Effects of hydrophobic chain lengths on the structure and properties of polymeric micelles: experimental and simulation studies.

Amphiphilic block copolymers with polyester-based hydrophobic segments, particularly PEG-PLA, exhibit considerable potential as carrier materials for delivering water-insoluble small-molecule drugs via self-assembled micelles. A comprehensive understanding of relationship between carrier material structures and micelle properties is critical for optimizing the drug-loading capacities, drug release behaviors and tumor cell inhibitory properties of micelle formulations. This study aims to elucidate the influences of different hydrophobic chain lengths of mPEG-PLLA on self-assembling to micelles processes, micelles crystalline properties and curcumin (CUR) encapsulation and release kinetics via experimental characterizations and dissipative particle dynamics (DPD) simulations. The results showed that micelles based on EO45LA56 with longest hydrophobic chains exhibited 107.1 nm of particle size and the optimal drug-loading performance with 80.94 % of encapsulation efficiency (EE%) and 7.36 % of loading capacity (DL%). DPD simulations clearly revealed the three-stage self-assembly processes including coarse particles, small clusters and core-shell spherical micelles. A quantitative correlation was established between the DSC-determined crystallinity of micelles and the CUR loading and release behaviors, confirming that crystallinity enhances drug-loading capacity and sustained-release performance. Release kinetic analyses based on the First-order, Korsmeyer-Peppas and Weibull models revealed that micelles with shorter hydrophobic chains exhibited diffusion-dominated release, whereas those with longer hydrophobic chains showed degradation-dominated release, with both following non-Fickian diffusion mechanisms. Therefore, this study systematically reveals the regulatory mechanisms of polyester carrier materials for drug-loaded micelle formulations underlying the quantitative structure-activity relationships of hydrophobic chain length with molecular self-assembly behaviors, crystalline properties, and drug release kinetics in mPEG-PLLA micelles via multi-scale strategies, providing mechanism insights and theoretical foundations for the rational design to meet the different requirements of indications.