Single-Dose Intra-Cartilage Delivery of Kartogenin Using a Cationic Multi-Arm Avidin Nanocarrier Suppresses Cytokine-Induced Osteoarthritis-Related Catabolism.
Single-Dose Intra-Cartilage Delivery of Kartogenin Using a Cationic Multi-Arm Avidin Nanocarrier Suppresses Cytokine-Induced Osteoarthritis-Related Catabolism.
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DOI：
10.1177/19476035221093072
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发表时间：
2022-04
期刊：
影响因子：
2.8
通讯作者：
Bajpayee, Ambika G.
中科院分区：
文献类型：
--
作者：
He, Tengfei;Shaw, Irfhan;Vedadghavami, Armin;Bajpayee, Ambika G.
Kartogenin(KGN)已被证明是骨性关节炎(OA)治疗的一种软骨生成和软骨保护药物。然而，作为一种小的疏水分子，KGN关节内给药后关节清除迅速，无法穿透软骨到达软骨细胞。因此，需要多次高剂量，以导致非靶点效应，包括刺激和组织生长。在这里，我们设计了基于电荷的软骨靶向制剂KGN，使用多臂阳离子亲和素纳米结构(MAV)，由于与带负电荷的聚集糖-糖胺聚糖(GAG)的弱可逆静电结合作用，可以在高浓度下快速渗透到软骨中，形成缓释药库，使其治疗效果只需一次剂量就能实现。我们合成了两种新的制剂，一种具有可释放的酯连接物(MAV-OH-KGN，释放半衰期~58h)，可使Kgn在2周内持续释放；另一种具有不可释放的酰胺连接物(MAV-NH-KGN)，依赖于MAV被软骨细胞摄取和内吞的能力来给药。采用软骨移植培养模型，体外评价其抑制细胞因子诱导的分解代谢的效果。在抑制细胞因子诱导的GAG丢失、细胞死亡、炎症反应和挽救细胞代谢方面，单剂100μM的MAV-KGN明显优于单剂游离KGN；需要多次的游离KGN才能匹配这种治疗反应。MAV介导的KGN给药前景看好，可以促进KGN的临床翻译，仅需一剂即可用于治疗骨性关节炎。
Kartogenin (KGN) has proven as a both chondrogenic and chondroprotective drug for osteoarthritis (OA) therapy. However, being a small hydrophobic molecule, KGN suffers from rapid joint clearance and inability to penetrate cartilage to reach chondrocytes following intra-articular administration. As such multiple high doses are needed that can lead to off-target effects including stimulation and tissue outgrowth. Here we design charge-based cartilage targeting formulation of KGN by using a multi-arm cationic nano-construct of Avidin (mAv) that can rapidly penetrate into cartilage in high concentrations owing to weak-reversible electrostatic binding interactions with negatively charged aggrecan-glycosaminoglycans (GAGs) and form an extended-release drug depot such that its therapeutic benefit can be reaped in just a single dose. We synthesized 2 novel formulations, one with a releasable ester linker (mAv-OH-KGN, release half-life ~58 h) that enables sustained KGN release over 2 weeks and another with a non-releasable amide linker (mAv-NH-KGN) that relies on mAv’s ability to be uptaken and endocytosed by chondrocytes for drug delivery. Their effectiveness in suppressing cytokine-induced catabolism was evaluated in vitro using cartilage explant culture model. A single 100 μM dose of cartilage homing mAv-KGN was significantly more effective in suppressing cytokine-induced GAG loss, cell death, inflammatory response and in rescuing cell metabolism than a single dose of free KGN; multiple doses of free KGN were needed to match this therapeutic response. mAv mediated delivery of KGN is promising and can facilitate clinical translation of KGN for OA treatment with only a single dose.
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影响因子：
10.8
作者：
Caliceti, P;Chinol, M;Paganelli, G
通讯作者：
Paganelli, G
影响因子：
7
作者：
Durigova, M.;Roughley, P. J.;Mort, J. S.
通讯作者：
Mort, J. S.
影响因子：
33.7
作者：
Bajpayee, Ambika G.;Grodzinsky, Alan J.
通讯作者：
Grodzinsky, Alan J.
关节内注射卡托根配基聚氨酯纳米粒子可减缓骨关节炎的进展
影响因子：
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作者：
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通讯作者：
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影响因子：
7
作者：
Bajpayee AG;Quadir MA;Hammond PT;Grodzinsky AJ
通讯作者：
Grodzinsky AJ