Stimuli-Responsive Polymersomes - Intracellular Delivery: Fundamentals and Applications - page 293

and non-antigenic (stealth) polymersomes for a long circulation time in the
bloodstream (Knop et al. 2010 ). The most used hydrophilic polymer is polyeth-
ylene glycol (PEG, also known as polyethylene oxide, PEO), which is a neutral
polymer and confer the steric stabilization to polymersomes (Lasic and
Papahadjopoulos 1998 ; Semple et al. 1998 ). Other neutral polymers have also
been developed, such as poly(2-methyloxazoline) (PMOXA) (Nardin et al. 2000 ),
which also shows low non-specific protein binding ability (Woodle et al. 1994 )
and poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC), a promising
hydrophilic block reported recently (Du et al. 2005 ; Du and Armes 2009 ). Several
hydrophilic polymers attempted first for stealth liposomes, including poly[N-
(2-hydroxypropyl)methacrylamide] (Whiteman et al. 2001 ), poly-N-vinylpyrroli-
dones (Torchilin et al. 2001 ), polyvinyl alcohol (Takeuchi et al. 2001 ) and
amino-acid-based biodegradable polymer (Romberg et al. 2007 ), can also be used
to design the hydrophilic block of polymersomes. Hydrophilic peptide-based
polymers have attracted considerable interests for their high biocompatibility
(Kukula et al. 2002 ; Bertin et al. 2010 ).
The polyacrylic acid (PAA) is a typical non-neutral hydrophilic block for
polymersome preparation (Zhang and Eisenberg 1995b ), which is anionic in physi-
ological pH (=7.4). Kataoka's group has shown that anionic polymer spherical
micelles had significant promise over neutral spherical micelles in evading the
mononuclear phagocytic system of liver and spleen that is primarily responsible for
the clearance of foreign particles (Yamamoto et al. 2001 ). A recent research in
Discher's group (Christian et al. 2010 ) has taken advantage of this anionic profile
to make very long-circulating polymersomes with a red cell-like surface charge.
As a matter of fact, the life span of healthy human red blood cells is of 100 days,
while the polymersomes with neutral PEG hydrophilic shell circulate for 1-2 days.
The red blood cells' external “glycocalyx” contains sialic acid which imparts a
negative surface charge of approximately −15 mV. Discher's group has achieved
this surface charge of polymersomes by blending an anionic diblock copolymer,
poly(acrylic acid)- b -polybutadiene (PAA- b -PBD), with a neutral diblock copolymer
(PEG- b -PBD) under physiological conditions.

1.2 Structural Consideration of Block Copolymers

for Polymersome Formation

The unfavourable contact between water and the hydrophobic part of amphiphilic
molecules leads to their self-assembly into small aggregates in water with a hydro-
phobic core and a hydrophilic shell. The aggregates display rich polymorphism, the
simplest structure being spherical micelles. If only isotropic fluidlike arrangements
are considered in the hydrophobic core and in the hydrophilic shell, the self-orga-
nizing structures can be partially predicted on the basis of concepts developed for
small amphiphilic molecules, such as the 'spontaneous curvature' or the 'critical
packing parameter', defined as p = v / al , where v is the hydrophobic volume, a is the