Biomedical Engineering Reference
In-Depth Information
as liposomes to facilitate the internalization of the genetic material into the cell. Cationic liposomes
contain positively charged lipids such as N-[1-(2,3-dioleoyloxy)propyl] N,N,N-trimethylammonium
chloride (DOTAP) which may complex with negatively charged macromolecules (e.g. DNA and
siRNA) to be used in gene therapy. The presence of fusogenic phospholipids such as 1,2-dideca-
noyl-sn-glycero-3-phosphocholine (DOPE) within formulation may facilitate the fusion of lipo-
somes with the target cells to enhance the internalization of the genetic material.
Thermosensitive liposomes are made from phospholipids whose membrane undergoes the gel-
to-liquid crystalline phase transition a few degrees above physiological temperature. Increasing the
temperature of tumor cells using an external source may induce drug release from thermosensitive
liposomes at the tumor site. It has been recently shown that when certain copolymers incorporated
in liposome bilayers, the vesicles become thermosensitive and the tumor targeting is enhanced
upon induction of hyperthermia.
Liposomes can be made by incorporating a phospholipid which becomes destabilized or fuso-
genic under the slightly acidic conditions of inflamed tissues or tumors, to release the encapsu-
lated therapeutic material intracellularly. This approach has been suggested by including
phospholipids such as palmitoyl homocysteine or a mixture of oleic acid and phosphatidyletha-
nolamine (3:7 mole ratio), which causes the resultant liposomes to fuse with endosomal mem-
brane (pH 5
6.5) and release the entrapped contents. Formation of the inverted hexagonal phase
is believed to be responsible for the fusogenic propensity of some lipids at mild acidic environ-
ments. An approach to preparation of pH-sensitive liposomes is to include materials within the
liposomes that maintain the bilayers stable at the physiological pH of the blood (pH 7.4) while
undergo instability at the mildly acidic environment inside the target cell, most specifically in
the late endosomes. This can result in fusion of the liposome vesicles with the membranes of the
late endosomes and subsequent release of the liposome-encapsulated contents in the cytosol,
avoiding degradation in the lysosomes.
Conventional liposomes are rapidly cleared by the RES of the blood circulation. The rapid
clearance may be overcome by the inclusion of certain amphiphiles within liposome formula-
tion such as monosialoganglioside (GM
1
), hydrogenated phosphatidylinositol (HPI), or more
recently the hydrophilic polymers polyethylene glycol. Incorporation of polyethylene glycol is
nowadays considered a novel strategy in manufacturing biologically stable liposomes. This
technology of liposome manufacture is termed the Stealth
technology, and liposomes made
by using this method are termed PEGylated, sterically stabilized or long-circulating lipo-
somes. Steric stabilization has resulted in the marketing of PEGylated doxorubicin HCl lipo-
somes as Doxil
s
in The United States and Caelyx
s
in Europe, for the treatment of Kaposi's
sarcoma.
Liposomes can be made elastic or ultradeformable by inclusion of certain surfactants or
cosolvents within liposome formulation in certain concentrations to make the vesicles able to
pass through the narrow pores of the skin and deliver associated small or large molecules.
Ultradeformable liposomes have been reported to be more efficient in transdermal delivery of
therapeutic agents compared to conventional liposomes such as in the delivery of protein vac-
cine, anticancer immunotherapeutic agent's gene, and dexamethasone. Cationic liposomes
have been prepared by inclusion of sodium cholate to be ultradeformable. The resultant vesi-
cles have been reported to enhance gene transportation through the skin.
t
