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

Abstract

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-g-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.

Controllable multicompartment morphologies from cooperative self-assembly of copolymer–copolymer blends

“…As a mesoscale method, DPD can be used to study physical phenomena at larger time and spatial scales than typical molecular dynamics. It has been successfully used for determining the mesophase self-assembly of block copolymers with various chain architectures 11,55 .…”

“…In DPD, the many-body system evolves under Newton's second law m dv i /dt = f i , where [55][56][57] .…”

“…55 . The repulsive parameters of 6 the three typical systems, i.e., AB, AB/AC and AB/AC/AD, were mainly based on the PS-b-PEO system.…”

Smart Polymers for Advanced Applications: A Mechanical Perspective Review

“…To understand their conformation change under different pH environments, the mesoscale simulation technique DPD has been widely adopted. For e.g., the self-assembly process of amphiphilic copolymers (PAE-g-PEG) into vesicles, and their drug loading/release of doxorubicin drug molecules at different pH environments, have been extensively studied through MD and DPD simulations (Luo and Jianwen, 2012;Luo et al, 2016). Note that in these MD and DPD simulations, the polymers have fixed charges according to the pH condition, which ignores the charge fluctuation in reality.…”

Nanoarchitectures by hierarchical self-assembly of ursolic acid: entrapment and release of fluorophores including anticancer drug doxorubicin

“…Release study of the entrapped dye molecules to buffer solutions at physiological pH (7.2) is an integral part of the drug entrapment studies for prospective use of the self assemblies in drug delivery experiments. [51][52][53][54] To examine this, initially a Rho-B (0.54 mM) loaded gel of ursolic acid (54.8 mM) in DMSO-water (5 : 3, 0.16 mL) was covered with a buffer solution (10 mM, 1 mL, pH 7.2) and the release was monitored by UV-visible spectroscopy at various time intervals. Slow release of Rho-B from the Rho-B-loaded gel to the buffer solution was observed.…”