Combined A³ Coupling and Click Chemistry Approach for the Synthesis of Dendrimer-Based Biological Tools

We report a versatile approach in which two highly efficient chemical reactions, multicomponent A³ coupling and alkyne-azide click chemistry, are combined to construct dendrimer-based tools for applications in biology. Using a convergent approach, dendrons with desired architecture and an alkyne at the focal point are first assembled and then stitched together via multicomponent A³ coupling reaction. The desired functional groups, including a stealth agent, imaging dye, and drug molecules, could be easily covalently linked to the surfaces of these hyperbranched macromolecules using alkyne-azide click chemistry. These A³-click dendrimers are noncytotoxic at concentrations as high as 1 μM and in fact reduce the toxicity of the drug. The dye-coated dendrimers specifically target and localize in lipid droplets. This unison methodology represents an attractive chemical strategy in exploiting the untapped potential of A³ coupling and facilitating the development of nanodevices for imaging and drug delivery.