VHPKQHR Peptide Modified Ultrasmall Paramagnetic Iron Oxide Nanoparticles Targeting Rheumatoid Arthritis for T1-Weighted Magnetic Resonance Imaging

Chunyu Zhang; Wentao Huang; Chen Huang; Chengqian Zhou; Yukuan Tang; Wei Wei; Yongsheng Li; Yukuan Tang; Yu Luo; Quan Zhou; Wenli Chen

doi:10.3389/fbioe.2022.821256

VHPKQHR Peptide Modified Ultrasmall Paramagnetic Iron Oxide Nanoparticles Targeting Rheumatoid Arthritis for T₁-Weighted Magnetic Resonance Imaging

Front Bioeng Biotechnol. 2022 Feb 28:10:821256. doi: 10.3389/fbioe.2022.821256. eCollection 2022.

Authors

Chunyu Zhang^{1

2

3}, Wentao Huang^{1

2

3}, Chen Huang⁴, Chengqian Zhou⁵, Yukuan Tang⁴, Wei Wei⁶, Yongsheng Li⁶, Yukuan Tang⁴, Yu Luo⁷, Quan Zhou⁸, Wenli Chen^{1

2

3}

Affiliations

¹ MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.
³ Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, China.
⁴ Department of Minimally Invasive Interventional Radiology, Guangzhou Panyu Central Hospital, Guangzhou, China.
⁵ Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States.
⁶ Institution of GuangDong Cord Blood Bank, Guangzhou, China.
⁷ Shanghai Engineering Technology Research Center for Pharmaceutical Intelligent Equipment, Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Noncoding RNA, Institute for Frontier Medical Technology, College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, China.
⁸ Department of Radiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.

Abstract

Magnetic resonance imaging (MRI) could be the ideal diagnostic modality for early rheumatoid arthritis (RA). Vascular cell adhesion molecule-1 (VCAM-1) is highly expressed in synovial locations in patients with RA, which could be a potential target protein for RA diagnosis. The peptide VHPKQHR (VHP) has a high affinity to VCAM-1. To make the contrast agent to target RA at an early stage, we used VHP and ultrasmall paramagnetic iron oxide (USPIO) to synthesize UVHP (U stands for USPIO) through a chemical reaction with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide. The size of UVHP was 6.7 nm; the potential was -27.7 mV, and the r ₂/r ₁ value was 1.73. Cytotoxicity assay exhibited that the cell survival rate was higher than 80% at even high concentrations of UVHP (Fe concentration 200 µg/mL), which showed the UVHP has low toxicity. Compared with no TNF-α stimulation, VCAM-1 expression was increased nearly 3-fold when mouse aortic endothelial cells (MAECs) were stimulated with 50 ng/mL TNF-α; cellular Fe uptake was increased very significantly with increasing UVHP concentration under TNF-α treatment; cellular Fe content was 17 times higher under UVHP with Fe concentration 200 µg/mL treating MAECs. These results indicate that UVHP can target overexpression of VCAM-1 at the cellular level. RA mice models were constructed with adjuvant-induced arthritis. In vivo MRI and biodistribution results show that the signal intensity of knee joints was increased significantly and Fe accumulation in RA model mice compared with normal wild-type mice after injecting UVHP 24 h. These results suggest that we have synthesized a simple, low-cost, and less toxic contrast agent UVHP, which targeted VCAM-1 for early-stage RA diagnosis and generates high contrast in T₁-weighted MRI.

Keywords: USPIO; UVHP; VCAM-1; magnetic resonance imaging; rheumatoid arthritis.