title: Cationic liposome-hyaluronic acid hybrid nanoparticles for intranasal vaccination with subunit antigens.
abstract: Here we report the development of a new cationic liposome-hyaluronic acid (HA) hybrid nanoparticle (NP) system and present our characterization of these NPs as an intranasal vaccine platform using a model antigen and F1-V, a candidate recombinant antigen for Yersinia pestis, the causative agent of plague. Incubation of cationic liposomes composed of DOTAP and DOPE with anionic HA biopolymer led to efficient ionic complexation and formation of homogenous liposome-polymer hybrid NPs, as evidenced by fluorescence resonance energy transfer, dynamic light scattering, and nanoparticle tracking analyses. Incorporation of cationic liposomes with thiolated HA allowed for facile surface decoration of NPs with thiol-PEG, resulting in the formation of DOTAP/HA core-PEG shell nanostructures. These NPs, termed DOTAP-HA NPs, exhibited improved colloidal stability and prolonged antigen release. In addition, cytotoxicity associated with DOTAP liposomes (LC50~0.2mg/ml) was significantly reduced by at least 20-fold with DOTAP-HA NPs (LC50>4mg/ml), as measured with bone marrow derived dendritic cells (BMDCs). Furthermore, NPs co-loaded with ovalbumin (OVA) and a molecular adjuvant, monophosphoryl lipid A (MPLA) promoted BMDC maturation and upregulation of co-stimulatory markers, including CD40, CD86, and MHC-II, and C57BL/6 mice vaccinated with NPs via intranasal route generated robust OVA-specific CD8(+) T cell and antibody responses. Importantly, intranasal vaccination with NPs co-loaded with F1-V and MPLA induced potent humoral immune responses with 11-, 23-, and 15-fold increases in F1-V-specific total IgG, IgG1, and IgG2c titers in immune sera by day 77, respectively, and induced balanced Th1/Th2 humoral immune responses, whereas mice immunized with the equivalent doses of soluble F1-V vaccine failed to achieve sero-conversion. Overall, these results suggest that liposome-polymer hybrid NPs may serve as a promising vaccine delivery platform for intranasal vaccination against Y. pestis and other infectious pathogens.
authors: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.|Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Yuchen
authors: Y
authors: Fan
authors: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.|Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Preety
authors: P
authors: Sahdev
authors: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.|Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Lukasz J
authors: LJ
authors: Ochyl
authors: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.|Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Jonathan
authors: J
authors: Akerberg
authors: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.|Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.|Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
authors: James J
authors: JJ
authors: Moon
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000281:Administration, Intranasal; D000818:Animals; D000941:Antigens / Q000008:administration & dosage*; D002412:Cations; D003102:Colloids; D003713:Dendritic Cells / Q000187:drug effects; D006820:Hyaluronic Acid / Q000737:chemistry*; D056724:Immunity, Humoral / Q000187:drug effects; D008050:Lipid A / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D010930:Plague / Q000276:immunology / Q000517:prevention & control; D014611:Vaccination / Q000379:methods*; D014612:Vaccines / Q000008:administration & dosage*; D015010:Yersinia pestis / Q000276:immunology
chemical_list: D000941:Antigens; D002412:Cations; D003102:Colloids; D008050:Lipid A; D008081:Liposomes; D014612:Vaccines; D006820:Hyaluronic Acid
keywords: Intranasal vaccine; Liposome; Nanoparticle; Subunit antigen; Yersinia pestis