pH-Sensitive Vesicles Formed by Amphiphilic Grafted
Copolymers with Tunable Membrane Permeability for Drug Loading/Release:
A Multiscale Simulation Study
Version 2 2016-08-12, 15:37Version 2 2016-08-12, 15:37
Version 1 2016-08-11, 16:03Version 1 2016-08-11, 16:03
journal contribution
posted on 2016-08-11, 00:00authored byZhonglin Luo, Yan Li, Biaobing Wang, Jianwen Jiang
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.