Format

Send to

Choose Destination
J Control Release. 2017 Jul 28;258:182-195. doi: 10.1016/j.jconrel.2017.05.014. Epub 2017 May 13.

Rational design of nanoparticles towards targeting antigen-presenting cells and improved T cell priming.

Author information

1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.; CNC - Center for Neuroscience and Cell Biology University of Coimbra, Portugal; Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
2
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
3
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
4
Department of Biological Services, The Weizmann Institute of Science, Rehovot, Israel.
5
Chemistry and Biochemistry Center, Sciences Faculty, Universidade de Lisboa, 1749-016 Lisbon, Portugal.
6
CNC - Center for Neuroscience and Cell Biology University of Coimbra, Portugal; FFUC - Faculty of Pharmacy, University of Coimbra, Portugal.
7
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Israel.
8
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.. Electronic address: hflorindo@ff.ul.pt.

Abstract

Vaccination is a promising strategy to trigger and boost immune responses against cancer or infectious disease. We have designed, synthesized and characterized aliphatic-polyester (poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) to investigate how the nature of protein association (adsorbed versus entrapped) and polymer/surfactant concentrations impact on the generation and modulation of antigen-specific immune responses. The ability of the NP formulations to target dendritic cells (DC), be internalized and activate the T cells was characterized and optimized in vitro and in vivo using markers of DC activation and co-stimulatory molecules. Ovalbumin (OVA) was used as a model antigen in combination with the engraftment of CD4+ and CD8+ T cells, carrying a transgenic OVA-responding T cell receptor (TCR), to trace and characterize the activation of antigen-specific CD4+ and CD8+ lymph node T cells upon NP vaccination. Accordingly, the phenotype and frequency of immune cell stimulation induced by the NP loaded with OVA, isolated or in combination with synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotide (ODN) motifs, were characterized. DC-NP interactions increased with incubation time, presenting internalization values between 50 and 60% and 30-40%, in vitro and in vivo, respectively. Interestingly, animal immunization with antigen-adsorbed NP up-regulated major histocompatibility complex (MHC) class II (MHCII), while NP entrapping the antigen up-regulated MHCI, suggesting a more efficient cross-presentation. On the other hand, rather surprisingly, the surfactant used in the NP formulation had a major impact on the activation of antigen presenting cells (APC). In fact, DC collected from lymph nodes of animals immunized with NP prepared using poly(vinil alcohol) (PVA), as a surfactant, expressed significantly higher levels of CD86, MHCI and MHCII. In addition, those NP prepared with PVA and co-entrapping OVA and the toll-like receptor (TLR) ligand CpG, induced the most profound antigen-specific T cell response, by both CD4+ and CD8+ T cells, in vivo. Overall, our data reveal the impact of NP composition and surface properties on the type and extension of induced immune responses. Deeper understanding on the NP-immune cell crosstalk can guide the rational development of nano-immunotherapeutic systems with improved and specific therapeutic efficacy and avoiding off-target effects.

KEYWORDS:

Alpha-lactalbumin; Dendritic cells; Ovalbumin; PLGA-peg; Polymeric nanoparticles; Vaccine delivery

PMID:
28511928
DOI:
10.1016/j.jconrel.2017.05.014
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center