Stimuli-Responsive Lipid -Based Self-Assembled Systems - Self-Assembled Supramolecular Architectures: Lyotropic Liquid Crystals - page 262

Figure 9.2 Schematic for enzymatically triggered cleavage of phospholipid structure
resulting in release of internal payload. [Adapted from Lan-rong et al. (1986) with
permission from Elsevier.]
interaction between the cationic compound and the negatively charged acid
provided the trigger for release, highlighting the potential for specifi c salt
effects to provide triggers for changes in self-assembly and or release in lipid-
based systems.
9.3.1.3 Increased Expression and Activity of Proteins The up -
regulation of proteins in tumors and infl ammation and the specifi city of protein
location throughout tissues in the body have afforded a tissue-specifi c target
for drug release. This has already been exploited in polymer systems for selec-
tive delivery in tumor tissues. Due to their quick and unusual growth, tumors
often overexpress macromolecules, in particular enzymes, which can recognize
and cleave specifi c linker groups between drug and carrier or within the carrier
structure itself. Infl ammatory conditions such as cystic fi brosis, rheumatoid
arthritis, and emphysema are accompanied by an increase in the release of
elastase from phagocytic cells into extracellular compartments.
Enzymatically activated drug delivery from liposomes has been investi-
gated and reviewed (Meers, 2001). Liposomes have been designed to be acti-
vated by many macromolecules resulting in the collapse of the liposome or to
induce membrane fusion under the action of the enzyme. A common strategy
is to incorporate an enzymatically sensitive lipid to facilitate conversion of
the lipid to a fusogenic derivative, such as dioleylphosphatidylethanolamine
(DOPE), or to otherwise disrupt the bilayer structure of the liposome (see Fig.
9.2). Phospholipids are natural substrates for phospholipase enzymes—with
phospholipase A2 (Andresen et al., 2005; Davidsen et al., 2001, 2003) and C
(Montes et al., 2004; Nieva et al., 1989; Ruiz-Arguello et al., 1998) having been
investigated for liposome destabilization. A more common and specifi c strat-
egy is to build a custom phospholipid or lipopeptide with a molecular feature
that is a substrate for specifi c enzymes overexpressed in diseased tissues.
Lipids sensitive to elastase were prepared by incorporation of the N - Ac - Ala -
Ala sequence into the head group (Pak et al., 1998, 1999). Similarly, matrix
metalloproteinase (MMP-9), often overexpressed in tumors, was found to