中文摘要：本研究构建了一种疫苗佐剂，该佐剂由经阳离子表面二甲基溴化铵修饰的聚乳酸-羟基乙酸共聚物纳米颗粒和免疫促进剂TDB组成。研究表明，采用聚合壳聚糖包被的脂质体聚合混合纳米颗粒（LPNs）免疫能够增强粘膜免疫反应。采用水包油的单乳状液溶剂挥发法制备乙二醇壳聚糖（GC）修饰的LPNs，并进行了系统性优化。优化后的GC包被LPNs佐剂免疫小鼠后，能够诱导小鼠肺部和生殖道产生抗重组Ct融合蛋白抗原CTH522的免疫反应，该粘膜免疫反应表现为激活产生CTH522特异性IgG/IgA抗体和CTH522特异性干扰素Th1细胞。该研究结果表明，将CTH522与壳聚糖包被的LPNs佐剂联用进行粘膜免疫代表了粘膜免疫疫苗批量生产的发展方向。
 
外文摘要：Induction of mucosal immunity with vaccines is attractive for the immunological protection against pathogen entry directly at the site of infection. An example is infection with Chlamydia trachomatis (Ct), which is the most common sexually transmitted infection in the world, and there is an unmet medical need for an effective vaccine. A vaccine against Ct should elicit protective humoral and cell-mediated immune (CMI) responses in the genital tract mucosa. We previously designed an antibody-and CMI-inducing adjuvant based on poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles modified with the cationic surfactant dimethyldioctadecylammonium bromide and the immunopotentiator trehalose-6,6'-dibehenate. Here we show that immunization with these lipid-polymer hybrid nanoparticles (LPNs) coated with the mucoadhesive polymer chitosan enhances mucosal immune responses. Glycol chitosan (GC)-modified LPNs were engineered using an oil-in-water single emulsion solvent evaporation method. The nanoparticle design was optimized in a highly systematic way by using a quality-by-design approach to define the optimal operating space and to gain maximal mechanistic information about the GC coating of the LPNs. Cryo-transmission electron microscopy revealed a PLGA core coated with one or several concentric lipid bilayers. The GC coating of the surface was identified as a saturable, GC concentration-dependent increase in particle size and a reduction of the zeta-potential, and the coating layer could be compressed upon addition of salt. Increased antigen-specific mucosal immune responses were induced in the lungs and the genital tract with the optimized GC-coated LPN adjuvant upon nasal immunization of mice with the recombinant Ct fusion antigen CTH522. The mucosal responses were characterized by CTH522-specific IgG/IgA antibodies, together with CTH522-specific interferon.-producing Th1 cells. This study demonstrates that mucosal administration of CTH522 adjuvanted with chitosan-coated LPNs represents a promising strategy to modulate the magnitude of mucosal vaccine responses.
外文关键词：Drug delivery, Adjuvant, Vaccine, PLGA, Nanomedicine, Liposomes, Glycol chitosan, Mucosal vaccination
作者：Rose, F; Wern, JE; Gavins, F; Andersen, P; Follmann, F; Foged, C
作者单位：丹麦哥本哈根大学
期刊名称：JOURNAL OF CONTROLLED RELEASE
期刊影响因子：7.56
出版年份：2018
出版刊次：2
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