Drug Targeting Organ-Specific Strategies

220 8 Strategies for Specific Drug Targeting to Tumour Cells
jugates have now also been introduced into clinical practice [90,94] as will be described in
Section 8.6.3.
8.5.5 Liposomes
Selective targeting of drugs using liposomes is expected to optimize the pharmacological
effect and toxicities of encapsulated drugs with the advantage that liposomal components are
non-toxic, non-immunogenic and biodegradable [95,96].Through encapsulation of drugs in a
macromolecular carrier such as a liposome, the volume of distribution is significantly reduced
and the concentration of drug in the tumour is increased. Under optimal conditions,
the drug is carried through the body associated with the lipid and/or aqueous moiety of the
liposome. On arrival at the tumour the system should leak at a sufficient rate for the encapsulated
drug to become bioavailable. The liposome protects the drug from metabolism and
inactivation in the plasma. Due to size limitations in the transport of large molecules across
healthy endothelium, the drug will accumulate to a reduced extent in healthy tissues. Discontinuities
in the endothelium of the tumour vasculature, on the other hand, may result in
an increased extravasation of large molecules and increased accumulation of liposomal drug
in the tumour. However, this increased penetration phenomenon may be highly dependent
on the type of tumour and the stage of tumour development.
Initially, liposomes seemed to be optimal drug carrier systems, but further research in general
showed disappointing results [97]. The clinical utility of what are now called ‘conventional’
liposomes was limited by their rapid uptake by phagocytic cells of the immune system,
predominantly in the liver and spleen, resulting in their largely uncontrollable properties
upon administration in vivo.
Interest in liposomes as drug carriers was rejuvenated by the introduction of new ideas
from membrane biophysics. Liposomes can now be designed as non-reactive (sterically stabilized)
particles, as well as cationic or fusogenic liposomes. The non-reactive liposomes can
also be designed to induce tumour-specific targeting, while cationic or fusogenic liposomes
can exhibit high specificity for nucleic acid and cell membrane interactions. Because of their
reduced recognition and uptake by the phagocytic system, these liposomes are referred to as
‘stealth’ liposomes [98].These may prove to be useful in cancer therapy, although it should be
noted that even if distribution to macrophages is slowed down, they will eventually find their
way into these cells.
In sterically-stabilized liposomes, the lipid bilayer contains hydrophilic polymers or hydrophilic
glycolipids, PEG and the ganglioside GM being the subjects of the most detailed
studies. These liposomes remain in the blood for up to 100 times longer than conventional liposomes
and thus can increase the pharmacological efficacy of encapsulated agents. Consequently,
on chronic administration side-effects related to macrophage function are certainly
not excluded and can become dose limiting [99].
The choice of the drug for delivery via liposomes is essential. To be effective as a carrier, a
liposome must be able to efficiently balance stability in the circulation with the ability to
make the drug bioavailable at the tumour. Furthermore the drug must have adequate activity
against the chosen tumour. A drug such as doxorubicin with a relatively broad activity
against a variety of tumour types is an ideal choice in this regard [100]. The drug also has to