Liposomal drug delivery systems have progressed significantly over the past
10 years, where technical barriers to the development of liposome-based ph
armaceutical agents have been largely overcome and the clinical benefits of
such systems have been established in several disease applications, partic
ularly for cancer chemotherapy. We now have the ability to design sophistic
ated liposomal drug delivery systems with multifunctional properties includ
ing steric stabilizing lipids, targeting ligands, pH and temperature sensit
ive lipid compositions as well as components that induce intracellular deli
very. However, the design of liposomes that exhibit optimized therapeutic a
ctivity will depend on the specific disease application as well as the chem
ical and biophysical properties of the pharmacological agent to be delivere
d. This is highlighted by the correlation between liposome physical charact
eristics and their biological behaviour as delivery systems for the antican
cer drugs vincristine and doxorubicin.
For doxorubicin, both EPC-based conventional and saturated, sterically stab
ilized liposome formulations have been shown to be effective against a wide
variety of tumor types and their clinical utility has been firmly establis
hed. It is unclear at this time which formulation may be most effective for
treating specific tumor types. This is somewhat surprising since the two c
ommercial formulations exhibit very different biophysical and pharmacokinet
ic properties. However, in the case of combined therapy with modulators of
P-glycoprotein such as PSC 833 we have observed a significant difference in
toxicity and efficacy properties between these two formulations. Doxorubic
in encapsulated inside EPC/cholesterol liposomes was adversely affected by
co-administration with PSC 833 whereas DSPC/cholesterol/DSPE-PEG formulatio
ns were minimally affected. This was related to the increased drug leakage
observed for the EPC/cholesterol system which resulted in elevated circulat
ing free doxorubicin due to PSC 833-induced impairment of drug excretion. A
s a result, EPC/cholesterol doxorubicin displayed a reduced maximum tolerat
ed dose with PSC 833 administration and modest antitumor activity against m
ultidrug resistant (MDR) human breast tumor xenografts. In contrast, the st
erically stabilized formulation could be administered at full dose, resulti
ng in complete reversal of MDR and significant atitumor activity.
Vincristine is a cell cycle specific whose antitumor potency increases dram
atically with increased duration of exposure. The therapeutic activity of l
iposome formulations of this drug against solid tumor appears most dependen
t on retention of vincristine in the liposomes. Increasing the order of the
liposome bilayer by moving from egg phosphatidylcholine (EPC) to distearoy
l PC (DSPC) and finally sphingomyelin (SM) dramatically increases therapeut
ic activity and is associated with increased drug retention in the liposome
s after iv administration. For these systems, incorporation of PEG-derivati
zed steric stabilizing lipids increased liposome circulation longevity, but
decreased drug retention, resulting in no net improvement of efficacy. Con
sequently, for this drug conventional liposomes composed of SM and choleste
rol appear to provide the optimum therapeutic index.
Taken together, the results described above highlight the importance of des
igning chemical and physical properties for liposomal formulations of antic
ancer drugs not only with respect to the agent being encapsulated but also
the specific clinical applications for which they will be used. This approa
ch is not only applicable for conventional and sterically stabilized liposo
mal formulations but should also be applied for more complex multifunctiona
l liposomes.