Drug-Carrying Bottlebrush Copolymers via ROMP of Anionically Polymerized Hyperbranched Polyglycerol

Abstract

This work presents the synthesis of bottlebrush copolymers with anionically polymerized hyperbranched polyglycerol (HPG) side chains via ring-opening metathesis polymerization (ROMP). The efficacy and mechanism of the bottlebrush copolymer and its macromonomer as carriers for the insoluble drug paclitaxel (PTX) were evaluated. Starting with O-(2-aminoethyl)polyethylene glycol (H₂N-PEG–OH), the terminal −NH₂ group was first protected by the triphenylmethyl (Trt) group, and then anionic ring-opening polymerization of PG was initiated from the −OH group by CsOH. Subsequently, ROMP was performed to obtain bottlebrush HPG with a degree of polymerization reaching 200. The abundant −OH groups of HPG were reacted with succinic anhydride and then PTX. The resulting covalent-bonded bottlebrush-PTX conjugate (denoted as BB-5-PTX) is amphiphilic and displayed two stages of self-assembly in the aqueous phase at a concentration above the critical micelle concentration (CMC). The antitumor activity of BB-5-PTX was examined at concentrations below the CMC and showed a notable enhancement compared to its macromonomer-PTX counterpart (MM-4-PTX₇). Cellular uptake studies and flow cytometry unveiled the mechanism of this increased efficacy. Despite endocytosing fewer molecules, the bottlebrush copolymer effectively delivers more drug units across the cell membrane due to its amphiphilicity and higher number of binding sites per molecule than its corresponding macromonomer.