title: Mannosylated poly(beta-amino esters) for targeted antigen presenting cell immune modulation.
abstract: Given the rise of antibiotic resistance and other difficult-to-treat diseases, genetic vaccination is a promising preventative approach that can be tailored and scaled according to the vector chosen for gene delivery. However, most vectors currently utilized rely on ubiquitous delivery mechanisms that ineffectively target important immune effectors such as antigen presenting cells (APCs). As such, APC targeting allows the option for tuning the direction (humoral vs cell-mediated) and strength of the resulting immune responses. In this work, we present the development and assessment of a library of mannosylated poly(beta-amino esters) (PBAEs) that represent a new class of easily synthesized APC-targeting cationic polymers. Polymeric characterization and assessment methodologies were designed to provide a more realistic physiochemical profile prior to in vivo evaluation. Gene delivery assessment in vitro showed significant improvement upon PBAE mannosylation and suggested that mannose-mediated uptake and processing influence the magnitude of gene delivery. Furthermore, mannosylated PBAEs demonstrated a strong, efficient, and safe in vivo humoral immune response without use of adjuvants when compared to genetic and protein control antigens. In summary, the gene delivery effectiveness provided by mannosylated PBAE vectors offers specificity and potency in directing APC activation and subsequent immune responses.
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Jones
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA.
authors.forename: Mingfu
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA.
authors.forename: Anitha
authors.initials: A
authors.lastname: Ravikrishnan
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Reddinger
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA.
authors.forename: Guojian
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA; The Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA.
authors.forename: Anders P
authors.initials: AP
authors.lastname: Hakansson
authors.affiliation: Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260-4200, USA. Electronic address: blainepf@buffalo.edu.
authors.forename: Blaine A
authors.initials: BA
authors.lastname: Pfeifer
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D005260:Female; D005453:Fluorescence; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007114:Immunization; D056747:Immunomodulation; D008358:Mannose / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D014162:Transfection
chemical_list: D011108:Polymers; C485184:enhanced green fluorescent protein; C507253:poly(beta-amino ester); D049452:Green Fluorescent Proteins; D008358:Mannose
keywords: Antigen presenting cells; Cationic polymers; Gene therapy; Nonviral vector; Vaccines