Self-Assembly and Structural Polymorphism of Polymer–Lipid Mimetics Prepared by Azide–Alkyne Cycloaddition

The use of the azide–alkyne cycloaddition click reaction was extended to the construction of lipid–polymer conjugates. A lipid mimetic (1,3-dihexadecyloxypropan-2-ol, DHP), functionalized with either azide or alkyne groups, was conjugated to end-functionalized polymers, yielding well-defined hybrid macromolecules composed of a lipid–mimetic moiety covalently linked to a polymer chain. A diverse range of polyethers, polyacrylates, and polyoxazolines with varying chain topology was employed. The polymers were prepared via anionic polymerization, atom transfer radical polymerization, and cationic ring-opening polymerization, followed by postpolymerization functionalization. The conjugation reactions proceeded quantitatively with high yields, enabling the straightforward and efficient preparation of well-defined lipid–polymer hybrids. The aqueous solution properties were investigated by a variety of methods─dye solubilization, turbidimetry, light scattering, and cryo-TEM. The lipid–polymer hybrids spontaneously self-associated above a certain critical concentration into a plethora of aggregates of different morphologies that were precisely parametrized in terms of size, molar mass, aggregation number, and ζ-potential. The structural polymorphism was mostly driven by polymer chain topology that changes from a long backbone without side groups to a shorter backbone with increasing in length/volume pendant groups.