Stimuli-Responsive Polymersomes - Intracellular Delivery: Fundamentals and Applications - page 292

by a bilayer membrane made of amphiphilic block copolymers. Because of the high
molecular weight of the block copolymers, the polymer bilayer has a higher thick-
ness (10-30 nm) than that of the lipid blilayer (3-5 nm). Moreover, the critical
micelle concentrations C CMC as well as the amphiphile exchange rates between
aggregates (generally proportional to C CMC ) are lower for polymersomes than those
for liposomes. These confer polymersomes greater toughness and superior stability
than liposomes. Polymersomes are therefore excellent candidates for drug carriers.
Their interior cavity can be used for the encapsulation of hydrophilic substances
such as hydrophilic therapeutics, while the hydrophobic bilayer membrane can trap
hydrophobic moieties such as hydrophobic therapeutics or dye molecules for bio-
medical imaging (Discher and Ahmed 2006 ). More interestingly, polymer chemis-
try enables almost unlimited molecular design of polymersomes (Taton and Gnanou
2006 ). Their membrane properties can be extensively tailored by variation of
chemical structures of each polymer component (Napoli et al. 2006 ; Mabrouk et al.
2009b ; Battaglia and Ryan 2005 ). Targeted transport can be achieved by taking
advantage of the many possibilities to end-functionalize the copolymers (Lin et al.
2004 ; Meng et al. 2005 ; Broz et al. 2005 ; Ben-Haim et al. 2008 ; Christian et al.
2007 ; Hammer et al. 2008 ; Zupancich et al. 2009 ; Robbins et al. 2010 ; Nehring
et al. 2009 ; Geng et al. 2006 ; Demirgoz et al. 2009 ; van Dongen et al. 2008 ;
Opsteen et al. 2007 ; Sun et al. 2009 ). The controlled release of therapeutic sub-
stances can be integrated through the use of copolymers with blocks that respond
to external or internal stimuli in the treated disease sites (Meng et al. 2009 ; Li and
Keller 2009 ; Du and O'Reilly 2009 ; Onaca et al. 2009 ).
In order to achieve effective intracellular drug delivery, the polymersomes
should be engineered to (1) survive in biological fluids and extracellular space,
(2) bind to cell surface, (3) escape or survive in the endocytic pathway, (4)
release drug when the cytosol or another desired intracellular compartment is
reached. Development of “smart” polymersomes, i.e., stimuli-responsive poly-
mersomes bearing a protective coat, site-specific targeting ligands and a cell-
penetrating function, is the current research trend in this field. In this review,
we will focus on the stimuli-responsive properties of polymersomes made from
amphiphilic block copolymers. The responsiveness is mainly achieved via
proper hydrophobic block design so that the hydrophobic core of the membrane
can be altered or destroyed under the action of chemical and physical stimuli.
Before the detail discussion of this issue, we first briefly discuss the choice of
hydrophilic block, the structural requirement of block copolymer for polymer-
some formation, and the techniques employed for polymersome preparation,
and strategies to get controlled release.

1.1 Hydrophilic Block Choice

Biocompatible and flexible hydrophilic polymers are usually utilized as the hydro-
philic block of the amphiphilic block copolymers in order to design non-fouling