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polymeric hydrogels (Satarkar and Hilt, 2008) and vesicles (Krack et al., 2008)
have also been reported.
9.3.2.4 Ultrasound-Responsive Systems
Ultrasound is an attractive
local physical stimulus as it can be easily focused in the body and is able to
penetrate into deep tissue (Wu and Nyborg, 2008). Low-frequency (LFU) and
high-frequency (HFU) ultrasound have been employed to release drugs from
acoustically active systems such as polymeric micelles and matrices (Husseini
et al., 2000; Kost and Langer, 2001), and more recently liposomes (Chen and
Wu, 2010; Lin and Thomas, 2003; Schroeder et al., 2007, 2009). It is proposed
that the presence of microbubbles in the structure affords the liposome sen-
sitivity to ultrasound. Insonation of acoustically active systems results in the
cavitation of nanoparticles and consequently the leakage of the vesicle con-
tents into its environment. Heating of the tissues through ultrasound may also
play a role in triggering drug release.
Research into creating lipid-based systems has focused on forming LFU-
responsive liposomes as contrast agents or for drug delivery as they have been
found to be more effective in contents release from liposomes than HFU
(Huang and MacDonald, 2004; Liu et al., 2006). However, the potential clinical
applications of ultrasound-activated liposomes may be more compatible with
HFU as they may integrate with readily available instruments. In lipid-based
self-assembled systems, it is well established that insonation and sonication of
suffi cient intensity can be employed to destabilize self-assembled systems and
so make multilamellar liposomes into unilamellar ones (Huang, 1969; Zasadz-
inski, 1986) and viscous cubic phase gels into cubosomes (Landh and Larsson,
1996; Ljusberg-Wahern et al., 1996). As ultrasound has the ability to disrupt
self-assembled bilayers, ultrasound can also penetrate through cell membranes,
which can result in cell death (Clarke and Hill, 1970; Liu et al., 1998). This
must be accounted for in ultrasound-responsive systems for use in drug deliv-
ery applications. Lin and Thomas, achieved this through the incorporation of
PEG lipids and oligo(ethylene glycol) surfactants (Lin and Thomas, 2003),
thereby tuning the liposome to be more sensitive to insonation than cell mem-
branes. Huang and MacDonald (2004) have formulated liposomes with differ-
ent lipids, which increase their sensitivity to LFU.
9.4
FUTURE DIRECTIONS OF STIMULI-RESPONSIVE SYSTEMS
As discussed, there are many types of stimuli that can be chosen to induce
phase transitions in lipid-based self-assembly systems. However, most work
has revolved around imparting responsiveness into liposomes. Other self-
assembled nanostructures such as nonlamellar liquid crystals have received
much less attention despite the potential for reversibility of structural changes
that could permit repeated on-demand administration of a drug with a single
injection. In particular, cubic and hexagonal phase dispersions may provide
future directions in which this research will head.
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