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Int J Nanomedicine. 2018 Apr 4;13:2051-2064. doi: 10.2147/IJN.S151233. eCollection 2018.

Fabrication of a triptolide-loaded and poly-γ-glutamic acid-based amphiphilic nanoparticle for the treatment of rheumatoid arthritis.

Zhang L1,2,3, Chang J1,2,3, Zhao Y1,2,3, Xu H1,2,3, Wang T1,2,3, Li Q1,2,3, Xing L4, Huang J5, Wang Y1,2,3,6, Liang Q1,2,3.

Author information

1
Department of Orthopaedics, Longhua Hospital.
2
Institute of Spine.
3
Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
4
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
5
School of Life Science, East China Normal University.
6
School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.

Abstract

Triptolide (TP) exhibits immunosuppressive, cartilage-protective and anti-inflammatory effects in rheumatoid arthritis. However, the toxicity of TP limits its widespread use. To decrease the toxic effects, we developed a novel nano-drug carrier system containing TP using poly-γ-glutamic acid-grafted di-tert-butyl L-aspartate hydrochloride (PAT). PAT had an average diameter of 79±18 nm, a narrow polydispersity index (0.18), a strong zeta potential (-32 mV) and a high drug encapsulation efficiency (EE1=48.6%) and loading capacity (EE2=19.2%), and exhibited controlled release (t1/2=29 h). The MTT assay and flow cytometry results indicated that PAT could decrease toxicity and apoptosis induced by free TP on RAW264.7 cells. PAT decreased lipopolysaccharides/interferon γ-induced cytokines expression of macrophage (P<0.05). In vivo, PAT accumulated at inflammatory joints, improved the survival rate and had fewer side effects on tumor necrosis factor α transgenic mice, compared to TP. The blood biochemical indexes revealed that PAT did not cause much damage to the kidney (urea nitrogen and creatinine) and liver (alanine aminotransferase and aspartate aminotransferase). In addition, PAT reduced inflammatory synovial tissue area (P<0.05), cartilage loss (P<0.05), tartrate-resistant acid phosphatase-positive osteoclast area (P<0.05) and bone erosion (P<0.05) in both knee and ankle joints, and showed similar beneficial effect as free TP. In summary, our newly formed nanoparticle, PAT, can reduce the toxicity and guarantee the efficacy of TP, which represents an effective drug candidate for RA with low adverse side effect.

KEYWORDS:

drug carrier system; rheumatoid arthritis; triptolide; tumor necrosis factor α transgenic mice; γ-PGA

PMID:
29670349
PMCID:
PMC5894725
DOI:
10.2147/IJN.S151233
[Indexed for MEDLINE]
Free PMC Article

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