Camptothecin-catalyzed phospholipid hydrolysis in liposomes

Camptothecin-catalyzed phospholipid hydrolysis in liposomes
January 2005
Ann Mari S?tern, Merete Skar, ?smund Braaten and Martin Brandl
International Journal of Pharmaceutics, Volume 288, Issue 1, 6 January 2005, Pages 73-80
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Hydrolysis of phospholipid (PL) within camptothecin (CPT)-containing liposomes was studied systematically, after elevated lyso-phosphatidylcholine (LPC)-concentrations in pH 5, CPT-containing liposomes (22.1 ? 0.9 mol%) relative to control-liposomes (7.3 ? 0.5 mol%) occasionally had been observed after four months storage in fridge. Liposomes were prepared by dispersing freeze?dried PL/CPT mixtures in 25 mM phosphate buffered saline (PBS) of varying pH (5.0?7.8) and CPT concentrations (0, 3 and 6 mM). PL-hydrolysis was monitored by HPTLC, quantifying LPC. In an accelerated stability study (60 ?C), a catalytic effect of CPT on PL-hydrolysis was observed after 40 h, but not up to 30 h of incubation. The pH profile of the hydrolysis indicated a stability optimum at pH 6.0 for the liposomes independent of CPT. The equilibrium point between the more active lactone- and the carboxylate-form of CPT was found to be pH 6.8. As a compromise, pH 6.0 was chosen, assuring > 85% CPT to be present in the lactone form. At this pH, both control- and CPT-liposomes showed only minor hydrolysis after autoclaving (121 ?C, 15 min). Storage at room temperature and in fridge (2 months), as well as accelerated ageing (70 ?C, 25 h), gave a significant elevation of LPC content in CPT-liposomes relative to control-liposomes. This study demonstrates a catalytic effect of CPT on PL-hydrolysis, the onset of which seems to require a certain threshold level of hydrolytic degradation.