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Reduction sensitive PEG hydrogels for co-delivery of antigen and adjuvant to induce potent CTLs.

Reduction sensitive PEG hydrogels for co-delivery of antigen and adjuvant to induce potent CTLs.
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Kapadia CH, Tian S, Perry JL, Luft JC, DeSimone JM,


Kapadia CH, Tian S, Perry JL, Luft JC, DeSimone JM, (click to view)

Kapadia CH, Tian S, Perry JL, Luft JC, DeSimone JM,

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Molecular pharmaceutics 2016 8 23()

Abstract

Educating our immune system via vaccination is an attractive approach to combat infectious diseases. Eliciting antigen specific cytotoxic T cells (CTLs), CD8+ effector T cells, are essential in controlling intracellular infectious diseases such as influenza (Flu), tuberculosis (TB), hepatitis, HIV/AIDS, as well as tumors. However, vaccination utilizing subunit peptides to elicit a potent CD8+ T cell response with antigenic peptides are typically ineffective due to poor immunogenicity. Here we have engineered a reduction sensitive nanoparticle (NP) based subunit vaccine for intracellular delivery of an antigenic peptide and immunostimulatory adjuvant. We have co-conjugated an antigenic peptide (ovalbumin-derived CTL epitope [OVA257-264 -SIINFEKL]) and an immunostimulatory adjuvant (CpG ODNs, TLR9 agonist) to PEG hydrogel NPs via a reduction sensitive linker. Bone-marrow derived dendritic cells (BMDCs) treated with the SIINFEKL-conjugated NPs efficiently cross-presented the antigenic peptide via MHC-I surface receptor and induced proliferation of OT-I T cells. CpG ODN-conjugated NPs induced maturation of BMDCs as evidenced by the overexpression of CD80 and CD40 co-stimulatory receptors. Moreover, co-delivery of NP conjugated SIINFEKL and CpG ODN significantly increased the frequency of IFN- producing CD8+ effector T cells in mice (∼6 fold improvement over soluble antigen and adjuvant). Furthermore, the NP subunit vaccine-induced effector T cells were able to kill up to 90% of the adoptively transferred antigenic peptide-loaded target cell. These results demonstrate that the reduction sensitive NP subunit vaccine elicits a potent CTL response and provide compelling evidence that this approach could be utilized to engineer particulate vaccines to deliver tumor- or pathogen-associated antigenic peptides to harness the immune system to fight against cancer and infectious diseases.

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