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

Research paper by Chintan H CH Kapadia, Shaomin S Tian, Jillian L JL Perry, J Christopher JC Luft, Joseph M JM DeSimone

Indexed on: 24 Aug '16Published on: 24 Aug '16Published in: Molecular Pharmaceutics



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.