ma5b01709_si_001.pdf (1.6 MB)
Acid-Disintegratable Polymersomes of pH-Responsive Amphiphilic Diblock Copolymers for Intracellular Drug Delivery
journal contribution
posted on 2015-10-13, 00:00 authored by Lei Wang, Guhuan Liu, Xiaorui Wang, Jinming Hu, Guoying Zhang, Shiyong LiuSupramolecular vesicles, also referred
to as polymersomes, self-assembled
from amphiphilic polymers capable of synchronically loading with both
hydrophilic and hydrophobic payloads have shown promising potential
in drug delivery application. Herein, we report the fabrication of
pH-responsive polymersomes via supramolecular self-assembly of amphiphilic
diblock copolymers, poly(ethylene oxide)-b-poly(2-((((5-methyl-2-(2,4,6-trimethoxyphenyl)-1,3-dioxan-5-yl)methoxy)carbonyl)amino)ethyl
methacrylate) (PEO-b-PTTAMA), which were synthesized
via reversible addition–fragmentation chain transfer (RAFT)
polymerization of a pH-responsive monomer (i.e., TTAMA) using a PEO-based
macroRAFT agent. The resultant amphiphilic diblock copolymer then
self-assembled into vesicles consisting of hydrophilic PEO coronas
and pH-responsive hydrophobic bilayers, as confirmed by TEM and DLS
measurements. The polymersomes containing cyclic benzylidene acetals
in the hydrophobic bilayers were relatively stable under neutral pH,
whereas they underwent hydrolysis with the liberation of hydrophobic
2,4,6-trimethoxybenzaldehyde and the simultaneous generation
of hydrophilic diol moieties upon exposure to acidic pH milieu, which
could be monitored by UV/vis spectroscopy, SEM, and TEM observations.
By loading hydrophobic model drug (Nile red) as well as hydrophilic
chemotherapeutic drug (doxorubicin hydrochloride, DOX·HCl) into
the bilayer and aqueous interior of the polymersomes, the subsequent
release of Nile red and DOX·HCl payloads was remarkably regulated
by the solution pH values, and a lower pH value led to a faster drug
release profile. In vitro experiment, observed by
a confocal laser scanning microscope (CLSM), revealed that the pH-responsive
polymersomes were easily taken up by HeLa cells and were primarily
located in the acidic organelles after internalization, where the
pH-responsive cyclic acetal moieties were hydrolyzed and the embedded
payloads were therefore released, allowing for on-demand release of
the encapsulants mediated by intracellular pH. In addition to small
molecule chemotherapeutic drugs, biomacromolecules (alkaline phosphatase,
ALP) can also be encapsulated into the aqueous lumen of the polymersomes.
Significantly, the pH-triggered degradation of polymersomes could
also regulate the release of encapsulated ALP, as confirmed by ALP-activated
fluorogenic reaction.
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Keywords
diol moietiespH valueIntracellular Drug DeliverySupramolecular vesiclescyclic benzylidene acetalsTEM observationsdrug delivery applicationamphiphilic polymersPEO coronasmolecule chemotherapeutic drugsacidic organellesbilayerUVHeLa cellschemotherapeutic drugsynchronically loadingDOXmodel drugDLS measurementsamphiphilic diblock copolymersSEMintracellular pHsolution pH valuesCLSMamphiphilic diblock copolymerpolymersomeconfocal laser scanning microscopepayloadsTTAMAencapsulated ALPacidic pH milieudoxorubicin hydrochloridedrug release profile
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