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Targeting delivery of anti-TNFalpha oligonucleotide into activated colonic macrophages protects against experimental

Longsheng Zuo1, Zhen Huang, Lei Dong

  • 1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China. jfzhang@nju.edu.cn

Gut
|December 3, 2009
PubMed
Abstract

Insights

This study developed a novel galactosylated chitosan nanoparticle to deliver antisense oligonucleotides targeting TNFalpha in Crohn's disease models. The treatment effectively reduced inflammation and disease severity by targeting activated macrophages in the colon.

Area of Science:

  • Biomedical Engineering
  • Drug Delivery
  • Immunology

Background:

  • Tumor Necrosis Factor alpha (TNFalpha) drives inflammation in Crohn's disease (CD).
  • Antisense oligonucleotides (ASOs) offer a way to block cytokines like TNFalpha.
  • Effective and safe delivery of ASOs to target cells remains a challenge in CD treatment.

Purpose of the Study:

  • To develop and evaluate a novel nano-complex for targeted delivery of an ASO against TNFalpha.
  • To investigate the targeting ability of the galactosylated low molecular weight chitosan (gal-LMWC)/ASO complex into activated macrophages.
  • To assess the therapeutic potential of this complex in experimental colitis models.

Main Methods:

  • A stable nano-complex was formed between gal-LMWC and an ASO targeting TNFalpha.
  • The gal-LMWC/ASO complex was administered intracolonically in mice.
  • Therapeutic effects were evaluated in TNBS-induced colitis and CD4(+)CD45RB(hi) T cell transfer colitis models.

Main Results:

  • The gal-LMWC/ASO complex successfully delivered ASO into activated colonic macrophages.
  • Significant reduction in colonic TNFalpha levels was observed in treated mice.
  • Both colitis models showed amelioration of clinical and histopathological severity, reduced inflammatory cytokines, and abrogated negative physiological effects.

Conclusions:

  • This study presents the first non-viral gene vector combined with an ASO targeted to activated macrophages for CD treatment.
  • Inhibiting TNFalpha using this targeted ASO strategy shows promise for CD therapy.
  • The gal-LMWC/ASO nano-complex offers a potential new therapeutic avenue for Crohn's disease.

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