Designing liposomal anticancer drug formulations for specific therapeutic applications

Citation
Ld. Mayer et al., Designing liposomal anticancer drug formulations for specific therapeutic applications, J LIPOS RES, 10(2-3), 2000, pp. 99-115
Citations number
31
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF LIPOSOME RESEARCH
ISSN journal
08982104 → ACNP
Volume
10
Issue
2-3
Year of publication
2000
Pages
99 - 115
Database
ISI
SICI code
0898-2104(2000)10:2-3<99:DLADFF>2.0.ZU;2-K
Abstract
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.