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

• Published in: Journal of controlled release 2017-07, Vol.258, p.182-195
• Main Authors: Zupančič, Eva, Curato, Caterina, Paisana, Maria, Rodrigues, Catarina, Porat, Ziv, Viana, Ana S., Afonso, Carlos A.M., Pinto, João, Gaspar, Rogério, Moreira, João N., Satchi-Fainaro, Ronit, Jung, Steffen, Florindo, Helena F.
• Format: Article
• Language: English
• Subjects: Alpha-lactalbumin; Animals; Antigens - administration & dosage; Antigens - immunology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cytokines - immunology; Dendritic cells; Dendritic Cells - immunology; Drug Delivery Systems; Female; Immunization; Lactic Acid - chemistry; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymphocyte Activation; Mice, Inbred C57BL; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Ovalbumin; Ovalbumin - administration & dosage; Ovalbumin - immunology; PLGA-peg; Polyglycolic Acid - chemistry; Polymeric nanoparticles; Surface-Active Agents - chemistry; Vaccine delivery
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.05.014

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. [Display omitted]