Hydrogen-Bonded Bottlebrush Copolymers Carrying “Two-in-One” Prodrug for Boosting Synergistic Chemo/Photothermal Antitumor Therapy

Employing hydrogen-bonded (H-bonded) bottlebrush architecture to realize intelligent therapeutics is particularly advantageous but rare. Herein, we target the construction of H-bond-mediated supramolecular bottlebrush copolymer micelles, FU-IR780@P1, for synergistic cancer chemo/photothermal therapies (CT/PTT). To do so, we first design an H-bonding amphiphilic bottlebrush random copolymer carrier, P(NBDAP-<i>co</i>-NBPEO) (i.e., P1, poly(norbornene-terminated diaminopyridine-<i>co</i>-norbornene-terminated poly(ethylene oxide)), featuring randomly dispersed dual functionalities: H-bonding DAP (diaminopyridine) motifs and hydrophilic PEO (poly(ethylene oxide)) content. On the other hand, by tethering the chemotherapeutic 5-fluorouracil (FU) onto the photothermal agent IR780, "two-in-one" multifunctional prodrug, FU-IR780, is fabricated, integrating an H-bonding site, chemodrug, photothermal, and fluorescence imaging in single formulation. Thanks to the H-bonding DAP/FU association-mediated self-assembly, supramolecular FU-IR780@P1 nanomedicine is thus created, where FU-IR780 can be released on demand via pH/thermal-responsive rupture of the DAP/FU H-bonding interaction, thus enabling intelligent and synergistic CT/PTT. Such H-bonded bottlebrush polymers contribute a fine toolbox that is conducive to attain biomedical requirements for intelligent antitumor treatments.