title: APC targeted micelle for enhanced intradermal delivery of hepatitis B DNA vaccine.
abstract: Chronic hepatitis B is a serious liver disease and puts people at high risk of death from cirrhosis and liver cancer. Although DNA vaccination has been emerged as a potential immunotherapeutic strategy for the treatment of chronic hepatitis B, the efficiencies were not adequate in clinical trials. Here we describe the design, synthesis, and evaluation of mannosylated phenylalanine grafted chitosan (Man-CS-Phe) as a DNA delivery vector for direct transfection of antigen presenting cells to improve cellular and humoral immunity to plasmid-coded antigen. The cationic Man-CS-Phe micelles condense plasmid DNA into nanoscale polyplexes and provide efficient protection of complexed DNA from nuclease degradation. The mannose receptor-mediated enhanced cell uptake and high in vitro transfection efficiency of the polyplexes were demonstrated in RAW 264.7 and DC 2.4 cells using GFP-expressing plasmid DNA. Furthermore, intradermal immunization of BALB/c mice indicated that hepatitis B DNA vaccine/Man-CS-Phe polyplexes not only induced multi-fold higher serum antibody titer in comparison to all other formulations including FuGENE HD, but also significantly stimulated T-cell proliferation and skewed T helper toward Th1 polarization. These results illustrate that the Man-CS-Phe can serve as a promising DNA delivery vector to harness both cellular and humoral arms of immune system.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nursing, and Allied Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Buddhadev
authors.initials: B
authors.lastname: Layek
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nursing, and Allied Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Lipp
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nursing, and Allied Sciences, North Dakota State University, Fargo, ND 58105, USA. Electronic address: Jagdish.Singh@ndsu.edu.
authors.forename: Jagdish
authors.initials: J
authors.lastname: Singh
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000821:virology; D015415:Biomarkers / Q000097:blood; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000031:analogs & derivatives / Q000737:chemistry* / Q000633:toxicity; D004337:Drug Carriers; D005260:Female; D006510:Hepatitis B Antibodies / Q000097:blood; D006514:Hepatitis B Surface Antigens / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007114:Immunization; D008213:Lymphocyte Activation; D008358:Mannose / Q000031:analogs & derivatives / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000633:toxicity; D000067996:RAW 264.7 Cells; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014162:Transfection; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
chemical_list: D015415:Biomarkers; D004337:Drug Carriers; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D008823:Micelles; D019444:Vaccines, DNA; D010649:Phenylalanine; D048271:Chitosan; D008358:Mannose
keywords: Antigen presenting cells; Chitosan; DNA vaccine; Micelles; Nonviral vector; Transfection