Stimuli-responsive multifunctional micelles of ABC vs. ACB triblock terpolymers using reversible covalent bonding of phenylboronic acid: controlled synthesis, self-assembly and model drug release

Abstract

We report the synthesis and self-assembly of well-defined, amphiphilic, biodegradable and glucose- and pH-responsive ABC and ACB triblock terpolymer multifunctional micelles in aqueous media using blocks consisting of poly(ethylene oxide) (PEO), poly(ε-caprolactone) (PCL), and boronic acid-functionalised poly(ε-caprolactone) (PBA). The terpolymers were synthesized by sequential ring–opening polymerisation (ROP) and functionalised using phenylboronic acid pinacolate via alkyne − azide cycloaddition (CuAAC). Lastly, the pinacole groups were deprotected by mild acidic catalysis to introduce phenylboronic acid for controlled drug solubilisation and delivery. ABC and ACB triblock terpolymers self-assembled into various multifunctional micelles in aqueous media depending on the state of the phenylboronic acid (pinacol protected, BAPin vs. deprotected, BA) and on the preparation procedure, as shown by dynamic and static light scattering (DLS and SLS) and by cryogenic transmission electron microscopy (cryo-TEM). The fluorescence probe Alizarin Red S (ARS) was used as a model drug, which covalently binds to BA, and its uptake was monitored by fluorescence spectroscopy and high-performance liquid chromatography (HPLC). When adding a surplus of glucose, which competitively binds to BA, ARS was released as a function of micelle morphology (core–shell corona (ABC) vs. mixed-shell (ACB) micelles). When transferring ARS-loaded nanoparticles to phosphate buffer saline (PBS) solutions at different pH values (7.4 and 5 or 3) simulating physiological and tumour conditions, respectively, ABC micelles released ARS only at low pH, while ACB micelles released ARS in response to glucose and to both low and physiological pH values. Therefore, in this system, ABC micelles are better suited for drug delivery to tumour cells than their ACB counterparts because they retain their cargo in PBS at high glucose concentrations but release it under acidic conditions, which occur in hypoxic cancer cells, thus highlighting the potential of ABC micelles for targeted drug delivery in the context of cancer therapy.