delivery. Small, 2011; DOI: 10.1002/smll.201002274

 

 

New shapes of microcompartments: Molecular shells that encapsulate cellular components

In nature and engineering, microcompartments -- molecular shells made of proteins that can encapsulate cellular components -- provide a tiny home for important reactions. In bacterial organelles, for example, microcompartments known as carboxysomes trap carbon dioxide and convert it into sugar as an energy source.

These shells naturally buckle into a specialized 20-sided shape called an icosahedron. But now researchers at Northwestern University's McCormick School of Engineering and Applied Science have discovered and explored new shapes of microcompartment shells. Understanding just how these shells form could lead to designed microreactors that mimic the functions of these cell containers or deliver therapeutic materials to cells at specific targeted locations.

The research, led by Monica Olvera de la Cruz, professor of materials science and chemical and biological engineering and chemistry, with Graziano Vernizzi, research assistant professor, and research associate Rastko Sknepnek, was recently published in the Proceedings of the National Academy of Sciences.

Olvera de la Cruz and her group knew how shells made up of just one structural unit worked -- their elasticity and rigidity cause them to naturally buckle into icosahedra. But they began considering how to create heterogenous shells by using more than one component. Using physical concepts, mathematical analysis, and running simulations, they formulated a new model for the spontaneous faceting of shells.

"The question was: if a shell is made up of components that have different rigidities or different mechanical properties, what would be the shape it takes?" Olvera de la Cruz said.

The only faceted shape previously known for molecular closed shells, such as viruses and fullerenes, was the icosahedron. But Olvera de la Cruz and her colleagues discovered that when a shell is made up of two components with different elasticities, they buckle into many different shapes, including dodecahedra (12 sides) and octahedra (8 sides) and irregular polyhedra, which surfaces are "decorated" by the natural segregation of components to yield the lowest energy conformation.

Some of these shapes had been seen in nature before -- sometimes in the bacterial organelles' carboxysomes -- but they were just called "quasi-icosahedra" because nobody knew how to characterize them and how they worked. Armed with their model, however, engineers could now potentially design shells to perform specific tasks.

"If you just want to pack something into a shell, you use a sphere," she said. "But if you want to create a shell that has intelligence and can fit somewhere perfectly because it is decorated with the right proteins, then you can use different shapes."

These designed shells could act as containers or microreactors within the body. "It's a very efficient way to deliver something," she said.

Next the group hopes to determine how general their model is and continue researching how different shapes are made.

"I think it can open a new field of research," Olvera de la Cruz said.

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by Northwestern University, via EurekAlert!, a service of AAAS.

Journal Reference:

G. Vernizzi, R. Sknepnek, M. Olvera de la Cruz. Platonic and Archimedean geometries in multicomponent elastic membranes. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1012872108