Colonic gene silencing using siRNA-loaded calcium phosphate/PLGA nanoparticles ameliorates intestinal inflammation in vivo

J Control Release. 2016 Jan 28;222:86-96. doi: 10.1016/j.jconrel.2015.12.021. Epub 2015 Dec 14.

Abstract

Cytokines and chemokines are predominant players in the progression of inflammatory bowel diseases. While systemic neutralization of these players with antibodies works well in some patients, serious contraindications and side effects have been reported. Therefore, the local interference of cytokine signaling mediated by siRNA-loaded nanoparticles might be a promising new therapeutic approach. In this study, we produced multi-shell nanoparticles consisting of a calcium phosphate (CaP) core coated with siRNA directed against pro-inflammatory mediators, encapsulated into poly(d,l-lactide-co-glycolide acid) (PLGA), and coated with a final outer layer of polyethyleneimine (PEI), for the local therapeutic treatment of colonic inflammation. In cell culture, siRNA-loaded CaP/PLGA nanoparticles exhibited a rapid cellular uptake, almost no toxicity, and an excellent in vitro gene silencing efficiency. Importantly, intrarectal application of these nanoparticles loaded with siRNA directed against TNF-α, KC or IP-10 to mice suffering from dextran sulfate sodium (DSS)-induced colonic inflammation led to a significant decrease of the target genes in colonic biopsies and mesenteric lymph nodes which was accompanied with a distinct amelioration of intestinal inflammation. Thus, this study provides evidence that the specific and local modulation of the inflammatory response by CaP/PLGA nanoparticle-mediated siRNA delivery could be a promising approach for the treatment of intestinal inflammation.

Keywords: Delivery; Intestinal inflammation; Nanoparticles; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Calcium Phosphates / chemistry
  • Cell Line
  • Colitis / chemically induced
  • Colitis / immunology
  • Colitis / pathology
  • Colitis / therapy*
  • Colon / drug effects
  • Colon / immunology
  • Colon / pathology
  • Cytokines / genetics*
  • Cytokines / immunology
  • Dextran Sulfate
  • Female
  • Gene Silencing
  • Intestinal Secretions / chemistry
  • Lactic Acid / chemistry
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Nanoparticles / therapeutic use
  • Polyethyleneimine / chemistry
  • Polyglycolic Acid / chemistry
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / pharmacology
  • RNA, Small Interfering / therapeutic use

Substances

  • Calcium Phosphates
  • Cytokines
  • RNA, Small Interfering
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Polyethyleneimine
  • Dextran Sulfate
  • calcium phosphate