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cleave lipopeptides containing the specifi c motif sensitive to this gelatinase
enzyme, resulting in release of the liposome cargo (Sarkar et al., 2005; Terada
et al., 2006). With a view to activation by quinone reductase, Ong et al. (2008)
have reported the reductive cleavage of quinone head groups from phospho-
lipid derivatives to reveal DOPE, leading to liposome release of incorporated
model drug molecules. An alternative approach has been to sensitize lipo-
somes through the use of cholesterol esters sensitive to alkaline phosphatase
(Davis and Szoka, 1998). Incorporation of transmembrane proteins into DOPE
particles has been known for decades to induce bilayer formation, providing
liposomes stabilized by incorporated proteins. The degradation of the protein
by trypsin has been long proposed as a means of inducing liposome destabi-
lization (Lan - rong et al., 1986 ).
9.3.2
External Stimuli
The clinical advantage of physiological triggers inducing phase changes in
materials and thus stimulate drug release centers on the simplicity and specifi c-
ity of the process. The problem with this approach, however, is the potential
for nonspecifi c activation and release of material in tissues other than the
target tissues.
Accidental release may occur, for example, in infl amed tissues when target-
ing tumors or tissues where enzymes are expressed albeit at much lower levels
than the target tissues, which may lead to side effects. Having specifi c temporal
and spatial control over exactly where the delivery system is activated over-
comes these concerns, although it introduces increased complexity and likely
requires health professional intervention. Hence systems that are responsive
to external stimuli that can be controlled in a noninvasive manner have
attracted signifi cant attention in the literature.
9.3.2.1 Temperature Change
Temperature is a popular trigger mecha-
nism to control the structure of self-assembled systems as the assembly of
molecules is inherently affected by changes in temperature, and temperature
is a very accessible trigger for many therapeutic applications. Hyperthermic
conditions have been used to induce cytotoxicity (Dewhirst et al., 1997) and
can augment some treatments (Hettinga et al., 1997). The primary means of
inducing the hyperthermic environment are summarized in Table 9.2. Laser
heating using a near-infrared (NIR) laser is commonly reported. An electric
fi eld is also reportedly able to induce localized heating and release of contents
from “magnetoliposomes.” The simple application of heat pack or cool pack
to manipulate self-assembled structure and modulate drug release has also
been reported. Hence there are a variety of potential approaches available to
induce drug release using hyperthemia as the common trigger.
Thermoliposomes
As is the case for enzymatically activated systems, lipo-
somal systems sensitive to temperature have received the most attention in
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