Engineering of a novel adjuvant based on lipid-polymer hybrid nanoparticles: A quality-by-design approach

Fabrice Rose; Jeanette Erbo Wern; Pall Thor Ingvarsson; Marco Van De Weert; Peter Andersen; Frank Follmann; Camilla Foged

doi:10.1016/j.jconrel.2015.05.004

Engineering of a novel adjuvant based on lipid-polymer hybrid nanoparticles: A quality-by-design approach

Fabrice Rose, Jeanette Erbo Wern, Pall Thor Ingvarsson, Marco Van De Weert, Peter Andersen, Frank Follmann, Camilla Foged^*

^*Corresponding author for this work

Faculty of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

65 Citations (Scopus)

Abstract

Abstract The purpose of this study was to design a novel and versatile adjuvant intended for mucosal 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), zeta-potential, 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. Cryo-transmission electron microscopy revealed that the main structural effect on the nanoparticle architecture is caused by the use of PVA, and two different morphologies were identified: i) A PLGA core coated with one or several concentric lipid bilayers, and ii) a PLGA nanoshell encapsulating lipid membrane 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.

Original language	English
Article number	7669
Pages (from-to)	48-57
Number of pages	10
Journal	Journal of Controlled Release
Volume	210
DOIs	https://doi.org/10.1016/j.jconrel.2015.05.004
Publication status	Published - 28 Jul 2015

Bibliographical note

Funding Information:
The work was funded by Innovation Fund Denmark (grant number 069-2011-1 and Centre for Nano-Vaccine , grant number 09-067052 ). We acknowledge the Danish Agency for Science, Technology and Innovation for funding the Zetasizer Nano ZS and Innovation Fund Denmark and the Danish Ministry of Science, Technology and Innovation for funding the nano-DSC. We also thank Apotekerfonden af 1991 for funding the Bomem IR spectrometer. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication.

Publisher Copyright:
© 2015 Elsevier B.V.

Other keywords

Adjuvant
Dimethyldioctadecylammonium (DDA)
Drug delivery
Nanomedicine
Nanoparticles
PLGA
Quality-by-design (QbD)
Trehalose 6,6-dibehenate
Vaccine

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10.1016/j.jconrel.2015.05.004

Cite this

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title = "Engineering of a novel adjuvant based on lipid-polymer hybrid nanoparticles: A quality-by-design approach",

abstract = "Abstract The purpose of this study was to design a novel and versatile adjuvant intended for mucosal 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), zeta-potential, 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. Cryo-transmission electron microscopy revealed that the main structural effect on the nanoparticle architecture is caused by the use of PVA, and two different morphologies were identified: i) A PLGA core coated with one or several concentric lipid bilayers, and ii) a PLGA nanoshell encapsulating lipid membrane 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.",

keywords = "Adjuvant, Dimethyldioctadecylammonium (DDA), Drug delivery, Nanomedicine, Nanoparticles, PLGA, Quality-by-design (QbD), Trehalose 6,6-dibehenate, Vaccine",

author = "Fabrice Rose and Wern, {Jeanette Erbo} and Ingvarsson, {Pall Thor} and {Van De Weert}, Marco and Peter Andersen and Frank Follmann and Camilla Foged",

note = "Funding Information: The work was funded by Innovation Fund Denmark (grant number 069-2011-1 and Centre for Nano-Vaccine , grant number 09-067052 ). We acknowledge the Danish Agency for Science, Technology and Innovation for funding the Zetasizer Nano ZS and Innovation Fund Denmark and the Danish Ministry of Science, Technology and Innovation for funding the nano-DSC. We also thank Apotekerfonden af 1991 for funding the Bomem IR spectrometer. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. Publisher Copyright: {\textcopyright} 2015 Elsevier B.V.",

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AU - Rose, Fabrice

AU - Wern, Jeanette Erbo

AU - Ingvarsson, Pall Thor

AU - Van De Weert, Marco

AU - Andersen, Peter

AU - Follmann, Frank

AU - Foged, Camilla

N1 - Funding Information: The work was funded by Innovation Fund Denmark (grant number 069-2011-1 and Centre for Nano-Vaccine , grant number 09-067052 ). We acknowledge the Danish Agency for Science, Technology and Innovation for funding the Zetasizer Nano ZS and Innovation Fund Denmark and the Danish Ministry of Science, Technology and Innovation for funding the nano-DSC. We also thank Apotekerfonden af 1991 for funding the Bomem IR spectrometer. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. Publisher Copyright: © 2015 Elsevier B.V.

PY - 2015/7/28

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N2 - Abstract The purpose of this study was to design a novel and versatile adjuvant intended for mucosal 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), zeta-potential, 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. Cryo-transmission electron microscopy revealed that the main structural effect on the nanoparticle architecture is caused by the use of PVA, and two different morphologies were identified: i) A PLGA core coated with one or several concentric lipid bilayers, and ii) a PLGA nanoshell encapsulating lipid membrane 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.

AB - Abstract The purpose of this study was to design a novel and versatile adjuvant intended for mucosal 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), zeta-potential, 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. Cryo-transmission electron microscopy revealed that the main structural effect on the nanoparticle architecture is caused by the use of PVA, and two different morphologies were identified: i) A PLGA core coated with one or several concentric lipid bilayers, and ii) a PLGA nanoshell encapsulating lipid membrane 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.

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KW - Drug delivery

KW - Nanomedicine

KW - Nanoparticles

KW - PLGA

KW - Quality-by-design (QbD)

KW - Trehalose 6,6-dibehenate

KW - Vaccine

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M1 - 7669

ER -

Engineering of a novel adjuvant based on lipid-polymer hybrid nanoparticles: A quality-by-design approach

Abstract

Bibliographical note

Other keywords

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