A potent peptide-steroid conjugate accumulates in cartilage and reverses arthritis without evidence of systemic corticosteroid exposure.

Science Translational Medicine
Michelle L Cook SangarJames M Olson

Abstract

On-target, off-tissue toxicity limits the systemic use of drugs that would otherwise reduce symptoms or reverse the damage of arthritic diseases, leaving millions of patients in pain and with limited physical mobility. We identified cystine-dense peptides (CDPs) that rapidly accumulate in cartilage of the knees, ankles, hips, shoulders, and intervertebral discs after systemic administration. These CDPs could be used to concentrate arthritis drugs in joints. A cartilage-accumulating peptide, CDP-11R, reached peak concentration in cartilage within 30 min after administration and remained detectable for more than 4 days. Structural analysis of the peptides by crystallography revealed that the distribution of positive charge may be a distinguishing feature of joint-accumulating CDPs. In addition, quantitative whole-body autoradiography showed that the disulfide-bonded tertiary structure is critical for cartilage accumulation and retention. CDP-11R distributed to joints while carrying a fluorophore imaging agent or one of two different steroid payloads, dexamethasone (dex) and triamcinolone acetonide (TAA). Of the two payloads, the dex conjugate did not advance because the free drug released into circulation was sufficient to cause ...Continue Reading

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Citations

Jul 23, 2020·Scientific Reports·Erica K WagnerAmbika G Bajpayee
Apr 4, 2020·Nature Reviews. Rheumatology·Jessica McHugh
Aug 29, 2020·Bioelectricity·Shreedevi Kumar, Blanka Sharma
Aug 18, 2020·Bioelectricity·Cameron C YoungAmbika G Bajpayee
Apr 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Amy McDermott
Aug 12, 2020·Journal of Biomedical Materials Research. Part a·Lina M Mancipe CastroRobert E Guldberg
Mar 13, 2021·Advanced Therapeutics·Carlisle R DeJuliusCraig L Duvall
Apr 4, 2021·Biomedicines·Natallia V DubashynskayaYury A Skorik
Aug 25, 2020·ACS Pharmacology & Translational Science·Seow Theng OngK George Chandy
Nov 6, 2021·ACS Nano·Lei LiuYang Li

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