Design and synthesis of amphiphilic statistical copolymers forming unimeric micelles with thermoresponsive behaviour in the physiological range

Abstract

A crucial aspect of drug development is designing carriers that efficiently solubilise therapeutic agents while ensuring stability, minimising cytotoxicity, and enabling targeted delivery. Multimolecular micelles are commonly used but often destabilise under physiological conditions. This study focuses on developing stable, unimolecular carriers with high loading capacity for hydrophobic cargos. The synthesis of amphiphilic copolymers based on oligoethylene glycol acrylate (OEGA) and butyl acrylate (BA) was optimised to achieve consistent statistical comonomer incorporation for molecular weights up to 600 kDa with low dispersity via activator regenerated by electron transfer atom transfer radical polymerisation (ARGET ATRP). The copolymers demonstrated reversible thermoresponsive behaviour in aqueous media, with adjustable lower critical solution temperature (LCST) between 25 and 70 °C based on the comonomer ratio. Below the LCST, unimolecular micelles formed with sizes tunable from 4 to 22 nm diameter through the copolymers’ molecular weight and hydrophobicity. Micellar stability was unaffected by dilution and physiological salt concentrations unless heated above the LCST, triggering aggregation into defined nanosized colloids, which holds potential for temperature-controlled accelerated drug release. The maximum loading capacity for pyrene as a small molecule proxy varied with molecular weight and copolymer composition and reached up to 36 molecules per unimolecular carrier, making these copolymers promising candidates for smart drug delivery systems.