Versatile polyion complex micelles for peptide and siRNA vectorization to engineer tolerogenic dendritic cells

Eur J Pharm Biopharm. 2015 May;92:216-27. doi: 10.1016/j.ejpb.2015.03.013. Epub 2015 Mar 18.

Abstract

Dendritic cells (DCs) are professional antigen-presenting cells that play a critical role in maintaining the balance between immunity and tolerance and, as such are a promising immunotherapy tool to induce immunity or to restore tolerance. The main challenge to harness the tolerogenic properties of DCs is to preserve their immature phenotype. We recently developed polyion complex micelles, formulated with double hydrophilic block copolymers of poly(methacrylic acid) and poly(ethylene oxide) blocks and able to entrap therapeutic molecules, which did not induce DC maturation. In the current study, the intrinsic destabilizing membrane properties of the polymers were used to optimize endosomal escape property of the micelles in order to propose various strategies to restore tolerance. On the first hand, we showed that high molecular weight (Mw) copolymer-based micelles were efficient to favor the release of the micelle-entrapped peptide into the endosomes, and thus to improve peptide presentation by immature (i) DCs. On the second hand, we put in evidence that low Mw copolymer-based micelles were able to favor the cytosolic release of micelle-entrapped small interfering RNAs, dampening the DCs immunogenicity. Therefore, we demonstrate the versatile use of polyionic complex micelles to preserve tolerogenic properties of DCs. Altogether, our results underscored the potential of such micelle-loaded iDCs as a therapeutic tool to restore tolerance in autoimmune diseases.

Keywords: Antigen presentation; Dendritic cells; Endosomal escape; Gene silencing; Polyion complex micelles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dendritic Cells / immunology*
  • Endosomes / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Immune Tolerance
  • Micelles
  • Molecular Weight
  • Peptides / administration & dosage*
  • Polyethylene Glycols / chemistry
  • Polymers / chemistry*
  • Polymethacrylic Acids / chemistry
  • RNA, Small Interfering / administration & dosage*

Substances

  • Micelles
  • Peptides
  • Polymers
  • Polymethacrylic Acids
  • RNA, Small Interfering
  • polymethacrylic acid
  • Polyethylene Glycols