Then researchers—with the ultimate goal of treatment after injury to prevent osteoarthritis—coupled dexamethasone with avidin and delivered the drug in vitro, using polyethylene glycol (PEG), the polymer most commonly used for drug delivery. They used both an ester linker, for faster release, and a hydrazone linker for slower release.4
“You have the ability to combine both fast release and slow release so you can get an early bolus release as soon as the avidin drags the dex in, and then a slower release during the subsequent time,” Dr. Grodzinsky said.
Cartilage explants were placed in a culture with inflammatory cytokines, and the solutions were injected with soluble dexamathesone; or avidin-dexamethasone with an ester linker; or avidin plus dexamethasone with hydrazone linker; or the avidin-dexamethasone-ester and avidin-dexamethasone-hydrazone in a 1:1 molar ratio. They found that the version with the best suppression of sulfated glycosaminoglycan (GAG) was the 1:1 combination.
“The concept is enhanced transport into the tissue because of charge, and then binding inside,” he said. “We’re now taking this into an animal and then going from there.”
Nanotubes
Massimo Bottini, PhD, associate professor of biochemistry at the University of Rome Tor Vergata, Rome, Italy, and adjunct assistant professor at the La Jolla-based Sanford Burnham Prebys Medical Discovery Institute, said there appears to be promise in the use of carbon nanotubes for intra-articular delivery of drugs straight to chondrocytes. In osteoarthritis (OA), chondrocytes have switched to a catabolic state. And the idea is to reestablish the balance between the anabolic and catabolic states by delivering gene inhibitors and/or gene activators.
Carbon nanotubes are very small cylindrical particles—as small as about 1 nanometer in diameter—that are known for their strength as well as their elasticity and conductivity. At Dr. Bottini’s center, researchers have tweaked them, including making them shorter and outfitting them with PEG, to make them biocompatible, biodegradable and more suitable to deliver their cargo of morpholino antisense oligonucleotides (mASO), used for gene inhibition.
Researchers found that, with just a single injection, the nanotubes were able to penetrate the dense cartilage extracellular matrix, translocate into the cytoplasm of the chondrocytes and deliver mASO—and had staying power once delivered.4
“Nanotubes persisted in the joint for more than 15 days in both healthy and OA rats,” Dr. Bottini said. “Importantly, they did not accumulate in major organs nor worsened OA per se.”
“There is still much room for improvement with the use of nanoparticles in drug delivery—particularly by specifically identifying ligands and receptors that could help promote particle and drug transport,” he said.
