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Nanosome-Mediated Delivery Of Protein Kinase D Inhibitor Protects Chondrocytes From Interleukin-1β-Induced Stress And Apoptotic Death

Authors Cho H, Bhatti FUR, Hasty KA, Yi AK

Received 10 June 2019

Accepted for publication 30 August 2019

Published 11 November 2019 Volume 2019:14 Pages 8835—8846

DOI https://doi.org/10.2147/IJN.S218901

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Thomas J. Webster


Hongsik Cho,1–3,* Fazal-Ur-Rehman Bhatti,1,3,* Karen A Hasty,1–3 Ae-Kyung Yi4

1Department of Orthopaedic Surgery and Biomedical Engineering, The University of Tennessee Health Science Center, Memphis, TN, USA; 2Department of Orthopaedic Surgery, Campbell Clinic, Memphis, TN, USA; 3151 Research Service, Veterans Affairs Medical Center, Memphis, TN, USA; 4Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN, USA

*These authors contributed equally to this work

Correspondence: Hongsik Cho
Department of Orthopaedic Surgery and Biomedical Engineering, The University of Tennessee Health Science Center, Research 151, VAMC, 1030 Jefferson Ave, Memphis TN 38104 USA
Tel +1 901 523-8990 (Ext: 6456)
Fax +1 901 577-7273
Email hcho4@uthsc.edu
Ae-Kyung Yi
Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, 858 Madison Ave., Suite 501C, Memphis, TN 38163, USA
Tel +1 901 448-1775
Fax +1 901 448-7360
Email ayi@uthsc.edu

Background: Inflammatory stress caused by protein kinase D (PKD) plays a critical role in damaging chondrocytes and extracellular matrix (ECM) during osteoarthritis (OA). The PKD inhibitor (PKDi) (CRT0066101) has been used to overcome inflammation in different cell types. However, the efficacy of a therapeutic drug can be limited due to off-target distribution, slow cellular internalization, and limited lysosomal escape. In order to overcome this issue, we developed nanosomes carrying CRT0066101 (PKDi-Nano) and tested their efficacy in vitro in chondrocytes.
Methods: Chondrocytes were subjected to IL-1β-induced inflammatory stress treated with either PKDi or PKDi-Nano. Effects of treatment were measured in terms of cytotoxicity, cellular morphology, viability, apoptosis, phosphorylation of protein kinase B (Akt), and anabolic/catabolic gene expression analyses related to cartilage tissue.
Results and Discussion: The effects of PKDi-Nano treatment were more pronounced as compared to PKDi treatment. Cytotoxicity and apoptosis were significantly reduced following PKDi-Nano treatment (P < 0.001). Cellular morphology was also restored to normal size and shape. The viability of chondrocytes was significantly enhanced in PKDi-Nano-treated cells (P < 0.001). The data indicated that PKDi-Nano acted independently of the Akt pathway. Gene expression analyses revealed significant increases in the expression levels of anabolic genes with concomitant decreases in the level of catabolic genes. Our results indicate that PKDi-Nano attenuated the effects of IL-1β via the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway.
Conclusion: Taken together, these results suggest that PKDi-Nano can be used as a successful strategy to reduce IL1β-induced inflammatory stress in chondrocytes.

Keywords: CRT0066101, liposome, cartilage, osteoarthritis, cytokine
 

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