Sustained-release losartan from peptide nanofibers promotes chondrogenesis.
Sustained-release losartan from peptide nanofibers promotes chondrogenesis.
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DOI：
10.3389/fbioe.2023.1122456
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发表时间：
2023
影响因子：
5.7
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中科院分区：
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前言：骨关节炎的主要病理特征是关节软骨进行性丧失，再生能力有限。转化生长因子-β-1抑制剂氯沙坦可以通过促进玻璃化而不是纤维软骨组织再生来促进软骨修复。然而，也有人担心在关节内注射后口服给药和关节内短暂滞留相关的副作用。为了促进局部和持续的关节内给药，我们设计了一种结合氯沙坦的可注射多肽两亲性(PA)纳米纤维。本研究的目的是表征氯沙坦在两种不同的PA纳米纤维组合物中的释放动力学，然后测试对软骨细胞的促再生生物活性。方法：我们测试了静电相互作用对带正电或带负电的PA纳米纤维中带负电的氯沙坦分子的纳米结构、形态和释放动力学的影响。随后，使用ATDC5对正常和IL-1β诱导的骨性关节炎软骨细胞模型进行了体外细胞毒性和生物活性的评估。结果：两种纳米纤维系统都能促进细胞增殖，但带正电荷的纳米纤维也显著增加了糖胺多糖的产量。此外，基因表达分析表明，在这个体外系统中，氯沙坦包裹的纳米纤维通过显著阻断转化生长因子-β1而具有显著的抗炎、抗退变和软骨再生作用。讨论：本研究的结果表明，带正电的氯沙坦缓释纳米纤维可能是一种通过阻断转化生长因子-β1来治疗软骨再生和骨性关节炎的新的有效方法。
Introduction: The central pathologic feature of osteoarthritis (OA) is the progressive loss of articular cartilage, which has a limited regenerative capacity. The TGF-β1 inhibitor, losartan, can improve cartilage repair by promoting hyaline rather that fibrous cartilage tissue regeneration. However, there are concerns about side effects associated with oral administration and short retention within the joint following intra-articular injections. To facilitate local and sustained intra-articular losartan delivery we have designed an injectable peptide amphiphile (PA) nanofiber that binds losartan. The aims of this study are to characterize the release kinetics of losartan from two different PA nanofiber compositions followed by testing pro-regenerative bioactivity on chondrocytes. Methods: We tested the impact of electrostatic interactions on nanostructure morphology and release kinetics of the negatively charged losartan molecule from either a positively or negatively charged PA nanofiber. Subsequently, cytotoxicity and bioactivity were evaluated in vitro in both normal and an IL-1β-induced OA chondrocyte model using ATDC5. Results: Both nanofiber systems promoted cell proliferation but that the positively-charged nanofibers also significantly increased glycosaminoglycans production. Furthermore, gene expression analysis suggested that losartan-encapsulated nanofibers had significant anti-inflammatory, anti-degenerative, and cartilage regenerative effects by significantly blocking TGF-β1 in this in vitro system. Discussion: The results of this study demonstrated that positively charged losartan sustained-release nanofibers may be a novel and useful treatment for cartilage regeneration and OA by blocking TGF-β1.