Clickable Cubosomes for Antibody-Free Drug Targeting and Imaging Applications

The combination of copper-free click chemistry with metabolic labeling offers new opportunities in drug delivery. The objective of this study was to determine whether cubosomes functionalized with azide or dibenzocyclooctyne (DBCO) groups are able to undergo copper-free click chemistry with a strained cyclooctyne or azide, respectively. Phytantriol-based cubosomes were functionalized using phospholipids bearing an azide or DBCO group. The modified cubosome dispersions were characterized using dynamic light scattering, cryo-TEM, and small-angle X-ray scattering. The efficiency of "clickability" was assessed by reacting the cubosomes with a complementary dye and determining bound and unbound dye via size exclusion chromatography. The clickable cubosomes reacted specifically and efficiently with a click-Cy5 dye with minor changes to the size, shape, and structure of the cubosomes. This indicates that cubosomes can retain their unique internal structure while participating in copper-free click chemistry. This proof of concept study paves the way for the use of copper-free click chemistry and metabolic labeling with cubosomes for targeted drug delivery and imaging.