Controlled application and removal of liposomal therapeutics: effective elimination of pegylated liposomal doxorubicin by double-filtration plasmapheresis in vitro.

摘要

INTRODUCTION: Nanoscale particle-based drug delivery systems like long circulating liposomal doxorubicin show unique pharmacokinetic properties and improved toxicity profiles. Liposomal doxorubicin accumulates in tumor tissue due to the enhanced permeation and retention effect, but only a small fraction of a total dose reaches the tumor site. Accumulation of liposomal doxorubicin is much faster in tumor sites than in certain organs where dose limiting adverse effects occur. Finding a way to detoxify the predominant part of a given dose, circulating in the blood after accumulation is completed, will presumably reduce severe side effects during chemotherapy. METHODS: Elimination properties of therapeutic used pegylated liposomal doxorubicin (Doxil/Caelyx) and therapeutic used double-filtration plasmapheresis systems were evaluated in vitro and in reconstituted human blood. RESULTS: Liposomes can be filtered by appropriate membranes without leakage of doxorubicin up to a pressure of 1 bar. At higher pressures, liposomes ( approximately 85 nm) may squeeze through much smaller pores without significant leakage of doxorubicin, whereas decreasing pore size to approximately 8 nm leads to increased leakage of doxorubicin. With therapeutic used apheresis systems, liposomal doxorubicin can be efficiently eliminated out of buffer medium and reconstituted human blood. No leakage of doxorubicin was detected, even when liposomes were circulating for 48 h in human plasma before apheresis. CONCLUSIONS: Convenient apheresis techniques are capable of a safe and efficient elimination of therapeutic used liposomal doxorubicin in an experimental model system.