Tailoring polyester-based diblock copolymers for boron-enhanced drug delivery: synthesis, kinetics, and nanoparticle characterization

Here, we present the synthesis of diblock copolymers of poly(ethylene glycol) methyl ether-b-poly(epsilon-caprolactone) (mPEG-b-PCL) with prop-2-ynyl (propargyl) substituents on epsilon-caprolactone (epsilon-CL) units. The copolymerization of epsilon-CL with its propargylated derivative initiated by mPEG, followed by a thiol-yne click reaction with 1-thioglycerol, results in copolymers featuring vicinal diols capable of reversibly binding boronic acid derivatives. Detailed kinetic experiments were conducted to monitor the homo- and copolymerization of epsilon-CL with 7-(prop-2-ynyl)oxepan-2-one. By analyzing the kinetic data, we calculated the copolymerization parameters and mapped the composition profile of the resulting copolymers. The resulting gradient copolymers exhibited a lightly tapered composition profile, with an increase in epsilon-CL consumption at higher conversions where the more reactive 7-(prop-2-ynyl)oxepan-2-one is almost depleted. These findings were further validated through quantum chemical calculations, providing insights into the precise structure and composition of the copolymers. Characterization of the self-assembled nanoparticles was performed using static and dynamic light scattering, and their morphology was visualized via conventional and cryogenic transmission electron microscopy, confirming the formation of small, homogeneous spherical micelles. To demonstrate their potential in drug delivery, we combined a model drug consisting of a phenylboronic acid-conjugated metallacarborane cluster with diblock copolymer, utilizing reversible bonding between diols and phenylboronic acid and investigated the impact of drug loading on nanoparticle properties. Our comprehensive study underscores the importance of precise synthesis and structural prediction in the development of biodegradable diblock copolymers, offering valuable insights into their synthesis, kinetic behavior, and nanoscale assembly for advanced drug delivery applications.