Nano-self-assemblies based on synthetic analogues of mycobacterial monomycoloyl glycerol and DDA: Supramolecular structure and adjuvant efficacy
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Nano-self-assemblies based on synthetic analogues of mycobacterial monomycoloyl glycerol and DDA: Supramolecular structure and adjuvant efficacy. / Martin-Bertelsen, Birte; Korsholm, Karen Smith; Christensen, Dennis; Franzyk, Henrik; Yaghmur, Anan; Foged, Camilla.
In: Molecular Pharmaceutics, Vol. 13, No. 8, 2016, p. 2771-2781.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Nano-self-assemblies based on synthetic analogues of mycobacterial monomycoloyl glycerol and DDA: Supramolecular structure and adjuvant efficacy
AU - Martin-Bertelsen, Birte
AU - Korsholm, Karen Smith
AU - Christensen, Dennis
AU - Franzyk, Henrik
AU - Yaghmur, Anan
AU - Foged, Camilla
PY - 2016
Y1 - 2016
N2 - The mycobacterial cell-wall lipid monomycoloyl glycerol (MMG) is a potent immunostimulator, and cationic liposomes composed of a shorter synthetic analogue (MMG-1) and dimethyldioctadecylammonium (DDA) bromide represent a promising adjuvant that induces strong antigen-specific Th1 and Th17 responses. In the present study, we investigated the supramolecular structure and in vivo adjuvant activity of dispersions based on binary mixtures of DDA and an array of synthetic MMG-1 analogues (MMG- 2/3/5/6) displaying longer (MMG-2) or shorter (MMG-3) alkyl chain lengths, or polar headgroup (MMG-5) and hydrophobic moiety stereochemistry (MMG-6). Synchrotron small-angle X-ray scattering experiments and cryo-transmission electron microscopy revealed that DDA:MMG-1/2/5/6 dispersions consisted of unilamellar and multilamellar vesicles (ULVs/MLVs), whereas a co-existence of both ULVs and hexosomes was observed for DDA:MMG-3, depending on the DDA:MMG molar ratio. The studies also showed that ULVs were formed, regardless of the structural characteristics of the neat MMG analogues in excess buffer [lamellar (MMG-1/2/5) or inverse hexagonal (MMG-3/6) phases]. Immunization of mice with a chlamydia antigen surface-adsorbed to DDA:MMG-1/3/6 dispersions revealed that all tested adjuvants were immunoactive and induced strong Th1 and Th17 responses with a potential for a central effector memory profile. The MMG-1 and MMG-6 analogues were equally immunoactive in vivo upon incorporation into DDA liposomes, despite the reported highly different immunostimulatory properties of the neat analogues in vitro, which were attributed to the different nanostructural charateristics. This clearly demonstrates that optimal formulation and delivery of MMG analogues to the immune system is of major importance and challenges the use of in vitro screening assays with non-dispersed compounds to identify potential new vaccine adjuvants.
AB - The mycobacterial cell-wall lipid monomycoloyl glycerol (MMG) is a potent immunostimulator, and cationic liposomes composed of a shorter synthetic analogue (MMG-1) and dimethyldioctadecylammonium (DDA) bromide represent a promising adjuvant that induces strong antigen-specific Th1 and Th17 responses. In the present study, we investigated the supramolecular structure and in vivo adjuvant activity of dispersions based on binary mixtures of DDA and an array of synthetic MMG-1 analogues (MMG- 2/3/5/6) displaying longer (MMG-2) or shorter (MMG-3) alkyl chain lengths, or polar headgroup (MMG-5) and hydrophobic moiety stereochemistry (MMG-6). Synchrotron small-angle X-ray scattering experiments and cryo-transmission electron microscopy revealed that DDA:MMG-1/2/5/6 dispersions consisted of unilamellar and multilamellar vesicles (ULVs/MLVs), whereas a co-existence of both ULVs and hexosomes was observed for DDA:MMG-3, depending on the DDA:MMG molar ratio. The studies also showed that ULVs were formed, regardless of the structural characteristics of the neat MMG analogues in excess buffer [lamellar (MMG-1/2/5) or inverse hexagonal (MMG-3/6) phases]. Immunization of mice with a chlamydia antigen surface-adsorbed to DDA:MMG-1/3/6 dispersions revealed that all tested adjuvants were immunoactive and induced strong Th1 and Th17 responses with a potential for a central effector memory profile. The MMG-1 and MMG-6 analogues were equally immunoactive in vivo upon incorporation into DDA liposomes, despite the reported highly different immunostimulatory properties of the neat analogues in vitro, which were attributed to the different nanostructural charateristics. This clearly demonstrates that optimal formulation and delivery of MMG analogues to the immune system is of major importance and challenges the use of in vitro screening assays with non-dispersed compounds to identify potential new vaccine adjuvants.
U2 - 10.1021/acs.molpharmaceut.6b00368
DO - 10.1021/acs.molpharmaceut.6b00368
M3 - Journal article
VL - 13
SP - 2771
EP - 2781
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 8
ER -
ID: 163777044