Zwitterionic Polycatechols for Covalent Conjugation With Bortezomib and pH-Triggered Release

Abstract

The therapeutic efficacy of Bortezomib (BTZ) is severely limited by its low solubility, poor stability in vivo and nonspecific toxicity. PEGylated nanocarriers can improve drug delivery efficiency, but their applications often suffer from low drug loading, premature leakage and accelerated blood clearance phenomenon. Herein a kind of catechol-functionalized and sulfobetaine-based zwitterionic block copolymer (PGMAD-PSBMA) is prepared by RAFT copolymerization and an epoxy-amino click reaction. And then PGMAD-PSBMA is readily used to conjugate with BTZ by the formation of dynamic boronate bonds to obtain zwitterionic BTZ prodrug (PGMAD@BTZ-PSBMA) and PGMAD@BTZ-PSBMA micelles. The structure and morphology, physicochemical characteristics, drug loading, pH-triggered drug release as well as in vitro cytotoxicity of PGMAD@BTZ-PSBMA micelles are investigated in detail. The results demonstrate that PGMAD@BTZ-PSBMA micelles can not only possess high drug loading (12.9%) and stable dispersion in physiological pH condition (pH 7.4), but also respond to the tumor acid microenvironment and achieve pH-responsive BTZ release. The nanocarriers designed here readily combine the desirable functions of polycatechols for stable conjugation and acid-triggered release and polysulfobetaines for long circulation in blood, which have great potential to enhance therapeutic efficacy and reduce toxic side effects of BTZ and other boronic acid-containing drugs, such as Ixazomib and Steboronine.