Scientists have developed a new system for delivering drugs to cartilage in which the drug, in this case a glucocorticoid, is linked to a peptide found in the venom of scorpions. In a rat model of arthritis, this drug conjugate could reverse signs of arthritis without evidence of glucocorticoid-related systemic toxicity.

Cystine-dense peptides (CDPs) are a family a miniproteins found in a wide variety of species and are often used for predation or protection. In a biodistribution screen of 42 CDPs from 20 species, the researchers identified a group of CDPs that accumulate and persist for several days in the cartilage of rats and mice. They hypothesized that these molecules could be used to deliver drugs for the treatment of arthritis.

Further experiments found that they could conjugate one of the cartilage-accumulating CDPs, CDP-11R, to a fluorophore or dexamethasone, without substantially altering its localization to cartilage. The researchers made further amendments to the drug conjugate by introducing a labile linker that hydrolyses at a desirable rate in the plasma, on the expectation that steric hindrance could otherwise prevent the therapeutic effects of the conjugated drug.

“Unfortunately, the small amounts of dexamethasone that made it into the bloodstream were sufficient to cause adverse effects that we considered unacceptable for long-term treatment,” explains James Olson, corresponding author of the new study. “We switched to triamcinolone acetonide (TAA) as the payload because TAA is rapidly metabolized to an inactive metabolite in the bloodstream.” In rats with collagen-induced arthritis, various doses of the CDP-11R–TAA conjugate could reduce inflammation in the arthritic joints, without signs of systemic adverse effects (such as atrophy of the spleen or thymus).

“Our vision is to create a version of this drug candidate that patients would administer to themselves infrequently,” explains Olson. “We hope that such a drug could provide arthritis relief with no or few adverse effects.”