PH-sensitive drug loading/releasing in amphiphilic copolymer PAE–PEG: Integrating molecular dynamics and dissipative particle dynamics simulations

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Molecular dynamics (MD) and dissipative particle dynamics (DPD) simulations are integrated to investigate the loading/releasing of anti-cancer drug camptothecin (CPT) in pH-sensitive amphiphilic copolymer, composed of hydrophobic poly(β-amino ester) (PAE) and hydrophilic methyl ether-capped poly(ethylene glycol) (PEG). MD simulation is used to estimate the Flory–Huggins interaction parameters and miscibility of binary components. On this basis, DPD simulation is applied to examine the micellization of PAE–PEG, CPT loading in PAE–PEG, and CPT releasing in PAEH–PEG. With increasing concentration, PAE–PEG forms spherical then disk-like micelles and finally vesicles, as a competitive counterbalance of free energies for the formation of shell, interface and core. CPT loading in PAE–PEG micelles/vesicles is governed by adsorption-growth-micellization mechanism, and CPT is loaded into both hydrophobic core and interface of hydrophobic core/hydrophilic shell. The predicted loading efficiency is close to experimental value. Similar to literature reports, the loading of high concentration of CPT is observed to cause morphology transition from micelles to vesicles. Upon protonation, CPT is released from micelles/vesicles by swelling-demicellization-releasing mechanism. This multi-scale simulation study provides microscopic insight into the mechanisms of drug loading and releasing, and might be useful for the design of new materials for high-efficacy drug delivery.