Stimuli-Responsive Polymersomes - Intracellular Delivery: Fundamentals and Applications - page 299

2.4 pH Response

2.4.1 pH Responsive Polymersomes Formed from Synthetic

Block Copolymers

Vesicles containing polymer blocks with solubility responding to changes in pH
present additional opportunities for controlled release. A pH-response can be
obtained either by using polyacid blocks (e.g. PAA) whose ionization status can be
changed by a pH variation, or by using polybase blocks (e.g. PVP: polyvinyl pyri-
dine) that can be rendered water soluble by protonation at low pH. One distinct
advantage of pH-triggered release is the fast response of the system. For example,
the acid-induced change for the polybase blocks solubility occur almost instanta-
neously, whereas the hydrolysis of PLA or PCL, occurs over time scales ranging
from minutes to days, even when it is acid-catalyzed.
We will first discuss systems based on polyacid. Since the early work of
Eisenberg's group (Zhang and Eisenberg 1995b ) on mapping the phase diagram of
“crew-cut” PAA- b -PS in dilute organic/aqueous solution, Liu & Eisenberg (Liu and
Eisenberg 2003 ) have shown rapid pH-triggered inversion of amphiphilic triblock
copolymer vesicles of PAA- b -PS- b -P4VP in organic/aqueous solution mixtures. For
vesicles formed from a PAA- b -PBD diblock copolymer in water, Discher's group
(Geng et al. 2005 ) observed that a sudden increase in pH induced the rapid (~min-
utes) transition of vesicles into worms and spheres. Chiu's group has recently
reported an interesting work on polymersomes with pH-responsive transmembrane
channels (Chiu et al. 2008 ). The copolymers used to form vesicles were not block
copolymers but rather random copolymers of acrylic acid (AAc) and distearin acry-
late (DSA), that were obtained from partial transesterification of poly(N-acryloxy-
succinimide) (poly(NAS)) with distearin (a lipid graft) followed by thorough
hydrolysis of the un-reacted NAS to AAc units. Using a double emulsion technique
in a water/oil/water system and a copolymer with an average molecular weight of
2.97 × 10 5 g mol −1 and a composition of 9.1 mol% DSA, they prepared large poly-
mersomes that contained small polymersomes and had a pH of 4.0-5.5 within the
interior aqueous compartment (see Fig. 3 ). When the pH was increased to 6.5, the
vesicles became permeable to hydrophilic solutes. The authors suggested that un-
ionized AAc-rich regions in the hydrophobic bilayer regions of distearate grafts
(parallel to the aligned lipid chains) could act as pH-responsive channels. When the
pH was increased to 6.5, AAc ionization would occur and the resulting abrupt
disruption of hydrogen bonds and hydrophobic association of un-ionized AAc
would create permeable channels. This system is an elegant example of vesicles
that were equipped with transmembrane channels without requiring the incorpora-
tion of channel-forming proteins. Similarly, Eisenberg's group (Yu et al. 2009 )
has also reported polymersomes with pH-induced reversible change of permeabil-
ity to water and to proton. They call them “breathing” polymerosmes, which
are prepared from triblock copolymer poly(ethylene oxide) 45 - b -polystyrene