Trauma Medical Center, Department of Orthopaedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Investigation performed at Department of Orthopaedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Am J Sports Med. 2023 Nov;51(13):3533-3545. doi: 10.1177/03635465231198501. Epub 2023 Oct 7.
The inhibition of IKKβ by the inhibitor 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridine carbonitrile (ACHP) is a promising strategy for the treatment of Achilles tendinopathy. However, the poor water solubility of ACHP severely hinders its in vivo application. Moreover, the effective local delivery of ACHP to the tendon and its therapeutic effects have not been reported.
To investigate the therapeutic effects of IKKβ inhibition via injection of ACHP incorporated into a DNA supramolecular hydrogel in a collagenase-induced tendinopathy rat model.
Controlled laboratory study.
Dendritic DNA, a Y-shaped monomer, and a crosslinking monomer were mixed with ACHP and self-assembled into an ACHP-DNA supramolecular hydrogel (ACHP-Gel). The effects of ACHP-Gel in tendon stem/progenitor cells were investigated via RNA sequencing and validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A total of 120 collagenase-induced rats were randomly assigned to 5 groups: blank, phosphate-buffered saline (PBS), DNA-Gel, ACHP, and ACHP-Gel. Healing outcomes were evaluated using biomechanic and histologic evaluations at 4 and 8 weeks.
ACHP-Gel enhanced the solubility of ACHP and sustained its release for ≥21 days in vivo, which significantly increased the retention time of ACHP and markedly reduced the frequency of administration. RNA sequencing and qRT-PCR showed that ACHP effectively downregulated genes related to inflammation and extracellular matrix remodeling and upregulated genes related to tenogenic differentiation. The cross-sectional area ( = .024), load to failure ( = .002), stiffness ( = .039), and elastic modulus ( = .048) significantly differed between the ACHP-Gel and PBS groups at 8 weeks. The ACHP-Gel group had better histologic scores than the ACHP group at 4 ( = .042) and 8 weeks ( = .009). Type I collagen expression (COL-I; = .034) and the COL-I/collagen type III ratio ( = .015) increased while interleukin 6 expression decreased ( < .001) in the ACHP-Gel group compared with the ACHP group at 8 weeks.
DNA supramolecular hydrogel significantly enhanced the aqueous solubility of ACHP and increased its release-retention time. Injection frequency was markedly reduced. ACHP-Gel suppressed inflammation in Achilles tendinopathy and promoted tendon healing in a rat model.
ACHP-Gel injection is a promising strategy for the treatment of Achilles tendinopathy in clinical practice.
通过使用 IKKβ 抑制剂 2-氨基-6-[2-(环丙甲氧基)-6-羟基苯基]-4-(4-哌啶基)-3-吡啶甲腈（ACHP）抑制 IKKβ 是治疗跟腱病的一种很有前途的策略。然而，ACHP 的水溶性差严重阻碍了其在体内的应用。此外，ACHP 向肌腱的有效局部递送及其治疗效果尚未报道。
研究通过将 ACHP 掺入胶原蛋白酶诱导的腱病大鼠模型中的 DNA 超分子水凝胶中抑制 IKKβ 的治疗效果。
对照实验室研究。
树枝状 DNA、Y 形单体和交联单体与 ACHP 混合并自组装成 ACHP-DNA 超分子水凝胶（ACHP-Gel）。通过 RNA 测序研究 ACHP-Gel 对肌腱干细胞/祖细胞的影响，并通过定量逆转录聚合酶链反应（qRT-PCR）进行验证。总共 120 只胶原蛋白酶诱导的大鼠被随机分为 5 组：空白组、磷酸盐缓冲盐水（PBS）组、DNA-Gel 组、ACHP 组和 ACHP-Gel 组。在 4 周和 8 周时，通过生物力学和组织学评估来评估愈合结果。
ACHP-Gel 提高了 ACHP 的溶解度，并在体内持续释放≥21 天，这显著增加了 ACHP 的保留时间并大大减少了给药频率。RNA 测序和 qRT-PCR 表明，ACHP 可有效下调与炎症和细胞外基质重塑相关的基因，并上调与肌腱分化相关的基因。8 周时，ACHP-Gel 组与 PBS 组的横截面积（ =.024）、失效负荷（ =.002）、刚度（ =.039）和弹性模量（ =.048）差异有统计学意义。4 周和 8 周时，ACHP-Gel 组的组织学评分均优于 ACHP 组（ =.042 和 =.009）。与 ACHP 组相比，ACHP-Gel 组在 8 周时的 I 型胶原表达（COL-I； =.034）和 COL-I/III 胶原比（ =.015）增加，而白细胞介素 6 表达减少（<.001）。
DNA 超分子水凝胶显著提高了 ACHP 的水溶解度并增加了其释放保留时间。给药频率明显降低。ACHP-Gel 抑制了跟腱病的炎症反应，并促进了大鼠模型中的肌腱愈合。
ACHP-Gel 注射是一种很有前途的治疗跟腱病的策略，在临床实践中具有潜在的应用价值。
