Design and synthesis of multifunctional gold nanoparticles bearing tumor-associated glycopeptide antigens as potential cancer vaccines.
The development of vaccines against specific types of cancers will offer new modalities for therapeutic intervention. Here, we describe the synthesis of a novel vaccine construction prepared from spherical gold nanoparticles of 3-5 nm core diameters. The particles were coated with both the tumor-associated glycopeptides antigens containing the cell-surface mucin MUC4 with Thomsen Friedenreich (TF) antigen attached at different sites and a 28-residue peptide from the complement derived protein C3d to act as a B-cell activating "molecular adjuvant". The synthesis entailed solid-phase glycopeptide synthesis, design of appropriate linkers, and attachment chemistry of the various molecules to the particles. Attachment to the gold surface was mediated by a novel thiol-containing 33 atom linker which was further modified to be included as a third "spacer" component in the synthesis of several three-component vaccine platforms. Groups of mice were vaccinated either with one of the nanoplatform constructs or with control particles without antigen coating. Evaluation of sera from the immunized animals in enzyme immunoassays (EIA) against each glycopeptide antigen showed a small but statistically significant immune response with production of both IgM and IgG isotypes. Vaccines with one carbohydrate antigen (B, C, and E) gave more robust responses than the one with two contiguous disaccharides (D), and vaccine E with a TF antigen attached to threonine at the 10th position of the peptide was selected for IgG over IgM suggesting isotype switching. The data suggested that this platform may be a viable delivery system for tumor-associated glycopeptide antigens.
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
Raymond P
RP
Brinãs
Andreas
A
Sundgren
Padmini
P
Sahoo
Susan
S
Morey
Kate
K
Rittenhouse-Olson
Greg E
GE
Wilding
Wei
W
Deng
Joseph J
JJ
Barchi
D000595:Amino Acid Sequence; D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D005260:Female; D006020:Glycopeptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006046:Gold / Q000737:chemistry*; D006801:Humans; D007106:Immune Sera / Q000097:blood / Q000276:immunology; D008024:Ligands; D008297:Male; D053768:Metal Nanoparticles; D051379:Mice; D008969:Molecular Sequence Data; D055264:Mucin-4 / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000276:immunology*
D015295:Antigens, Tumor-Associated, Carbohydrate; D019496:Cancer Vaccines; D006020:Glycopeptides; D007106:Immune Sera; D008024:Ligands; D055264:Mucin-4; D006046:Gold