Direct 99mTc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies
Direct 99mTc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies
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DOI：
10.1124/jpet.103.059535
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发表时间：
2004-02-01
影响因子：
3.5
通讯作者：
Phillips, WT
中科院分区：
文献类型：
--
作者：
Bao, AD;Goins, B;Phillips, WT
脂质体药物在人体内的药代动力学和器官分布研究是一个挑战。本文介绍了一种用Tc-99 m-N，N-双（2-巯基乙基）-N '，N'-二乙基乙二胺（BMEDA）直接标记市售多柔比星脂质体Doxil的方法。本文通过测定Tc-99 m-Doxil在正常大鼠体内的生物分布，探讨了其用于药物脂质体药代动力学监测的可行性。Tc-99 m-Doxil的标记效率为70.6 ± 0.8%（n=3）。Tc-99 m-Doxil在50%胎牛血清或50%人血清中37 ℃体外孵育显示良好的标记稳定性，24 h时与Doxil相关的活性分别为72.3 ± 3.6%或78.6 ± 1.8%（n=3）。正常大鼠静脉推注给药后，血药清除呈双相，半清除时间为2.2和26.2 h。注射后44小时，Tc-99 m-Doxil在血液中的分布为注射剂量的19.8+/-1.3%，在肝脏中为14.1+/-1.7%，在脾脏中为2.6+/-0.3%，在骨髓中为9.0+/-0.8%，在皮肤中为6.0+/-0.5%，在肠中为15.3+/-4.3%（n=5）。未包封的Tc-99 m-BMEDA具有非常快速的血液清除，半清除时间仅为0.12 h（n=4）。利用这种Tc-99 m标记方法，可无创性地用放射性成像技术测定包封药物的铵梯度脂质体的生物分布和药代动力学。这种标记方法可推广到Re-186和Re-188标记，用于联合收割机化疗和放射性核素治疗肿瘤。
Pharmacokinetic and organ distribution studies of liposomal drugs in humans are a challenge. A direct labeling method using Tc-99m-N,N-bis(2-mercaptoethyl)-N',N'-diethyl-ethylenediamine (BMEDA) complex to label the commercially available pegylated liposomal doxorubicin, Doxil, has been introduced. Biodistributions of Tc-99m-Doxil in normal rats were performed to evaluate the feasibility of using it for monitoring the pharmacokinetics of liposomes encapsulating drugs. Labeling efficiency of Tc-99m-Doxil was 70.6+/-0.8% (n=3). In vitro incubation of Tc-99m-Doxil in 50% fetal bovine serum or 50% human serum at 37degreesC showed good labeling stability with 72.3+/-3.6% or 78.6+/-1.8% of activity associated with Doxil at 24 h, respectively (n=3). There was a two-phase blood clearance with half-clearance times of 2.2 and 26.2 h after bolus intravenous injection in normal rats. Distribution of Tc-99m-Doxil at 44 h after injection had 19.8+/-1.3% of injected dose in blood, 14.1+/-1.7% in liver, 2.6+/-0.3% in spleen, 9.0+/-0.8% in bone with marrow, 6.0+/-0.5% in skin, and 15.3+/-4.3% in bowel (n=5). Unencapsulated Tc-99m-BMEDA had a very rapid blood clearance with a half-clearance time of only 0.12 h (n=4). By using this Tc-99m labeling method, biodistribution and pharmacokinetics of ammonium gradient liposomes encapsulating drugs can be determined by noninvasive scintigraphic imaging. This labeling method may be extended to Re-186 and Re-188 labeling to combine chemotherapy and radionuclide therapy for tumor treatment.