Kawano Hiroki, Shakushiro Kohsuke, Nakata Mari, Kita Aya, Maeda Atsushi, Watanabe Shunsuke, Sako Kazuhiro, Oku Naoto
Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., Yaizu-shi, Japan; Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Japan.
Pharmaceutical Research and Technology Labs., Technology, Astellas Pharma Inc., Yaizu-shi, Japan; Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Japan.
Eur J Pharm Biopharm. 2014 Sep;88(1):283-9. doi: 10.1016/j.ejpb.2014.06.015. Epub 2014 Jun 30.
Sepantronium bromide (YM155) exhibits time-dependent antitumor activity, although the plasma half-life of YM155 after a bolus intravenous (i.v.) administration is very short. Therefore, greater antitumor efficacy is obtained by continuous infusion than by bolus i.v. administration. In the present study, we attempted to liposomalize YM155 to obtain a longer circulation time than that achieved by bolus i.v. administration and yet retain sufficient antitumor activity. Encapsulation of YM155 in polyethylene glycol-coated liposomes extended the half-life of the drug, and high tumor accumulation of the drug was observed. Bolus i.v. administration of liposomal YM155 by a weekly administration regimen showed antitumor activity comparable to that obtained by the continuous infusion without severe toxicity in a murine xenograft model. Therefore, this liposomal formulation can be a new dosage form of YM155 that achieves sufficient efficacy and safety and is a more convenient administration regimen for users. It should be noted that liposomal YM155 showed unexpectedly high accumulation in the kidneys. This is a specific finding for liposomal YM155, offering important information for the consideration of the potential toxicity of liposomal YM155.
溴化司帕曲铵（YM155）具有时间依赖性抗肿瘤活性，尽管单次静脉推注给药后YM155的血浆半衰期很短。因此，持续输注比静脉推注给药具有更高的抗肿瘤疗效。在本研究中，我们试图将YM155脂质体化，以获得比静脉推注给药更长的循环时间，并同时保留足够的抗肿瘤活性。将YM155包裹于聚乙二醇包被的脂质体中可延长药物的半衰期，并且观察到药物在肿瘤中的高蓄积。在小鼠异种移植模型中，每周一次静脉推注脂质体YM155的给药方案显示出与持续输注相当的抗肿瘤活性，且无严重毒性。因此，这种脂质体制剂可以成为YM155的一种新剂型，其疗效和安全性良好，对使用者而言给药方案更方便。应当注意的是，脂质体YM155在肾脏中显示出意外的高蓄积。这是脂质体YM155的一个特异性发现，为考虑脂质体YM155的潜在毒性提供了重要信息。
