pH-Sensitive Vesicles Formed by Amphiphilic Grafted Copolymers with Tunable Membrane Permeability for Drug Loading/Release: A Multiscale Simulation Study

By synergizing molecular dynamics and dissipative particle dynamics simulations, we investigate the assembly of amphiphilic grafted copolymers into vesicles and the loading/release of doxorubicin hydrochloride (DOX·HCl). The copolymers, PAE-<i>g</i>-PEGLA, comprise pH-sensitive poly­(β-amino ester) grafted with hydrophilic poly­(ethylene glycol) and hydrophobic poly­(d,l-lactide). The vesicle formation is revealed to follow an aggregation–rearrangement mechanism, in which small clusters first form, then rearrange, and finally merge into bilayer-structured vesicles. The vesicle interior size and membrane thickness are substantially affected by the exchange quantity and frequency between tetrahydrofuran and water. At pH = 7, DOX·HCl is loaded into the vesicle interior, and the loading efficiency increases with increasing polymer concentration. At pH < 7, PAE blocks are protonated and hydrophilic, which causes the structure transition of membrane thus tuning membrane permeability for DOX·HCl release. When PLA blocks become longer, vesicle stability is enhanced and DOX·HCl release is suppressed. To mimic controlled release, a mixture of two copolymers is proposed, which form hybrid vesicles and lead to a moderate release rate of DOX·HCl. After multiple sequential pH variations between acidic and neutral circulatory environment, DOX·HCl is gradually released from the hybrid vesicles. This multiscale simulation study identifies the key factors governing vesicle formation and drug loading/release, and provides bottom-up insights toward the design and optimization of new amphiphilic polymers for high-efficacy drug delivery.