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Multifunctional folate receptor-targeting and pH-responsive nanocarriers loaded with methotrexate for treatment of rheumatoid arthritis

Authors Zhao J, Zhao M, Yu C, Zhang X, Liu J, Cheng X, Lee RJ, Sun F, Teng L, Li Y

Received 3 May 2017

Accepted for publication 25 July 2017

Published 11 September 2017 Volume 2017:12 Pages 6735—6746


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Dongwoo Khang

Jinlong Zhao,1 Menghui Zhao,1 Changhui Yu,1 Xueyan Zhang,1 Jiaxin Liu,1 Xinwei Cheng,2 Robert J Lee,1,2 Fengying Sun,1 Lesheng Teng,1 Youxin Li1

1School of Life Sciences, Jilin University, Changchun, China; 2College of Pharmacy, Ohio State University, Columbus, OH, USA

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive cartilage and bone destruction. Activated macrophages that overexpress folic acid (FA) receptors play an important role in RA, due to their abundance in inflamed synovial membrane and joints. In an effort to deliver drugs to the inflamed tissues, multifunctional FA receptor-targeting and pH-responsive nanocarriers were developed. They were composed of lipids, polyethylene glycol (PEG)–poly(lactic-co-glycolic acid) (PLGA) forming a hydrophilic shell, FA around the hydrophilic shell as a targeting ligand, and poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) and PLGA as a hydrophobic core. PCADK also acts as a pH-responsive material. Methotrexate (Mtx) was encapsulated in the nanoparticles, which exhibited pH-responsive release in vitro. Cellular uptake and cytotoxicity experiments revealed that FA-PEG-PLGA/PCADK–lipid nanoparticles loaded with Mtx (FA-PPLNPs) exhibited superior cellular uptake and higher cytotoxicity to activated macrophages than PPLNPs/Mtx. The therapeutic effect of FA-PPLNPs/Mtx in RA was confirmed in an adjuvant-induced arthritis rat model. These results suggest that the multifunctional folate receptor-targeting and pH-responsive nanocarriers are promising for the treatment of RA.

Keywords: rheumatoid arthritis, methotrexate, nanoparticles, folate, pH-responsive, PCADK

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