Artificial Membrane Fusion Triggered by Strain-Promoted Alkyne–Azide Cycloaddition

Artificial systems for controlled membrane fusion applicable for drug delivery would ideally use triggers that are orthogonal to biology. To apply the strain-promoted alkyne–azide cycloaddition (SPAAC) to drive membrane fusion, oxo-dibenzocyclooctyne (ODIBO)–lipid 1 was designed, synthesized, and st...

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Bibliographic Details
Published in:Bioconjugate chemistry 2017-04, Vol.28 (4), p.923-932
Main Authors: Whitehead, Stuart A, McNitt, Christopher D, Mattern-Schain, Samuel I, Carr, Adam J, Alam, Shahrina, Popik, Vladimir V, Best, Michael D
Format: Article
Language:English
Subjects:
Alkynes
Alkynes - chemistry
Aza Compounds - chemistry
Azides - chemistry
Biochemistry
Biology
Composition effects
Cycloaddition
Cycloaddition Reaction
Cyclooctanes - chemistry
Dilution
Drug delivery
Fluorescence resonance energy transfer
Lipid structure
Lipids
Lipids - chemistry
Liposomes
Liposomes - chemistry
Liposomes - ultrastructure
Membrane composition
Membrane Fusion
Membranes
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Summary:Artificial systems for controlled membrane fusion applicable for drug delivery would ideally use triggers that are orthogonal to biology. To apply the strain-promoted alkyne–azide cycloaddition (SPAAC) to drive membrane fusion, oxo-dibenzocyclooctyne (ODIBO)–lipid 1 was designed, synthesized, and studied alongside azadibenzocyclooctyne (ADIBO)–lipids 2–4 to assess fusion with liposomes containing azido–lipid 5. Lipids 1–2 were first shown to be effective for liposome derivatization. Next, fusion was evaluated using liposomes containing 1 and varying ratios of PC and PE via a FRET dilution fusion assay, and a 1:1 PC-to-PE ratio yielded the greatest signal change attributed to fusion. Finally, lipids 1–4 were compared, and 1 yielded the greatest triggering of fusion, while 2–4 yielded varying efficacies depending on the structural features of each lipid. Fusion was further validated through STEM studies showing larger multilamellar assemblies after liposome mixing, and FRET assay results supporting the mixing of liposome aqueous contents. This work provides a platform for triggered fusion toward drug delivery applications and an understanding of the effects of lipid structure and membrane composition on fusion.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.6b00578