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Patricia Van Arnum was executive editor of Pharmaceutical Technology.
Nanotechnology often is associated with parenteral drug delivery, particularly for anticancer therapies, but it also has applications in oral drug delivery
Nanotechnology often is associated with parenteral drug delivery, particularly for anticancer therapies, but it also has applications in oral drug delivery. Some recent developments show the potential of nanotechnology through this route of administration.
Researchers at the Georgia Institute of Technology (Georgia Tech) and Emory University recently developed a novel approach for delivering small bits of genetic material into the body to improve the treatment of inflammatory bowel diseases, according to an Oct. 10, 2010 Georgia Tech press release. Delivering short strands of RNA into cells has potential therapeutic applications, but delivering them into targeted cells in a living organism has been an obstacle.
In their work, the researchers encapsulated short pieces of RNA into engineered particles called thioketal nanoparticles and orally delivered the genetic material directly to the inflamed intestines of animals. "The thioketal nanoparticles we designed are stable in both acids and bases and only break open to release the pieces of RNA in the presence of reactive oxygen species, which are found in and around inflamed tissue in the gastrointestinal tract of individuals with inflammatory bowel diseases," said Niren Murthy, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, in the Georgia Tech press release. This work was done in collaboration with Emory University Division of Digestive Diseases professor Shanthi Sitaraman, associate professor Didier Merlin, and postdoctoral fellow Guillaume Dalmasso.
The thioketal nanoparticles protect the small interfering RNAs (siRNAs) from the harsh environment of the gastrointestinal tract and target them directly to the inflamed intestinal tissues. This localized approach is necessary because siRNAs can cause major side effects if injected systemically. The researchers reported that the thioketal nanoparticles were formulated from a new polymer—poly-(1,4-phenyleneacetone dimethylene thioketal)—and engineered to have a diameter of approximately 600 nm for optimal oral delivery (1).
For their experiments, the researchers used a mouse model of ulcerative colitis. The researchers orally administered thioketal nanoparticles loaded with siRNA that inhibits an inflammation-promoting cytokine called tumor necrosis factor–alpha. The nanoparticles traveled directly to the mouse colons, where reactive oxygen species were being produced in excess, and decreased the cytokine production levels there. Tissue samples from the colons treated with siRNA delivered by these thioketal nanoparticles exhibited intact epitheliums, well-defined, fingerlike "crypt" structures, and low levels of inflammation—signs that the colon was protected against ulcerative colitis.
"Since ulcerative colitis is restricted to the colon, these results confirm that the siRNA-loaded thioketal nanoparticles remain stable in noninflamed regions of the gastrointestinal tract while targeting siRNA to inflamed intestinal tissues," explained Scott Wilson, a graduate student in the Georgia Tech School of Chemical and Biomolecular Engineering, in the press release.
The researchers showed that thioketal nanoparticles have the chemical and physical properties needed to overcome the obstacles of gastrointestinal fluids, intestinal mucosa, and cellular barriers to provide therapy to inflamed intestinal tissues. The researchers are currently working on increasing the degradation rate of the nanoparticles and enhancing their reactivity with reactive oxygen species. The team also plans to conduct a biodistribution study to detail how the nanoparticles travel through the body.
"Polymer toxicity is something we'll have to investigate further, but during this study, we discovered that thioketal nanoparticles loaded with siRNA have a cell-toxicity profile similar to nanoparticles formulated from the FDA-approved material poly(lactic-co-glycolic acid)," said Murthy in the press release. In the future, thioketal nanoparticles may become a significant player in the treatment of numerous gastrointestinal diseases linked to intestinal inflammation, including gastrointestinal cancers, inflammatory bowel diseases and viral infections, according to Murthy.
In other work, researchers from the University of Texas at Austin used nanoparticles in oral drug delivery to the colon. They noted that oral drug delivery to the colon is a difficult, but desirable method of administration. A dosage form to the colon must overcome several challenges, including barriers in the gastrointestinal tract. These challenges may include a steep pH gradient, binding to the mucus layer, premature clearance, and premature cellular uptake. The researchers reported on nanoparticles that have been designed to address these problems. These areas include drug entrapment with particle coating, surface modification, drug adhesion to a nanoparticle surface, and nanogel systems to target drug delivery to the colon following oral administration. Nanoparticles may be further used to target specific cells in the colon, such as tumor cells or inflamed tissues (2). Converting a drug powder into nanoparticles can often solubilize a compound that is poorly soluble in water or increase bioavailability through an increase in the surface-area-to-volume ratio. Smaller particles mean a bigger surface area to interact with absorbing surfaces in the gastrointestinal tract.
In addition to advancing oral drug delivery, nanotechnology can play an important role in all routes of administration by addressing specific problems, such as poor solubility. Poor solubility is particularly problematic when developing anticancer therapeutics because the goal is to achieve clinical efficacy while limiting the dosage of chemotherapeutic agents. To address this issue, researchers at Northwestern University in Evanston, Illinois, recently used nanodiamond-mediated delivery for several water-insoluble drugs. In their study, the researchers reported that nanodiamonds enhanced the water dispersion of three anticancer agents: purvalanol A, a treatment for liver cancer; 4-hydroxytamoxifen, a drug to treat breast cancer; and dexamethasone, an antiflammatory agent to treat complications from certain types of cancer (3, 4).
The researchers showed that the water-insoluble compounds interact with the nanodiamonds, a biocompatible material, and form complexes that disperse the drug in water for sustained periods of time, while maintaining the functionality of the drug. Nanodiamonds are a class of nanomaterials, 4–6 nm in diameter in single-particle form, that can be manipulated to form clusters with diameters in the range of 50–100 nm. This composition makes them suitable for drug delivery by shielding and slowly releasing drugs that are trapped with the clusters of the diamond aggregates. Benefits in drug delivery from the nanodiamond cluster include the capability of trapping more drug in the nanodiamond cluster compared with conventional drug-delivery methods and easy dissolution of the nanodiamond in water. Nanodiamonds' surfaces are functionalized with carboxyl groups that promote their dispersibility in water.
1. D.S. Wilson et al., Nat. Mater. 9 (11), 923–928 (2010).
2. K. O' Donnell and R.O. Williams, Int. J. Nanotechnol. 8 (1–2), 4–20 (2011).
3. P. Van Arnum, Pharm. Technol. 34 (1), 48 (2010)
4. D. Ho et al., ACS Nano 3 (7), 2016–2022 (2009).