Uchegbu I F, Double J A, Turton J A, Florence A T
Centre for Drug Delivery Research, School of Pharmacy, University of London.
Pharm Res. 1995 Jul;12(7):1019-24. doi: 10.1023/a:1016210515134.
Encapsulation of doxorubicin in niosomes was sought as a route to tumour targeting and improved tumoricidal through the alteration of doxorubicin pharmacokinetics and metabolism.
Doxorubicin niosomes (10 mg kg-1 doxorubicin) prepared from sorbitan monostearate (Span 60), cholesterol and choleth-24 (a 24 oxyethylene cholesteryl ether) in the molar ratio 45:45:10 were administered intravenously to female NMRI mice bearing the MAC 15A subcutaneously implanted tumour. Plasma doxorubicin was fractionated by gel filtration and quantified by HPLC with fluorometric detection as niosome-associated doxorubicin and released doxorubicin. Tumoricidal activity of the formulation was assessed by the intravenous injection of 5 mg kg-1 and 10 mg kg-1 doxorubicin niosomes to male NMRI mice bearing a 6 day old MAC 15A tumour.
At least 90% of the plasma doxorubicin was associated with the niosome fraction 4 h after dosing, and 50% was still associated after 24 h. The clearance of doxorubicin released from the niosomes was about 10 fold greater than the clearance of niosomal doxorubicin (176.5 mL h-1 and 16.2 mL h-1, respectively). The area under the plasma level-time curve increased 6 fold when doxorubicin was administered in niosomes, compared to doxorubicin solution (66.0 micrograms.h mL-1 and 10.3 micrograms. h mL-1, respectively). The area under the tumour level time curve was increased by over 50% by the administration of doxorubicin in niosomes when compared to the drug administered in solution (58.6 micrograms.h mL-1 and 34.3 micrograms.h mL-1, respectively). There was no statistically significant difference between levels of the drug in the heart when niosomal doxorubicin or doxorubicin solution were administered. Doxorubicin metabolites, namely doxorubicinol and the aglycones doxorubicinone, doxorubicinolone and 7-deoxydoxorubicinone, were found associated with the niosomes in the plasma, possibly due to their adsorption to the vesicle surface once formed outside the niosome. Overall metabolite levels in the liver were increased when doxorubicin niosomes were administered compared to the drug in solution. A 5 mg kg-1 injection of doxorubicin niosomes produced a terminal mean tumour weight that was similar to that obtained from animals administered 10 mg kg-1 doxorubicin solution.
Modest tumour targeting was achieved by the delivery of doxorubicin in sorbitan monostearate niosomes, increasing the tumour to heart AUC0-24 ratio from 0.27 to 0.36 and a doubling of tumoricidal activity. The overall level of doxorubicin metabolites was also increased.
寻求将阿霉素包裹于非离子表面活性剂囊泡中，通过改变阿霉素的药代动力学和代谢过程，实现肿瘤靶向及增强杀瘤效果。
由单硬脂酸山梨醇酯（司盘60）、胆固醇和胆甾醇聚氧乙烯醚（摩尔比45:45:10）制备阿霉素非离子表面活性剂囊泡（10mg/kg阿霉素），静脉注射给皮下植入MAC 15A肿瘤的雌性NMRI小鼠。血浆阿霉素经凝胶过滤分离，采用高效液相色谱荧光检测法定量，分为与囊泡相关的阿霉素和游离阿霉素。将5mg/kg和10mg/kg阿霉素非离子表面活性剂囊泡静脉注射给荷6日龄MAC 15A肿瘤的雄性NMRI小鼠，评估该制剂的杀瘤活性。
给药后4小时，至少90%的血浆阿霉素与囊泡部分结合，24小时后仍有50%结合。从囊泡中释放的阿霉素清除率比囊泡结合阿霉素的清除率高约10倍（分别为176.5mL/h和16.2mL/h）。与阿霉素溶液相比，阿霉素以非离子表面活性剂囊泡形式给药时，血浆浓度-时间曲线下面积增加了6倍（分别为66.0μg·h/mL和10.3μg·h/mL）。与溶液给药相比，阿霉素以非离子表面活性剂囊泡形式给药时，肿瘤浓度-时间曲线下面积增加了50%以上（分别为58.6μg·h/mL和34.3μg·h/mL）。给予囊泡结合阿霉素或阿霉素溶液后，心脏中药物水平无统计学显著差异。发现阿霉素代谢产物，即阿霉素醇和糖苷配基阿霉素酮、阿霉素醇酮和7-脱氧阿霉素酮，与血浆中的囊泡相关，这可能归因于它们一旦在囊泡外形成就吸附到囊泡表面。与溶液给药相比，给予阿霉素非离子表面活性剂囊泡后，肝脏中代谢产物总体水平升高。注射5mg/kg阿霉素非离子表面活性剂囊泡产生的最终平均肿瘤重量与给予10mg/kg阿霉素溶液的动物相似。
通过单硬脂酸山梨醇酯非离子表面活性剂囊泡递送阿霉素实现了适度的肿瘤靶向，使肿瘤与心脏的AUC0-24比值从0.27提高到0.36，杀瘤活性增加了一倍。阿霉素代谢产物的总体水平也有所升高。
