Pioglitazone-Loaded Cartilage-Targeted Nanomicelles (Pio@C-HA-DOs) for Osteoarthritis Treatment

Junyan Chen; Wuyan Xu; Tianming Dai; Songsong Jiao; Xiang Xue; Jiayang Jiang; Siming Li; Qingqi Meng

doi:10.2147/IJN.S428938

Pioglitazone-Loaded Cartilage-Targeted Nanomicelles (Pio@C-HA-DOs) for Osteoarthritis Treatment

Int J Nanomedicine. 2023 Oct 18:18:5871-5890. doi: 10.2147/IJN.S428938. eCollection 2023.

Authors

Junyan Chen^#^{1

2}, Wuyan Xu^#², Tianming Dai^#³, Songsong Jiao², Xiang Xue², Jiayang Jiang^{1

2}, Siming Li^{1

3}, Qingqi Meng³

Affiliations

¹ Guizhou Medical University, Guiyang, 550025, People's Republic of China.
² Department of Orthopaedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, People's Republic of China.
³ Guangzhou Institute of Traumatic Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, People's Republic of China.

^# Contributed equally.

Abstract

Background: Hyaluronic acid (HA) is a popular biological material for osteoarthritis (OA) treatment. Pioglitazone, a PPAR-γ agonist, has been found to inhibit OA, but its use is limited because achieving the desired local drug concentration after administration is challenging.

Purpose: Herein, we constructed HA-based cartilage-targeted nanomicelles (C-HA-DOs) to deliver pioglitazone in a sustained manner and evaluated their efficacy in vitro and in vivo.

Methods: C-HA-DOs were chemically synthesized with HA and the WYRGRL peptide and dodecylamine. The products were characterized by FT-IR, ¹H NMR, zeta potential and TEM. The drug loading rate and cumulative, sustained drug release from Pio@C-HA-DOs were determined, and their biocompatibility and effect on oxidative stress in chondrocytes were evaluated. The uptake of C-HA-DOs by chondrocytes and their effect on OA-related genes were examined in vitro. The nanomicelle distribution in the joint cavity was observed by in vivo small animal fluorescence imaging (IVIS). The therapeutic effects of C-HA-DOs and Pio@C-HA-DOs in OA rats were analysed histologically.

Results: The C-HA-DOs had a particle size of 198.4±2.431 nm, a surface charge of -8.290±0.308 mV, and a critical micelle concentration of 25.66 mg/Land were stable in solution. The cumulative drug release from the Pio@C-HA-DOs was approximately 40% at pH 7.4 over 24 hours and approximately 50% at pH 6.4 over 4 hours. Chondrocytes rapidly take up C-HA-DOs, and the uptake efficiency is higher under oxidative stress. In chondrocytes, C-HA-DOs, and Pio@C-HA-DOs inhibited H₂O₂-induced death, reduced intracellular ROS levels, and restored the mitochondrial membrane potential. The IVIS images confirmed that the micelles target cartilage. Pio@C-HA-DOs reduced the degradation of collagen II and proteoglycans by inhibiting the expression of MMP and ADAMTS, ultimately delaying OA progression in vitro and in vivo.

Conclusion: Herein, C-HA-DOs provided targeted drug delivery to articular cartilage and improved the role of pioglitazone in the treatment of OA.

Keywords: drug delivery; hyaluronic acid; knee joint; micelles; nanoparticles.

MeSH terms

Animals
Cartilage, Articular*
Chondrocytes
Hyaluronic Acid / chemistry
Hydrogen Peroxide / metabolism
Osteoarthritis* / pathology
Pioglitazone / metabolism
Pioglitazone / pharmacology
Pioglitazone / therapeutic use
Rats
Spectroscopy, Fourier Transform Infrared

Substances

Hyaluronic Acid
Pioglitazone
Hydrogen Peroxide

Grants and funding

This work was financially supported by the Guangdong Provincial Natural Science Foundation [grant number 2019A1515011085] to S.L. and Science and Technology Program of Guangzhou [grant number 202102080344] to Q.M.