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Why have many osteoarthritis investigation therapies failed in human studies? A team of scientists at the Massachusetts Institute of Technology believes the problem lies in the short half-life of the drug in diseased joints. They decided to design a material that could help medications penetrate deeper into the cartilage-producing tissues. They came back with promising results for the animals.
MIT engineers have estimated that many drugs are removed from the joint even before they can reach chondrocytes, cells that produce cartilage. They designed a round "nanocarrier" to overcome this obstacle. The molecule contains many branch-like structures called dendrimers, which are positively charged at their ends. This allows them to bind to the negatively charged cartilage for dissemination, the team explained in the journal Science Translational Medicine.
To help the molecules sink deeper into the tissues, the researchers used a water-loving polymer called PEG that can partially cover the positive charge as they move. In this way, charged molecules can briefly disconnect cartilage and dive deeper into diseased tissue.
"We found an optimal load range so that the material could both bind to the fabric and bind it for subsequent diffusion without being too strong to stick to the surface," said Brett Geiger lead author of the newspaper, in a statement.
The dendrimer nanoparticle is simply the vehicle, although it needs an active therapeutic agent as a passenger. In their study, MIT scientists used an experimental drug called insulin-like growth factor (IGF-1), a protein that stimulates the growth of many tissues, including cartilage. In therapy, it has shown regenerative effects on cartilage in animals.
In models of osteoarthritis in rats, the researchers found that the IGF-1 linked to a nanocarrier had a half-life of about four days, or 10 times longer than the previous one. IGF-1 alone. In addition, the level of drug concentration in the rodent's knee joints remained high enough to produce a therapeutic effect for about 30 days, the team said. This has resulted in better cartilage restoration and a reduction in joint inflammation and bone spurs compared to IGF-1 alone, the team said.
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Several arthritis medications have recently experienced difficulties in advanced clinical trials. Anika Therapeutics' Cingal, intended to treat joint pain due to osteoarthritis, failed in a phase 3 trial comparing this molecule with steroidal triamcinolone hexacetonide. In addition, Regeneron has put an end to the safety concerns of fasinumab, a high dose anti-NGF antibody, in a Phase 3 trial.
MIT researchers hope their technology can one day be used to improve arthritis medications that treat the underlying cartilage problem. Thus, in order to further prove the utility of their method, researchers adopted large animal models. They tested the combined particle in cows with cartilage thicknesses similar to that of humans and observed that the drug could penetrate their cartilage in two days.
"It's a very difficult thing to do. The drugs will usually be eliminated before they can go through much of the cartilage, "said Geiger. "When you begin to think that this technology, derived from rat studies, should be applied to larger animals and, one day, to humans, its ability to succeed depends on its ability to work in cartilage thicker."
For now, the material is being developed to treat osteoarthritis caused by traumatic injury, but the researchers believe that it could also be used in the broader indication related to l & # 39; age. And they plan to associate the carrier with other drugs, such as those that block inflammatory cytokines, DNA or RNA.
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