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Nanomaterials 2015, 5(4), 2317-2334; doi:10.3390/nano5042317

Nanocarriers for DNA Vaccines: Co-Delivery of TLR-9 and NLR-2 Ligands Leads to Synergistic Enhancement of Proinflammatory Cytokine Release

1
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest Ansermet 30, 1211 Geneva, Switzerland
2
Vaccine Formulation Laboratory, Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland
*
Author to whom correspondence should be addressed.
Academic Editor: Andrea Danani
Received: 22 October 2015 / Revised: 23 November 2015 / Accepted: 2 December 2015 / Published: 17 December 2015
(This article belongs to the Special Issue Nanoparticles Assisted Drug Delivery)
View Full-Text   |   Download PDF [788 KB, uploaded 17 December 2015]   |  

Abstract

Adjuvants enhance immunogenicity of vaccines through either targeted antigen delivery or stimulation of immune receptors. Three cationic nanoparticle formulations were evaluated for their potential as carriers for a DNA vaccine, and muramyl dipeptide (MDP) as immunostimulatory agent, to induce and increase immunogenicity of Mycobacterium tuberculosis antigen encoding plasmid DNA (pDNA). The formulations included (1) trimethyl chitosan (TMC) nanoparticles, (2) a squalene-in-water nanoemulsion, and (3) a mineral oil-in-water nanoemulsion. The adjuvant effect of the pDNA-nanocomplexes was evaluated by serum antibody analysis in immunized mice. All three carriers display a strong adjuvant effect, however, only TMC nanoparticles were capable to bias immune responses towards Th1. pDNA naturally contains immunostimulatory unmethylated CpG motifs that are recognized by Toll-like receptor 9 (TLR-9). In mechanistic in vitro studies, activation of TLR-9 and the ability to enhance immunogenicity by simultaneously targeting TLR-9 and NOD-like receptor 2 (NLR-2) was determined by proinflammatory cytokine release in RAW264.7 macrophages. pDNA in combination with MDP was shown to significantly increase proinflammatory cytokine release in a synergistic manner, dependent on NLR-2 activation. In summary, novel pDNA-Ag85A loaded nanoparticle formulations, which induce antigen specific immune responses in mice were developed, taking advantage of the synergistic combinations of TLR and NLR agonists to increase the adjuvanticity of the carriers used. View Full-Text
Keywords: adjuvants; toll-like receptor; NOD-like receptor; cationic nanoparticles; DNA vaccine; muramyl dipeptide adjuvants; toll-like receptor; NOD-like receptor; cationic nanoparticles; DNA vaccine; muramyl dipeptide
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Poecheim, J.; Heuking, S.; Brunner, L.; Barnier-Quer, C.; Collin, N.; Borchard, G. Nanocarriers for DNA Vaccines: Co-Delivery of TLR-9 and NLR-2 Ligands Leads to Synergistic Enhancement of Proinflammatory Cytokine Release. Nanomaterials 2015, 5, 2317-2334.

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