posted on 2021-10-15, 11:25authored byKevin
R. Trabbic, Kristopher A. Kleski, Joseph J. Barchi
We
have developed a novel antigen delivery system based on polysaccharide-coated
gold nanoparticles (AuNPs) targeted to antigen-presenting cells (APCs)
expressing Dectin-1. AuNPs were synthesized de novo using yeast-derived
β-1,3-glucans (B13G) as the reductant and passivating agent
in a microwave-catalyzed procedure, yielding highly uniform and serum-stable
particles. These were further functionalized with both a peptide and
a specific glycosylated form from the tandem repeat sequence of mucin
4 (MUC4), a glycoprotein overexpressed in pancreatic tumors. The glycosylated
sequence contained the Thomsen–Friedenreich disaccharide, a
pan-carcinoma, tumor-associated carbohydrate antigen (TACA), which
has been a traditional target for antitumor vaccine design. These
motifs were prepared with a cathepsin B protease cleavage site (Gly-Phe-Leu-Gly),
loaded on the B13G-coated particles, and these constructs were examined
for Dectin-1 binding, APC processing, and presentation in a model
in vitro system and for immune responses in mice. We showed that these
particles elicit strong in vivo immune responses through the production
of both high-titer antibodies and priming of antigen-recognizing T-cells.
Further examination showed that a favorable antitumor balance of expressed
cytokines was generated, with limited expression of immunosuppressive
Il-10. This system is modular in that any range of antigens can be
conjugated to our particles and efficiently delivered to APCs expressing
Dectin-1.