Stimuli-Responsive Lipid -Based Self-Assembled Systems - Self-Assembled Supramolecular Architectures: Lyotropic Liquid Crystals - page 259

The use of physiological triggers to date in drug delivery, particularly in
polymers, has largely exploited the difference in physiological conditions
between pathological and normal tissues in conditions such as cancer and
infl ammatory diseases.
9.3.1.1 pH Variation Differences in pH in tissue and cellular components
in pathological conditions provide points of potential exploitation. Normal
pH gradients exist naturally throughout the body, for instance, inside some
parts of the gastrointestinal tract, and cellular components differ from the
extracellular pH of 7.4. This is commonly utilized to enhance oral drug bio-
availability through the formulation of drug molecules as salts of base forms.
In drug delivery it is utilized in selective drug release through preparation of
enteric coatings for tablets, which protect a drug from the harsh acidic environ-
ment of the stomach, allowing a drug to be released at a more acceptable pH
in the intestines.
Abnormal pH gradients exist between normal tissues and those affected by
conditions such as cancer, infl ammation, and infection. Sites of infection, site
of infl ammation, metastasized tumors and primary tumors have a signifi cantly
lower pH to normal tissues (Gerweck and Seetharaman, 1996). For instance,
60 min after an infl ammatory infection, the pH at the site of infl ammation
drops to 6.5. These disease states have been the target of many lipid-based
self - assembly systems.
pH-Sensitive systems have been extensively investigated since the early
1980s as a means of increasing drug delivery to tumors. Liposomal systems
have been designed to be systemically dosed and accumulate in tumors where
they are designed to release their contents under mildly acidic conditions
(Yatvin et al., 1980). These are made responsive by the inclusion of a modifi ed
lipid as a sensitizer, and the mechanisms of release have been suggested to be
one or a mixture of the following:
1. The pH change triggers a morphology change from the lamellar lipid
bilayer (L α ) to, for example, micellar or hexagonal phase (Gerasimov et al.,
1999). The liposome contains negatively charged lipids, for example, lipids with
a carboxyl group that neutralize in acidic pH and so causes the collapse of L α
into a hexagonal phase. This concept is exploited in the enteric coating of
pharmaceuticals to protect them from degradation in the stomach at low pH
where the carboxylate groups of the coating polymer are protonated, impart-
ing low solubility, but ionize in the small intestine to allow polymer dissolution.
In self-assembled systems this concept has been rarely employed but has
recently been demonstrated in lyotropic liquid crystalline systems prepared
using monoglycerides doped with fatty acid to induce a morphology change
from the hexagonal phase to the bicontinuous cubic phase (Negrini and Mez-
zenga, 2011). The hexagonal phase present under simulated gastric conditions
at low pH released the model drug probucol slowly, compared to the cubic
phase structure present at intestinal pH.