Hossann Martin, Wiggenhorn Michael, Schwerdt Alenka, Wachholz Kirsten, Teichert Nicole, Eibl Hansjörg, Issels Rolf D, Lindner Lars H
Department of Internal Medicine III, Klinikum Grosshadern Medical Center (KGMC), Ludwig-Maximilians University, Munich, Germany.
Biochim Biophys Acta. 2007 Oct;1768(10):2491-9. doi: 10.1016/j.bbamem.2007.05.021. Epub 2007 Jun 2.
Recently, we reported that 1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG) prolongs the circulation time of thermosensitive liposomes (TSL). Since the only TSL formulation in clinical trials applies DSPE-PEG2000 and lysophosphatidylcholine (P-lyso-PC), the objective of this study was to compare the influence of these lipids with DPPGOG on in vitro stability and heat-induced drug release properties of TSL. The content release rate was significantly increased by incorporating DPPGOG or P-lyso-PC in TSL formulations. DPPC/DSPC/DPPGOG 50:20:30 (m/m) and DPPC/P-lyso-PC/DSPE-PEG2000 90:10:4 (m/m) did not differ significantly in their release rate of carboxyfluorescein with >70% being released within the first 10s at their phase transition temperature. Furthermore, DPPC/DSPC/DPPGOG showed an improved stability at 37 degrees C in serum compared to the PEGylated TSL. The in vitro properties of DPPGOG-containing TSL remained unchanged when encapsulating doxorubicin instead of carboxyfluorescein. The TSL retained 89.1+/-4.0% of doxorubicin over 3 h at 37 degrees C in the presence of serum. The drug was almost completely released within 120s at 42 degrees C. In conclusion, DPPGOG improves the in vitro properties in TSL formulations compared to DSPE-PEG2000, since it not only increases the in vivo half-life, it even increases the content release rate without negative effect on TSL stability at 37 degrees C which has been seen for DSPE-PEG2000/P-lyso-PC containing TSL.
最近，我们报道了1,2-二棕榈酰-sn-甘油-3-磷酸甘油甘油酯（DPPGOG）可3）可延长热敏脂质体（TSL）的循环时间。由于临床试验中唯一的TSL制剂使用了二硬脂酰磷脂酰乙醇胺-聚乙二醇2000（DSPE-PEG2000）和溶血磷脂酰胆碱（P-lyso-PC），本研究的目的是比较这些脂质与DPPGOG对TSL体外稳定性和热诱导药物释放特性的影响。通过在TSL制剂中加入DPPGOG或P-lyso-PC，内容物释放速率显著提高。DPPC/DSPC/DPPGOG 50:20:30（质量比）和DPPC/P-lyso-PC/DSPE-PEG2000 90:10:4（质量比）在相变温度下，羧基荧光素的释放速率没有显著差异，在前10秒内超过70%被释放。此外，与聚乙二醇化TSL相比，DPPC/DSPC/DPPGOG在37℃血清中显示出更好的稳定性。当包封阿霉素而不是羧基荧光素时，含DPPGOG的TSL的体外性质保持不变。在37℃血清存在下，TSL在3小时内保留了89.1±4.0%的阿霉素。在42℃时，药物在120秒内几乎完全释放。总之，与DSPE-PEG2000相比，DPPGOG改善了TSL制剂的体外性质，因为它不仅增加了体内半衰期，甚至提高了内容物释放速率，且对37℃下TSL的稳定性没有负面影响，而含DSPE-PEG2000/P-lyso-PC的TSL则有这种负面影响。
