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Cationic peptide carriers enable long-term delivery of insulin-like growth factor-1 to suppress osteoarthritis-induced matrix degradation
Arthritis Research & Therapy ( IF 4.4 ) Pub Date : 2022-07-20 , DOI: 10.1186/s13075-022-02855-1
Armin Vedadghavami 1 , Bill Hakim 1 , Tengfei He 1 , Ambika G Bajpayee 1, 2
Affiliation  

Insulin-like growth factor-1 (IGF-1) has the potential to be used for osteoarthritis (OA) treatment but has not been evaluated in clinics yet owing to toxicity concerns. It suffers from short intra-joint residence time and a lack of cartilage targeting following its intra-articular administration. Here, we synthesize an electrically charged cationic formulation of IGF-1 by using a short-length arginine-rich, hydrophilic cationic peptide carrier (CPC) with a net charge of +14, designed for rapid and high uptake and retention in both healthy and arthritic cartilage. IGF-1 was conjugated to CPC by using a site-specific sulfhydryl reaction via a bifunctional linker. Intra-cartilage depth of penetration and retention of CPC-IGF-1 was compared with the unmodified IGF-1. The therapeutic effectiveness of a single dose of CPC-IGF-1 was compared with free IGF-1 in an IL-1α-challenged cartilage explant culture post-traumatic OA model. CPC-IGF-1 rapidly penetrated through the full thickness of cartilage creating a drug depot owing to electrostatic interactions with negatively charged aggrecan-glycosaminoglycans (GAGs). CPC-IGF-1 remained bound within the tissue while unmodified IGF-1 cleared out. Treatment with a single dose of CPC-IGF-1 effectively suppressed IL-1α-induced GAG loss and nitrite release and rescued cell metabolism and viability throughout the 16-day culture period, while free IGF at the equivalent dose was not effective. CPC-mediated depot delivery of IGF-1 protected cartilage by suppressing cytokine-induced catabolism with only a single dose. CPC is a versatile cationic motif that can be used for intra-cartilage delivery of other similar-sized drugs.

中文翻译:


阳离子肽载体能够长期输送胰岛素样生长因子-1,以抑制骨关节炎引起的基质降解



胰岛素样生长因子-1 (IGF-1) 有潜力用于骨关节炎 (OA) 治疗,但由于毒性问题尚未在临床中进行评估。它的缺点是关节内停留时间短,并且在关节内给药后缺乏软骨靶向。在这里,我们使用净电荷为 +14 的短长度富含精氨酸的亲水性阳离子肽载体 (CPC) 合成了 IGF-1 的带电阳离子制剂,专为健康和健康人群的快速、高吸收和保留而设计。关节炎软骨。 IGF-1 通过双功能接头使用位点特异性巯基反应与 CPC 缀合。将 CPC-IGF-1 的软骨内渗透深度和保留量与未修饰的 IGF-1 进行比较。在 IL-1α 攻击的软骨外植体培养的创伤后 OA 模型中,比较了单剂量 CPC-IGF-1 与游离 IGF-1 的治疗效果。由于与带负电的聚集蛋白聚糖-糖胺聚糖 (GAG) 的静电相互作用,CPC-IGF-1 迅速渗透整个软骨厚度,形成药物库。 CPC-IGF-1 仍结合在组织内,而未修饰的 IGF-1 则被清除。单剂量的 CPC-IGF-1 治疗可有效抑制 IL-1α 诱导的 GAG 损失和亚硝酸盐释放,并在整个 16 天培养期内挽救细胞代谢和活力,而同等剂量的游离 IGF 则无效。 CPC 介导的 IGF-1 储库递送仅通过单剂量抑制细胞因子诱导的分解代谢来保护软骨。 CPC 是一种多功能阳离子基序,可用于软骨内输送其他类似大小的药物。
更新日期:2022-07-20
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