Protein, RNA, DNA: Nanotechnology finds a multitude of paths to attack cancer cells

Nanoparticles designed to deliver drugs for cancer therapy made from nanoporous silica or from HDL cholesterol have been highlighted in recent posts. As evidence for the variety of approaches under development, these three items concern three different types of nanoparticles based respectively on protein, RNA, and DNA. In the first of these, cytoplasmic vaults, large structures of protein with some small RNA molecules, found in the cytoplasm of most eukaryotes, have been engineered to encapsulate large cargoes of toxic and water-insoluble drugs and deliver them into cancer cells. points to this UCLA news release: “Scientists engineer nanoscale vaults to encapsulate ‘nanodisks’ for drug delivery

… 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 (and currently available online [abstract]), 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. …

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.” …

In a major advance for the nascent field of RNA nanotechnology, nanoparticles composed solely of chemically modified RNA were assembled, found to survive circulation in the bloodstream, be non-toxic and non-immunogenic, internalize into cancer cells specifically, and silence expression of cancer-promoting genes. points to this Univerity of Cincinnati news release “Researchers Construct RNA Nanoparticles to Safely Deliver Long-Lasting Therapy to Cells“:

Nanotechnology researchers have known for years that RNA, the cousin of DNA, is a promising tool for nanotherapy, in which therapeutic agents can be delivered inside the body via nanoparticles. But the difficulties of producing long-lasting, therapeutic RNA that remains stable and non-toxic while entering targeted cells have posed challenges for their progress.

In two new publications in the journal Molecular Therapy, University of Cincinnati (UC) biomedical engineering professor Peixuan Guo, PhD, details successful methods of producing large RNA nanoparticles and testing their safety in the delivery of therapeutics to targeted cells.

The articles, in advance online publication, represent “two very important milestones in RNA nanotherapy,” says Guo.

“One problem in RNA therapy is the requirement for the generation of relatively large quantities of RNA,” he says. “In this research [abstract], we focused on solving the most challenging problem of industry-scale production of large RNA molecules by a bipartite approach, finding that pRNA can be assembled from two pieces of smaller RNA modules.” …

In his most recent research, Guo and colleagues detail multiple approaches for the construction of a functional 117-base pRNA molecule containing small interfering RNA (siRNA). siRNA has already been shown to be an efficient tool for silencing genes in cells, but previous attempts have produced chemically modified siRNA lasting only 15-45 minutes in the body and often inducing undesired immune responses.

“The pRNA particles we constructed to harbor siRNA have a half life of between five and 10 hours in animal models, are non-toxic and produce no immune response,” says Guo [abstract]. “The tenfold increase of circulation time in the body is important in drug development and paves the way towards clinical trials of RNA nanoparticles as therapeutic drugs.”

Guo says the size of the constructed pRNA molecule is crucial for the effective delivery of therapeutics to diseased tissues.

RNA nanoparticles must be within the range of 15 to 50 nanometers,” he says, “large enough to be retained by the body and not enter cells randomly, causing toxicity, but small enough to enter the targeted cells with the aid of cell surface receptions.…

Previous studies have encased therapeutic siRNA in a polymer coating or liposome for delivery to cells.

“To our knowledge, this is the first naked RNA nanoparticles to have been comprehensively examined pharmacologically in vivo and demonstrated to be safe, as well as deliver itself to tumor tissues by a specific targeting mechanism,” he says. “It suggests that the pRNA nanoparticles without coating have all the preferred pharmacological features to serve as an efficient nanodelivery platform for broad medical applications.”

Finally Y-shaped DNA molecules can assemble into core-shell structures that incorporate defined functions into engineered molecules. points to this Cornell University article by Bill Steele “‘DNAsomes’ can deliver multiple drugs or genetic therapy

DNA isn’t just for genetics anymore. Cornell researchers are using synthetic DNA to make nanoparticles, dubbed DNAsomes, that can deliver drugs and genetic therapy to the insides of cells.

Dan Luo, professor of biological and environmental engineering, and colleagues report their work in the Jan. 3 issue of the journal Small [abstract, free PDF].

DNAsomes, Luo said, can carry multiple drugs as well as RNA molecules designed to block the expression of genes, an improvement over other drug-delivery systems such as liposomes (tiny wrappers of the phospholipid molecules that make up cell membranes) or polymer nanoparticles. Also, some other delivery systems can be toxic to cells, the researchers said.

In its natural habitat in the nucleus of a cell, DNA consists of long chain molecules that are complementary, attaching to one another like a string of Lego blocks over their entire length to form the famous double helix. The Luo research group creates short chains of synthetic DNA designed to attach over only part of their length so they will join into shapes like crosses, Ts or Ys.

DNAsomes are assembled from Y-shaped units, each made up of three strands of DNA. A lipid molecule is attached to the tail of the Y, and drugs to be delivered are chemically bonded to the arms. When the goal is to block the expression of genes with molecules of siRNA (small interfering RNA), the synthetic DNA can be designed with a section complementary to the RNA so that the RNA will loosely attach to it. Delivering siRNA has been a particular challenge for other drug-delivery systems, the researchers noted.

In water solution, the combination of DNA, which is attracted to water molecules, and lipids, which are repelled by water, causes the Y units to self-assemble into hollow spheres from 100 to 5,000 nanometers in diameter, consisting of multiple layers of DNA, lipid and cargo.

“The beauty of this is that the body of the thing is also a body of drugs,” Luo said. About the size of a virus, the DNAsome will be engulfed by the cell membrane and taken into a cell in a similar way as a virus, he explained. The DNAsome can be tagged with molecules that target a particular kind of cell, such as a cancer cell. …

The variety of very different molecular architectures that these researchers have engineered to meet similar purposes illustrates the richness of the toolkit that nanotechnology is providing to satisfy major unmet medical needs.

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