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Targeting delivery of anti-TNF-α oligonucleotide into activated colonic macrophages protects against experimental colitis
  1. Longsheng Zuo,
  2. Zhen Huang,
  3. Lei Dong,
  4. Lingqing Xu,
  5. Yi'an Zhu,
  6. Chenyu Zhang,
  7. Jiangning Chen,
  8. Junfeng Zhang*
  1. 1 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China
  1. Correspondence to: Junfeng Zhang, Nanjing University, Hankou Road 22, Nanjing, China, Nanjing, 210093, China; jfzhang{at}nju.edu.cn

Abstract

Background: Tumor necrosis factor α (TNF-α) is a focal point of the inflammatory cascade in Crohn's disease (CD). As an emerging approach to blockade cytokines, antisense oligonucleotide (ASO) has developed quickly, but is stymied by a key obstacle-safe and effective delivery to specified cells. Here we present a novel nano-complex, based on galactosylated low molecular weight chitosan (gal-LMWC) and an ASO against TNF-α, which may be effective for CD treatment.

Aims: To investigate the targeting delivery ability of gal-LMWC/ASO complex into activated macrophages and its potential therapeutic action in experimental colitis.

Methods: Gal-LMWC was associated with ASO to form a stable nano-complex and the complex was injected into mice by intracolonic administration. Cellular localization of gal-LMWC/ASO complex in the colons was determined. The therapeutic effects were further studied in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and CD4+CD45RBhi T cells transfer colitis.

Results: Intracolonic administration of gal-LMWC/ASO complex resulted in the successful delivery of ASO into activated colonic macrophages and a significant reduction of colonic TNF-α in colitis mice. The single injection in TNBS colitis or repeated treatment in CD45RBhi transfer colitis both significantly ameliorated the clinical and histopathologic severity of the wasting disease, reduced tissue levels of inflammatory cytokines, and abrogated body weight loss, diarrhea and intestinal protein loss.

Conclusions: It is the first time to combine a non-viral gene vector with ASO targeting to activated macrophages in CD's therapy. The inhibition of TNF-α by this strategy represents a promising therapeutic approach for the treatment of CD.

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