Drug Targeting Organ-Specific Strategies

2.4.3 Liposomes as Drug Carriers
2.4.3.1 Conventional Liposomes and Small Molecules
Liposomes, in addition to oligonucleotides [104], are often used as carriers for low molecular
weight drugs and peptides [103]. It has been demonstrated that encapsulation within liposomes
can dramatically alter the fate of the encapsulated drug in vivo [105]. Liposomal formulations
may protect against metabolic degradation and can influence plasma clearance
and tissue distribution of a variety of drugs. Loading efficiency, contents retention, plasma
stability and pharmacokinetic properties can often be adjusted by appropriate formulation
of conventional liposomal drug carriers [105,106]. However, conventional liposomes do not
undergo significant blood–brain barrier transport [107]. This is also true for small unilamellar
vesicles as demonstrated in a study where 60-nm liposomes radiollabeled with 111 Indium
did not penetrate the blood–brain barrier of a normal brain [108]. In this study brain penetration
was only observed following non-specific pharmacological disruption of the
blood–brain barrier by infusion of high doses (25 mg kg –1 ) of etoposide or at sites of brain tumours
where the vasculature is porous.
2.4.3.2 Brain Targeting Using Immunoliposomes
2.4 Drug Delivery Strategies 47
Conventional liposomes are rapidly removed from the circulation by cells of the reticuloendothelial
system [109].This rapid accumulation of conventional liposomes in the liver and the
spleen and the resulting high plasma clearance can be slowed down by coating the liposome
surface with inert and hydrophilic polymers such as PEG [110]. The half-life of liposomes
containing PEG-derivatized lipids increases up to 100-fold [106]. Such liposomes are often
referred to as sterically-stabilized liposomes. The PEG polymers can also be used for covalent
conjugation of an antibody or an antibody fragment to the liposome. In this case a chemically
reactive linker lipid can be used (Figure 2.10) that consists of a bi-functional PEG molecule
covalently bound at one side to a phospholipid headgroup and at the other side to a thiol-reactive
maleimide group. Thus modified antibodies bearing a thiol group can be coupled
under mild conditions to sterically-stabilized liposomes [111]. Such immunoliposomes retain
both their prolonged circulation properties and their target specificity in vivo. Similar results
can be obtained using alternative coupling techniques such as biotin–avidin conjugation
[112].
SH + N
S
O
N
O
O
O
(CH2 ) 2O n
(CH2 ) 2O n
H
N Phospholipid
O
H
N Phospholipid
O
Figure 2.10. Schematic diagram of coupling of a
thiolated antibody to a linker lipid (maleimide–
PEG–phospholipid) which is part of a preformed
liposome. The resulting thioether bond is metabolically
stable. The strategy shown here was used to
synthesize OX26-immunoliposomes [111].