Development of TLR7 Ligand-Glycan-Immobilized Gold Nanoparticles as Novel Adjuvants
Keywords:
Adjuvant, Toll-like receptor, Gold nanoparticles, C-type lectin, Innate immunityAbstract
Adjuvants enhance the immune system during vaccination. Among FDA-approved adjuvants, aluminum salts are most commonly used for vaccines. Although aluminum salts enhance antibody production, they show a limited effect on the cell-mediated immune response. Thus, further development of adjuvants inducing T cell-mediated immune responses is significant. Toll-like receptors (TLRs) are immune-related receptors that recognize specific pathogenassociated molecular patterns. They play important roles in the activation of innate immunity, which is crucial to shaping adaptive immunity. Therefore, studies using TLR ligands as novel adjuvants for anti-microbial and anti-cancer immunotherapies have attracted much attention. Among them, a low molecular weight TLR7 ligand, Imiquimod, has been approved for clinical use, but its use is restricted for local administration due to unwanted adverse effects. Since TLR7 is mainly located in the endosomal compartment of immune cells, efficient transport of the ligand into the cell is important for activating TLR7. Our previous work indicated that the conjugation of a low molecular weight TLR7 ligand with serum albumin and polysaccharides can greatly enhance its potency. In this study, we examined gold nanoparticles (GNPs) as carriers, since GNPs are less toxic and can immobilize multiple molecules including antigens for pathogens and tumors. Furthermore, α-mannose for targeting antigen-presenting cells was also examined for the efficient delivery of GNPs. In this paper, we describe the preparation of a low molecular weight TLR7 ligand and α-mannose immobilized GNPs, and its in vitro and in vivo immunostimulatory activities.
References
Dowling JK, Mansell A, 2016, Toll-like Receptors: the Swiss Army Knife of Immunity and Vaccine Development. Clin Transl Immunology, 2016(5): e85.
Smith M, Garcia-Martinez E, Pitter MR, et al., 2018, Trial Watch: Toll-like Receptor Agonists in Cancer Immunotherapy. Oncoimmunology, 2018(7): e1526250.
Zhang Z, Ohto U, Shibata T, et al., 2016, Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA. Immunity, 2016(45): 737–748.
Ignacio BJ, Albin TJ, Esser-Kahn AP, et al., 2018, Toll-like Receptor Agonist Conjugation: A Chemical Perspective. Bioconjug Chem, 2018(29): 587–603.
Chan M, Hayashi T, Kuy CS, et al., 2009, Synthesis and Immunological Characterization of Toll-like Receptor 7 Agonistic Conjugates. Bioconjug Chem, 2009(20): 1194–1200.
Shinchi H, Crain B, Yao S, et al., 2015, Enhancement of the Immunostimulatory Activity of a TLR7 Ligand by Conjugation to Polysaccharides. Bioconjug Chem, 2015(26): 1713–1723.
Shinchi H, Yamaguchi T, Moroishi T, et al., 2019, Gold Nanoparticles Coimmobilized with Small Molecule Toll-like Receptor 7 Ligand and α-mannose as Adjuvants. Bioconjug Chem, 30(11): 2811–2821. https://doi.org/10.1021/acs.bioconjchem.9b00560
Saha K, Agasti SS, Kim C, et al., 2012, Gold Nanoparticles in Chemical and Biological Sensing. Chem Rev, 2012(112): 2739–2779.
Libutti SK, Paciotti GF, Byrnes AA, et al., 2010, Phase I and Pharmacokinetic Studies of CYT-6091, a Novel PEGylated Colloidal Gold rhTNF Nanomedicine. Clin Cancer Res, 2010(16): 6139–6149.
Koonce NA, Quick CM, Hardee ME, et al., 2015, Combination of Gold Nanoparticle—Conjugated Tumor Necrosis Factor-Alpha and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models. Int J Radiat Oncol Biol Phys, 2015(93): 588–596.
Yang X, Yang M, Pang B, et al., 2015, Gold Nanomaterials at Work in Biomedicine. Chem Rev, 2015(115): 10410–10488.
Geijtenbeek TB, Gringhuis SI, 2016, C-type Lectin Receptors in the Control of T Helper Cell Differentiation. Nat Rev Immunol, 2016(16): 433–448.
Nakamura-Tsuruta S, Kishimoto Y, Nishimura T, et al., 2008, One-step Purification of Lectins from Banana Pulpusing Sugar-Immobilized Gold Nano-Particles. J Biochem, 2008(143): 833–839.
Mantovani A, Sica A, Sozzani S, et al., 2004, The Chemokine System in Diverse Forms of Macrophage Activation and Polarization. Trends Immunol, 2004(25): 677–686.
