title: Precise manipulation of biophysical particle parameters enables control of proinflammatory cytokine production in presence of TLR 3 and 4 ligands.
abstract: The biophysical parameters governing nanoparticle (NP)-cell interactions significantly affect biological responses, particularly in the application of NP-based immunotherapeutics. Modulation of the surface biophysical character of NPs can be achieved via introduction of amino acids, which offer the ability to fine tune a range of biophysical parameters of interest. We employed this approach using monodisperse silica NPs coated with numerous poly(amino acid)s (PAAs). The NPs were incubated with dendritic cells (DCs) in conjunction with TLR ligands and production of IL-1β from DCs and IFNγ from T cells primed by these DCs were measured. These key cytokines can prognosticate the efficacy of the NP platform as a potential vaccine or active cellular immunotherapy carrier. IL-1β production showed a correlation with both NP size and degree of hydrophobicity. High IFNγ secretion from T cells was shown to be correlated with both the hydrophobicity and charge of the NPs used to activate the DCs. Other cytokines were also screened in order to compare the immune responses. The results of this study highlight the importance of nanoparticle biophysical parameters and the selection of TLR ligands to the rational design of nanoparticle-based vaccines and immunotherapies.
  
  
  
  The manuscript describes a systematic investigation into the effects of biophysical parameters of nanoparticles (NPs) on immune cells. Modulation of the biophysical character of the NP surface can be achieved by introduction of amino acids on monodisperse silica NPs, introducing a range of tunable biophysical parameters of interest, i.e. distinct sizes, different surface charges and varying degrees of surface hydrophobicity. We examine internalization of the NP in dendritic cells (DCs) and measure a myriad of cytokines, including IL-1β and IFNγ, which prognosticate the efficacy of the NPs as a potential vaccine (IL-1β metric) or active cellular immunotherapy carrier (IFNγ metric). Two different TLR ligands (a viral TLR3 ligand and a bacterial TLR4 ligand) were used along with the PAA NPs to compare their costimulatory immunogenicity. We strongly believe that this study will provide crucial information to many readers of Acta Biomaterialia and further drive the use of nanoparticle platforms in modulating immune responses.
authors.affiliation: Department of Biomedical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT 06511, USA; New Frontiers Research Laboratories, Toray Industries, Inc., Kanagawa 248-8555, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kakizawa
authors.affiliation: Department of Biomedical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT 06511, USA.
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT 06511, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Bell
authors.affiliation: Department of Biomedical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT 06511, USA; Chemical and Environmental Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT 06511, USA; Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA. Electronic address: Tarek.fahmy@yale.edu.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D017705:Lignans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D013601:T-Lymphocytes / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000819:agonists* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology
chemical_list: C000611649:IFNG protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D017705:Lignans; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma
keywords: Dendritic cell; Immunotherapy; Poly(amino acid); Silica particle; T cell; Vaccine