title: Intrinsic immunogenicity of rapidly-degradable polymers evolves during degradation.
abstract: Recent studies reveal many biomaterial vaccine carriers are able to activate immunostimulatory pathways, even in the absence of other immune signals. How the changing properties of polymers during biodegradation impact this intrinsic immunogenicity is not well studied, yet this information could contribute to rational design of degradable vaccine carriers that help direct immune response. We use degradable poly(beta-amino esters) (PBAEs) to explore intrinsic immunogenicity as a function of the degree of polymer degradation and polymer form (e.g., soluble, particles). PBAE particles condensed by electrostatic interaction to mimic a common vaccine approach strongly activate dendritic cells, drive antigen presentation, and enhance T cell proliferation in the presence of antigen. Polymer molecular weight strongly influences these effects, with maximum stimulation at short degradation times--corresponding to high molecular weight--and waning levels as degradation continues. In contrast, free polymer is immunologically inert. In mice, PBAE particles increase the numbers and activation state of cells in lymph nodes. Mechanistic studies reveal that this evolving immunogenicity occurs as the physicochemical properties and concentration of particles change during polymer degradation. This work confirms the immunological profile of degradable, synthetic polymers can evolve over time and creates an opportunity to leverage this feature in new vaccines.
  
  
  CONCLUSIONS
  Degradable polymers are increasingly important in vaccination, but how the inherent immunogenicity of polymers changes during degradation is poorly understood. Using common rapidly-degradable vaccine carriers, we show that the activation of immune cells--even in the absence of other adjuvants--depends on polymer form (e.g., free, particulate) and the extent of degradation. These changing characteristics alter the physicochemical properties (e.g., charge, size, molecular weight) of polymer particles, driving changes in immunogenicity. Our results are important as many common biomaterials (e.g., PLGA) are now known to exhibit immune activity that alters how vaccines are processed. Thus, the results of this study could contribute to more rational design of biomaterial carriers that also actively direct the properties of responses generated by vaccines.
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States.
authors.forename: James I
authors.initials: JI
authors.lastname: Andorko
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States.
authors.forename: Krystina L
authors.initials: KL
authors.lastname: Hess
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pineault
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States; Department of Microbiology and Immunology, University of Maryland Medical School, Baltimore, MD, United States; Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, United States. Electronic address: cmjewell@umd.edu.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jewell
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007109:Immunity / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011108:Polymers; C507253:poly(beta-amino ester)
keywords: Dendritic cell; Immune response and inflammation; Microparticle and nanoparticle; Poly(beta-amino esters); Vaccine