Biology Reference
In-Depth Information
mild hyperthermia where they rapidly (10s of seconds) released their drug load. Finally, the
'Stealth' thermo-liposomes are being further modified by adding components (biological
species including monoclonal antibodies or fragments, vitamins, lectins, specific antigens,
peptides, growth factors, glycoproteins, carbohydrates or other appropriate ligands
[14]
)
that will specifically target and bind the liposomes to the diseased cells.
A final aspect of delivering drugs to target cells or tissues involves the methods of gener-
ating localized, but limited, heat. This is referred to as 'mild hyperthermia.' The target tumor
is locally heated by focusing electromagnetic or ultrasound energy on the tumor. In some
cases radiofrequency electrodes are directly implanted into the tumor. More frequently, local-
ized heating is achieved non-invasively by microwave antennas or ultrasound transducers
e
focused ultrasound (FUS)
[22]
. Upon heating, the liposomes rapidly release their sequestered
anti-cancer drug directly inside the tumor.
7. pH-Sensitive Liposomes
In the previous sections we have discussed some of the many challenges associated with
the use of liposomes as drug delivery agents. Another problem involves the ultimate fate of
the liposomes after they have been internalized into a cell through endocytosis. Once inter-
nalized into an endosome, the liposomes and associated drugs are targeted to the lysosome
where they are destroyed. In most cases it would be tremendously advantageous if the drug
(or plasmid DNA or RNA) could be released from the liposome, and escape from the endo-
some into the cell's cytoplasm before encountering the lysosome. Early endosome studies
showed that their interior pH is mildly acidic (pH is ~5), offering a possible target for
liposome drug release
[23]
. This observation led to the development of a wide variety of
'pH-sensitive liposomes'
[24,25]
. pH-sensitive liposomes are stable (non-leaky) at physiolog-
ical pH (pH ~7.4), but become unstable (leaky) at low pH (pH ~5.0). The pH-sensitive
liposomes must also avoid the RES, be stable in the presence of blood plasma, and have
the ability to fuse with the endosome membrane in order to eventually release their load
into the cytoplasm.
Many pH-sensitive liposome compositions have been tested, but most have been mixtures
of a lipid containing a pH titratable group and, as the bulk lipid, an unsaturated chain PE
[26]
. The titratable group is responsible for pH sensitivity and is often an acylated amino
acid, a phospholipid derivative (usually a PE), a free fatty acid, a cholesterol derivative or
a double chain amphiphile. The earliest pH-sensitive liposomes
[27]
were composed of PE
as the major lipid component and single-chain amphiphiles such as fatty acids or N-acyl
amino acids as the pH-sensitive group. Unfortunately, these early liposomes were destroyed
in the plasma. Although liposome stability was shown to be increased by incorporation of
cholesterol, the sterol unfortunately decreased liposome fusion to the endosome membrane,
creating yet another problem. Therefore the initial objective of a functional pH-sensitive
liposome was to produce a cholesterol-free liposome that remained stable in the plasma
yet still retained fusogenicity and pH sensitivity.
One popular paradigm for the design of pH-sensitive liposomes is based on lipid-
anchored compounds that exist in two different conformations, one existing in mildly acidic
conditions (the compound is protonated) and the other in neutral or slightly basic conditions
(the compound is dissociated). Most of these compounds have been lipid-linked to homocys-
teine or succinate. The original 1980 report of a pH-sensitive liposome by Yatvin et al.
[27]
