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2. The pH change causes the ionization of bilayer surfactants. Cholesterol
hemisuccinate (Kirpotin et al., 1996; Slepushkin et al., 1997; Zhang et al., 2004)
and oleic acid (Hong et al., 2002; Torchilin et al., 1992) are two mildly acidic
amphiphiles that become protonated when in acidic conditions. When exposed
to the acidic environment, a decrease in hydration of the lipid head groups
results, and, as a consequence, there is the formation of a nonbilayer structure
that can fuse with the endosome membrane and so release contents into the
cytoplasm (Chernomordik, 1996 ).
3. The pH change results in acid - catalyzed hydrolysis of specifi cally engi-
neered lipids resulting in the formation of detergents or fusion. Acid-labile
PEG-conjugated vinyl ether lipids have been used by Thompson et al. to sta-
bilize liposomes. At pH
5, hydrolysis of the ether bond results in the removal
of the PEG moiety and consequently allowing the liposome to become fuso-
genic (Boomer et al., 2003; Shin et al., 2003). Other groups have employed
acid-labile and ester (Guo and Szoka, 2001; Heller et al., 1985) linkages in
order to render liposomes pH sensitive.
4. The pH change leads to the destabilization of the bilayer through lysis,
phase separation, pore formation, or fusion. This can be achieved in vesicles
with incorporated pH-sensitive polymers such as poly(2-ethylacrylic acid)
(Mills et al., 1999) and poly(glycidol)s (Yuba et al., 2010).
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In the presence of serum, however, some liposomes lose their pH sensitivity
or become unstable (Collins et al., 1990; Roux, Lafl eur et al., 2003). This has
been somewhat overcome through the use of a sterically stabilizing PEG
coating, which is removable (i.e., dePEGylation) in order to maximize release
response on encountering a low pH.
However, two limiting issues exist for the application of pH-sensitive lipo-
somes in tumor treatment. First, the narrow pH window of between pH 7.4 in
normal tissues and tumor pH, which is typically at a minimum at 6.5, provides
only a narrow range over which the stimuli must be tuned to occur. Second,
the region of highest acidity in the tumor is in the tumor interstitium, which
is not close to the vasculature, thereby limiting its effectiveness. In light of
the issues of application to tumor treatment, the focus on potential clinical
applications of pH-sensitive liposomes has shifted somewhat to the control
of drug release in cellular components such as endosomes and lysosomes,
where the pH may be lower than 5. The pH-sensitive liposomes have been
reviewed recently for these applications (Drummond et al., 2000; Guo and
Szoka, 2003 ).
9.3.1.2 Redox, Ionic, and Osmotic Variation
Drug delivery systems
have been designed to take advantage of cellular reduction potential at dif-
ferent locations within and around cells (Saito et al., 2003; West and Otto,
2005 ). Disulfi de linkages (-S-S-) exist most commonly in cellular material as
oxidized sulfhydryl (SH) groups of cysteine moieties in peptides and proteins.
They are unique in that they form reversible covalent bonds, a property that
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