Sustained intra-cartilage delivery of interleukin-1 receptor antagonist using cationic peptide and protein-based carriers.
Sustained intra-cartilage delivery of interleukin-1 receptor antagonist using cationic peptide and protein-based carriers.
复制标题
使用阳离子肽和基于蛋白质的载体持续软骨内递送白细胞介素 1 受体拮抗剂。
DOI：
10.1016/j.joca.2023.01.573
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发表时间：
2023
影响因子：
7
通讯作者：
Bajpayee,AG
中科院分区：
文献类型：
--
作者：
Mehta,S;Boyer,TL;Akhtar,S;He,T;Zhang,C;Vedadghavami,A;Bajpayee,AG
IL-1受体拮抗剂IL-1 Ra可阻断关节创伤后白细胞介素-1（IL-1）分解代谢级联反应。然而，由于其快速关节清除以及在治疗浓度下缺乏靶向和渗透到深层软骨层，其用于骨关节炎治疗的临床转化一直不成功。在这里，我们通过将阳离子载体连接到IL-1 Ra来靶向软骨聚集蛋白聚糖-糖胺聚糖（GAG）的高负电荷。IL-1 Ra与软骨靶向糖蛋白、抗生物素蛋白和短长度的最佳电荷阳离子肽载体（CPC+14）缀合。假设IL-1 Ra-抗生物素蛋白和IL-1 Ra-CPC +14的电扩散转运和结合特性将产生IL-1 Ra的软骨内储库，导致仅用单次施用长期抑制IL-1催化剂。和质谱分析。将缀合物的软骨内转运和保留与天然IL-1 Ra进行比较。采用IL-1α刺激的牛软骨，观察一次性IL-1 Ra-CPC +14和IL-1 Ra-Avidin对IL-1分解代谢信号的抑制作用，并与未修饰的IL-1 Ra进行比较。单剂量未修饰的IL-1 Ra不足以在16天内减弱IL-1诱导的软骨退化。然而，当使用抗生物素蛋白，并在更大程度上CPC+14，IL-1 Ra显着抑制细胞因子诱导的GAG损失和亚硝酸盐释放，同时提高细胞代谢和viability.ConclusionCharge-based软骨靶向药物递送系统持有承诺，因为它们可以使长期的治疗效益，只有一个单一的剂量。
ObjectiveBlocking the interleukin-1 (IL-1) catabolic cascade following joint trauma can be achieved using its receptor antagonist, IL-1Ra. However, its clinical translation for osteoarthritis therapy has been unsuccessful due to its rapid joint clearance and lack of targeting and penetration into deep cartilage layers at therapeutic concentrations. Here, we target the high negative charge of cartilage aggrecan-glycosaminoglycans (GAGs) by attaching cationic carriers to IL-1Ra. IL-1Ra was conjugated to the cartilage targeting glycoprotein, Avidin, and a short length optimally charged cationic peptide carrier (CPC+14). It is hypothesized that electro-diffusive transport and binding properties of IL-1Ra-Avidin and IL-1Ra-CPC+14 will create intra-cartilage depots of IL-1Ra, resulting in long-term suppression of IL-1 catabolism with only a single administration.DesignIL-1Ra was conjugated to Avidin or CPC+14 using site specific maleimide linkers, and confirmed using gel electrophoresis, high-performance liquid chromatography (HPLC), and mass spectrometry. Intra-cartilage transport and retention of conjugates was compared with native IL-1Ra. Attenuation of IL-1 catabolic signaling with one-time dose of IL-1Ra-CPC+14 and IL-1Ra-Avidin was assessed over 16 days using IL-1α challenged bovine cartilage and compared with unmodified IL-1Ra.ResultsPositively charged IL-1Ra penetrated through the full-thickness of cartilage, creating a drug depot. A single dose of unmodified IL-1Ra was not sufficient to attenuate IL-1-induced cartilage deterioration over 16 days. However, when delivered using Avidin, and to a greater extent CPC+14, IL-1Ra significantly suppressed cytokine induced GAG loss and nitrite release while improving cell metabolism and viability.ConclusionCharge-based cartilage targeting drug delivery systems hold promise as they can enable long-term therapeutic benefit with only a single dose.