期刊
JOURNAL OF CONTROLLED RELEASE
卷 210, 期 -, 页码 48-57出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2015.05.004
关键词
Drug delivery; Adjuvant; Vaccine; PLGA; Nanomedicine; Nanoparticles; Quality-by-design (QbD); Dimethyldioctadecylammonium (DDA); Trehalose 6,6-dibehenate
资金
- Innovation Fund Denmark [069-2011-1, 09-067052]
- Danish Agency for Science, Technology and Innovation
- Innovation Fund Denmark
- Danish Ministry of Science, Technology and Innovation
- Apotekerfonden
The purpose of this studywas to design a novel and versatile adjuvant intended formucosal vaccination based on biodegradable poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with the cationic surfactant dimethyldioctadecylammonium (DDA) bromide and the immunopotentiator trehalose-6,6'-dibehenate (TDB) (CAF01) to tailor humoral and cellular immunity characterized by antibodies and Th1/Th17 responses. Such responses are important for the protection against diseases caused by intracellular bacteria such as Chlamydia trachomatis and Mycobacterium tuberculosis. The hybrid NPs were engineered using an oil-in-water single emulsion method and a quality-by-design approach was adopted to define the optimal operating space (OOS). Four critical process parameters (CPPs) were identified, including the acetone concentration in the water phase, the stabilizer [ polyvinylalcohol (PVA)] concentration, the lipid-to-total solid ratio, and the total concentration. The CPPs were linked to critical quality attributes consisting of the particle size, polydispersity index (PDI), zetapotential, thermotropic phase behavior, yield and stability. A central composite face-centered design was performed followed by multiple linear regression analysis. The size, PDI, enthalpy of the phase transition and yield were successfully modeled, whereas the models for the zeta-potential and the stability were poor. Cryotransmission electron microscopy revealed that the main structural effect on the nanoparticle architecture is caused by the use of PVA, and two differentmorphologieswere identified: i) A PLGA core coatedwith one or several concentric lipid bilayers, and ii) a PLGA nanoshell encapsulating lipidmembrane structures. The optimal formulation, identified from the OOS, was evaluated in vivo. The hybrid NPs induced antibody and Th1/Th17 immune responses that were similar in quality and magnitude to the response induced by DDA/TDB liposomes, showing that the adjuvant properties of DDA/TDB are maintained in the PLGA hybrid matrix. This study demonstrates the complexity of formulation design for the engineering of a hybrid lipid-polymer nanoparticle adjuvant. (C) 2015 Elsevier B.V. All rights reserved.
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