Synthesis and evaluation of clickable block copolymers for targeted nanoparticle drug delivery.

Polymeric nanoparticles with multifunctional capabilities, including surface functionalization, hold great promise to address challenges in targeted drug delivery. Here, we describe a concise, robust synthesis of a heterofunctional polyethylene glycol (PEG), HO-PEG-azide. This macromer was used to synthesize polylactide (PLA)-PEG-azide, a functional diblock copolymer. Rapid precipitation of this copolymer with a hydrophobic cargo resulted in the generation of monodisperse nanoparticles with azides in the surface corona. To demonstrate conjugation to these nanoparticles, a regioselectively modified alkyne-folate was employed as a model small molecule ligand, and the artificial protein A1 with an alkyne moiety introduced by unnatural amino acid substitution was selected as a model macromolecular ligand. Using the copper-catalyzed azide-alkyne ligation reaction, both ligands exhibited good conjugation efficiency even when low concentrations of ligands were used.