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general aspects of each of these stimuli-responsive areas. Advances in stimuli-
responsive drug delivery from self-assembled systems have been recently
reviewed (Bayer and Peppas, 2008; Couvreur and Vauthier, 2006; Torchilin,
2009), with a focus on cancer therapy and on liposomes and other lipid systems
(Andresen et al., 2005 ; Kaasgaard and Andresen, 2010 ).
It is somewhat obvious that for application in drug delivery, the aim is to
control the availability of the drug from the carrier to the general circulation
if systemic availability is desired or the intended site of action for localized
delivery. It is, therefore, useful to briefl y discuss drug release mechanisms so
that subsequent discussion of stimuli responsiveness can be understood in
terms of the particular mechanism at play.
Release of a drug from self-assembled systems is recognized as being via
three means, namely, (i) passive diffusion, (ii) nonspecifi c degradation of the
carrier through normal physiological processes such as phagocytic uptake and/
or hydrolytic destruction, or (iii) through covalent release. Passive diffusion
relies on a chemical potential gradient to drive the drug from the self-assembled
system into the bulk liquid into which it is introduced, such as the bloodstream.
Drug is maintained inside the self-assembled system prior to administration
purely by partitioning or equivalence of concentration in the internal and
external aqueous compartments—dilution is the trigger by which drug is
released by reducing the concentration of a drug in the external surrounding
fl uid. Degradation is the usual mechanism controlling release from solid matri-
ces made from, for example, biodegradable polymer or solid lipid nanoparti-
cles, in which hydrolysis induces chemical degradation of the polymer structure
and erosion of the particle. Covalent drug release is usually achieved through
incorporation of a functional linker within the self-assembled system that is
cleaved in the particular environment of the target tissue. These latter systems
often are achieved through pH-sensitive functional groups that decouple drug
from the carrier in hypoxic environments or enzymatically activated systems.
Both of these types of systems are reviewed later in the chapter.
9.3.1
Endogenous Stimuli
The “holy grail” of therapy is for there to be absolutely no intervention in the
management and treatment of disease—the development of biochemical
markers or symptoms that are not noticeable to the patient would trigger drug
release automatically in response to some measured indicator. Such systems
are already in use for the treatment of diabetes—implantable mechanical
pumps that release insulin in response to falling glucose levels in the blood
are on the market. Hence, drug delivery systems that are responsive to varia-
tion in physiological conditions are sought after. The ability to induce variation
in lipid-based systems (rather than mechanical-based systems) using physio-
logical stimuli has not been used to such great advantage, particularly in
consideration of the vast capability of cellular structures to utilize changes in
lipid assembly to modulate function.
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