Why have many investigative osteoarthritis therapies flunked human studies? A team of scientists at the Massachusetts Institute of Technology believe that the problem lies in the drugs’ short half-life in diseased joints. So they set out to design a material that could help drugs penetrate deeper into cartilage-generating tissues, and they’ve returned with promising animal results.
The MIT engineers figured many drugs are washed away from the joint before they can even reach chondrocytes, which are cells that produce cartilage. They designed a round-shaped “nanocarrier” to overcome that barrier. The molecule contains many branch-like structures called dendrimers, which are positively charged at their tips. That allows them to bind to the negatively charged cartilage for diffusion, the team explained in the journal Science Translational Medicine.
To help the molecules move deeper into the tissue, the researchers employed a water-loving polymer called PEG that can partially cover the positive charge as they move. In that way, the charged molecules can briefly disconnect from the cartilage and dive deeper into diseased tissues.
“We found an optimal charge range so that the material can both bind the tissue and unbind for further diffusion, and not be so strong that it just gets stuck at the surface,” Brett Geiger, the paper’s lead author, said in a statement.
The dendrimer nanoparticle is merely the vehicle, though, in need of an active therapeutic as its passenger. In their study, the MIT scientists used an experimental drug called insulin-like growth factor 1 (IGF-1), which is a protein that stimulates the growth of many tissues, including cartilage. As a therapeutic, it has shown cartilage-regenerative effects in animals.
In rat models of osteoarthritis, the researchers found that the nanocarrier-attached IGF-1 had a half-life of about four days, which is 10 times longer than IGF-1 alone. Furthermore, the concentration level of the drug in the rodents’ knee joints remained high enough to deliver a therapeutic effect for about 30 days, the team reported. That translated into better cartilage restoration, and reductions in joint inflammation and bone spurs, as compared to IGF-1 alone, said the team.
Several arthritis drugs have recently struggled in late-stage clinical tests. Anika Therapeutics’ Cingal, which is meant to manage osteoarthritis joint pain, failed in a phase 3 trial comparing it to the steroid triamcinolone hexacetonide. And Regeneron halted the high-dose arms of a phase 3 trial of its anti-NGF antibody fasinumab over safety concerns.
The MIT researchers hope their technology could one day be used to improve arthritis drugs that treat the underlying cartilage problem. So in an effort to further prove the utility of their method, the researchers have moved to large-animal models. They tested the combo particle in cows, which have cartilage that's similar in thickness to that of people, and observed that the drug could penetrate their cartilage in two days.
“That is a very hard thing to do. Drugs typically will get cleared before they are able to move through much of the cartilage,” Geiger said. “When you start to think about translating this technology from studies in rats to larger animals and someday humans, the ability of this technology to succeed depends on its ability to work in thicker cartilage.”
For now, the material is being developed to treat osteoarthritis caused by traumatic injury, but the researchers believe it could be used in the larger age-related indication as well. And they’re planning to pair the carrier with other drugs, such as those that block inflammatory cytokines, DNA or RNA.