title: Analysis of human innate immune responses to PRINT fabricated nanoparticles with cross validation using a humanized mouse model.
abstract: Ideal nanoparticle (NP)-based drug and vaccine delivery vectors should be free of inherent cytotoxic or immunostimulatory properties. Therefore, determining baseline immune responses to nanomaterials is of utmost importance when designing human therapeutics. We characterized the response of human immune cells to hydrogel NPs fabricated using Particle Replication in Non-wetting Templates (PRINT) technology. We found preferential NP uptake by primary CD14(+) monocytes, which was significantly reduced upon PEGylation of the NP surface. Multiplex cytokine analysis of NP treated primary human peripheral blood mononuclear cells suggests that PRINT based hydrogel NPs do not evoke significant inflammatory responses nor induce cytotoxicity or complement activation. We furthered these studies using an in vivo humanized mouse model and similarly found preferential NP uptake by human CD14(+) monocytes without systemic inflammatory cytokine responses. These studies suggest that PRINT hydrogel particles form a desirable platform for vaccine and drug delivery as they neither induce inflammation nor toxicity. From the clinical editor: The authors here fabricated hydrogel nanorods using the PRINT (Particle Replication In Nonwetting Templates) fabrication process. They tested the interaction of human immune cells with these particles and found no immunoreactivity. This finding would suggest that monodisperse PRINT particles of identical shape and size could serve a variety of clinical applications.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Robbins
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Reid A
authors.initials: RA
authors.lastname: Roberts
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Reuter
authors.affiliation: Department of Pharmaceutical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Shen
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Sempowski
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Karen P
authors.initials: KP
authors.lastname: McKinnon
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmaceutical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Chemical and Biomolecular Engineering, NC State University, Raleigh, NC, USA; Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: DeSimone
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Translational Immunology and Institute of Inflammatory Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: jenny_ting@med.unc.edu.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007113:Immunity, Innate; D007114:Immunization / Q000379:methods*; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D053758:Nanoparticles / Q000737:chemistry*; D014612:Vaccines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D014612:Vaccines
keywords: Complement; Humanized mice; Monocytes; Nanoparticles; PEGylation; PRINT; Toxicity