Stimuli-Responsive Polymersomes - Intracellular Delivery: Fundamentals and Applications - page 298

O

S SS O

OMe

16

S

30

Self-assembling and
hydrophilic drug loading

-S-S- -S-S-

-S-S- -S-S-

-S-S- -S-S-

Hydrophilic core

-S-S- -S-S-

-S-S- -S-S- Hydrophobic membrane

-S-S- -S-S-

-S-S- Reductive site

-S-S- -S-S-

Fig. 2 Polymersomes formed from the block copolymer, PEG 17 -SS-PPS 30 , where the hydrophilic
poly(ethylene glycol) (PEG) and the hydrophobic poly(propylene sulfide) (PPS) are connected
with a reductive disulfide group. (Reproduced from ref. Cerritelli et al. 2007 )

reduction-sensitive disulphide link (-S-S-) was placed between the two blocks
(see Fig. 2 ) (Cerritelli et al. 2007 ). Intracellular glutathione or cysteine can reduc-
tively cleave these links and thereby destabilise the system. Other reductive com-
pounds such as dithiothreitol and tris(2-carboxyethyl)phosphine can also cleave the
disulfide bonds (Li et al. 2006b ).
Polymersomes formed from the block copolymer PEG-SS-PPS were demon-
strated to break down in the presence of intracellular concentrations of cysteine. In
cellular experiments, uptake, disruption, and release were observed within 10 min
of exposure to cells, well within the time frame of early endosome and endolyso-
somal processing. This system presents obvious advantages over the hydolysis and
the oxidation responsive polymersomes reviewed above. The hydrolysis process is
not nearly as fast (>hours) and the low pH needed to accelerate the hydrolysis is
encountered only within the lysosomal compartment of the endosomal-lysosomal
processing pathway. Oxidative conditions are also not encountered until the vesi-
cles are processed within the lysosome. In both cases, the release can be too late for
sensitive biological macromolecules, i.e. within the less desirable lysosome, where
biomolecular drugs are exposed to very harsh conditions, rather than the more
desirable endosome. In contrast, reduction-responsive polymersomes can rapidly
burst within the early endosome, releasing their contents prior to exposure to the
harsh conditions encountered after lysosomal fusion. This system may be useful in
cytoplasmic delivery of biomolecular drugs such as peptides, proteins, oligonucle-
otides, and DNA.