2. Academic Validation
  3. Inhibition of IKKβ via a DNA-Based In Situ Delivery System Improves Achilles Tendinopathy Healing in a Rat Model

Inhibition of IKKβ via a DNA-Based In Situ Delivery System Improves Achilles Tendinopathy Healing in a Rat Model

  • Am J Sports Med. 2023 Oct 7:3635465231198501. doi: 10.1177/03635465231198501.
Zilu Ge 1 2,  Mingyu Yang 3 2,  Danfeng Wei 4 2,  Dong Wang 1 2,  Renliang Zhao 1 2,  Xiangtian Deng 1 2,  Yunfeng Tang 1 2,  Qian Fang 1 2,  Zhencheng Xiong 1 2,  Chengshi Wang 5 2,  Guanglin Wang 1 2,  Wei Li 5 2,  Kanglai Tang 3 2
Affiliations

Affiliations

  • 1 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.
  • 2 Investigation performed at Department of Orthopaedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3 Department of Orthopedics/Sports Medicine Center, First Affiliated Hospital of Third Military Medical University [Army Medical University], Chongqing, China.
  • 4 Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China.
  • 5 Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu, China.
PMID: 37804159 DOI: 10.1177/03635465231198501
Abstract

Background: 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.

Purpose: 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.

Study design: Controlled laboratory study.

Methods: 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.

Results: 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 (P = .024), load to failure (P = .002), stiffness (P = .039), and elastic modulus (P = .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 (P = .042) and 8 weeks (P = .009). Type I collagen expression (COL-I; P = .034) and the COL-I/collagen type III ratio (P = .015) increased while interleukin 6 expression decreased (P < .001) in the ACHP-Gel group compared with the ACHP group at 8 weeks.

Conclusion: 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.

Clinical relevance: ACHP-Gel injection is a promising strategy for the treatment of Achilles tendinopathy in clinical practice.

Keywords

Achilles tendinopathy; DNA supramolecular hydrogel; RNA sequencing; collagenase; rat model.

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