Injectable kartogenin and apocynin loaded micelle enhances the alleviation of intervertebral disc degeneration by adipose-derived stem cell

Chao Yu; Dongdong Li; Chenggui Wang; Kaishun Xia; Jingkai Wang; Xiaopeng Zhou; Liwei Ying; Jiawei Shu; Xianpeng Huang; Haibin Xu; Bin Han; Qixin Chen; Fangcai Li; Jianbin Tang; Chengzhen Liang; Nigel Slater

doi:10.1016/j.bioactmat.2021.03.018

Injectable kartogenin and apocynin loaded micelle enhances the alleviation of intervertebral disc degeneration by adipose-derived stem cell

Bioact Mater. 2021 Mar 23;6(10):3568-3579. doi: 10.1016/j.bioactmat.2021.03.018. eCollection 2021 Oct.

Authors

Chao Yu^{1

2

3}, Dongdong Li⁴, Chenggui Wang^{1

2

3}, Kaishun Xia^{1

2

3}, Jingkai Wang^{1

2

3}, Xiaopeng Zhou^{1

2

3}, Liwei Ying^{1

2

3}, Jiawei Shu^{1

2

3}, Xianpeng Huang^{1

2

3}, Haibin Xu^{1

2

3}, Bin Han^{1

2

3}, Qixin Chen^{1

2

3}, Fangcai Li^{1

2

3}, Jianbin Tang⁴, Chengzhen Liang^{1

2

3}, Nigel Slater⁵

Affiliations

¹ Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China.
² Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China.
³ Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China.
⁴ Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Center for Bionanoengineering, and College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China.
⁵ Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom.

Abstract

Cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration (IVDD). However, the increased levels of reactive oxygen species (ROS) in the degenerated region will impede the efficiency of human adipose-derived stem cells (human ADSCs) transplantation therapy. It inhibits human ADSCs proliferation, and increases human ADSCs apoptosis. Herein, we firstly devised a novel amphiphilic copolymer PEG-PAPO, which could self-assemble into a nanosized micelle and load lipophilic kartogenin (KGN), as a single complex (PAKM). It was an injectable esterase-responsive micelle, and showed controlled release ability of KGN and apocynin (APO). Oxidative stimulation promoted the esterase activity in human ADSCs, which accelerate degradation of esterase-responsive micelle. Compared its monomer, the PAKM micelle possessed better bioactivities, which were attributed to their synergistic effect. It enhanced the viability, autophagic activation (P62, LC3 II), ECM-related transcription factor (SOX9), and ECM (Collagen II, Aggrecan) maintenance in human ADSCs. Furthermore, it is demonstrated that the injection of PAKM with human ADSCs yielded higher disc height and water content in rats. Therefore, PAKM micelles perform promoting cell survival and differentiation effects, and may be a potential therapeutic agent for IVDD.

Keywords: Intervertebral disc degeneration; Mesenchymal stem cell; Polymer-drug conjugates; Reactive oxygen species; Stem cell therapy.