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 on-target toxicity. In contrast, the CDP-11R–TAA conjugate alleviated joint inflammation in the rat collagen–induced model of rheumatoid arthritis while avoiding toxicities that occurred with nontargeted steroid treatment at the same molar dose. This conjugate shows promise for clinical development and establishes proof of concept for multijoint targeting of disease-modifying therapeutic payloads.

靶向性、组织外毒性限制了药物的全身使用，否则这些药物会减轻症状或逆转关节炎疾病的损害，使数百万患者处于疼痛之中，身体活动受限。我们鉴定了在全身给药后迅速积聚在膝盖、脚踝、臀部、肩部和椎间盘的软骨中的胱氨酸致密肽 (CDP)。这些 CDP 可用于在关节中浓缩关节炎药物。软骨积聚肽 CDP-11R 在给药后 30 分钟内达到软骨中的峰值浓度，并且可检测到超过 4 天。通过晶体学对肽的结构分析表明，正电荷的分布可能是联合积累 CDP 的一个显着特征。此外，定量全身放射自显影显示二硫键三级结构对于软骨的积累和保留至关重要。CDP-11R 分布到关节，同时携带荧光团显像剂或两种不同的类固醇有效载荷之一，地塞米松 (dex) 和曲安奈德 (TAA)。在这两种有效载荷中，dex 偶联物没有前进，因为释放到循环中的游离药物足以引起靶向毒性。相比之下，CDP-11R-TAA 偶联物减轻了大鼠胶原诱导的类风湿关节炎模型中的关节炎症，同时避免了相同摩尔剂量下非靶向类固醇治疗所产生的毒性。该偶联物显示出临床开发的前景，并为多联合靶向疾病修饰治疗有效载荷建立了概念证明。