Fabrication of unimolecular micelle-based nanomedicines from hyperbranched polymers containing both terminal and internal reactive groups

Abstract Unimolecular micelles are an attractive type of nanocarriers for drug delivery, but developing unimolecular micelle-based nanomedicine with high drug loading capacity and excellent unimolecular stability is challenging. Herein, we report the design and synthesis of hyperbranched polymers containing both terminal and internal reactive groups for fabricating the unimolecular micelle-based nanocarriers with high drug loading ability and superior unimolecular stability using selective modification. Specifically, we synthesized hyperbranched poly(amino ester)s containing terminal acrylate groups and internal R groups (named HBPAE-R) via the Michael addition polymerization of A2 + BʹB2-R monomers, wherein A represents acrylate, and B, Bʹ represents the hydrogen in primary amine and secondary amine group, respectively, whereas R represents hydroxy, alkene or alkyne groups that do not participate in the polymerization process but assist in additional modification. Then, poly(ethylene glycol) (PEG) chains were linked to the surface of HBPAE-OH (representative molecules) with the subsequent conjugation of doxorubicin (DOX, representative drug) to the internal hydroxy groups through an acid-labile hydrazide bond, to afford anti-cancer drug-loaded hyperbranched star copolymers PEG-HBPAE-DOX. The obtained nanomedicines exhibited good unimolecular stability, relatively high drug loading content and a controlled drug release behavior. The in vitro cytotoxicity experiments further demonstrated the anti-tumor efficacy of these unimolecular nanomedicines. Our approach is expected to further boost research on the fabrication of multifunctional unimolecular nanomedicines form hyperbranched polymers containing both terminal and internal reactive groups.