Plasma clearance, biodistribution and therapeutic properties of mitoxantrone encapsulated in conventional and sterically stabilized liposomes after intravenous administration in BDF1 mice.
Plasma clearance, biodistribution and therapeutic properties of mitoxantrone encapsulated in conventional and sterically stabilized liposomes after intravenous administration in BDF1 mice.
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DOI：
10.1038/bjc.1997.28
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发表时间：
1997
影响因子：
8.8
通讯作者：
Madden TD
中科院分区：
文献类型：
--
作者：
Chang CW;Barber L;Ouyang C;Masin D;Bally MB;Madden TD
使用跨膜 pH 梯度可以将米托蒽醌有效加载到大的单层囊泡中。释放研究表明，这些载药载体高度稳定，甚至在残余 pH 梯度消散后，在 37°C 透析 5 天后仍保留超过 85% 的封装米托蒽醌。在小鼠研究中，我们比较了静脉注射游离药物或封装在常规或空间稳定脂质体中的米托蒽醌后米托蒽醌和脂质体脂质的血浆清除率和生物分布。与游离米托蒽醌观察到的快速血液清除相反，两种脂质体系统都提供了延长的循环寿命，给药后 1 小时内有超过 90% 的药物存在，24 小时时有 15-30% 剩余。与之前的报道一致，观察到空间稳定脂质体的血浆半衰期比传统系统更长。此外，药物和载体的生物分布之间存在很强的相关性，吸收主要发生在肝脏和脾脏中，并且与血浆清除率平行。这表明组织分布反映了载药脂质体的分布，而不是单个成分的分布。脂质体封装还显着降低了米托蒽醌的毒性，从而允许施用更高、更有效的药物剂量。例如，在小鼠 L1210 肿瘤模型中，在用游离药物治疗的动物组中没有看到长期存活者，而在脂质体米托蒽醌最大治疗剂量下观察到存活率为 40%。
Mitoxantrone can be efficiently loaded into large unilamellar vesicles using a transmembrane pH gradient. Release studies indicate that these drug-loaded carriers are highly stable and even after dissipation of the residual pH gradient retain more than 85% of encapsulated mitoxantrone following dialysis at 37 degrees C for 5 days. In murine studies we have compared the plasma clearance and biodistribution of both mitoxantrone and liposomal lipid following intravenous administration of free drug or mitoxantrone encapsulated in either conventional or sterically stabilized liposomes. In contrast to the rapid blood clearance observed for free mitoxantrone, both liposomal systems provided extended circulation lifetimes, with over 90% of the drug present 1 h after administration and 15-30% remaining at 24 h. In agreement with previous reports, longer plasma half-lives were observed for sterically stabilized liposomes than for conventional systems. In addition, a strong correlation between drug and carrier biodistribution was seen, with uptake occurring mainly in the liver and spleen and paralleling plasma clearance. This would suggest that tissue disposition reflects that of drug-loaded liposomes rather than the individual components. Liposomal encapsulation also significantly reduced mitoxantrone toxicity, allowing administration of higher, more efficacious drug doses. In a murine L1210 tumour model, for example, no long-term survivors were seen in animal groups treated with free drug, whereas at the maximum therapeutic dose of liposomal mitoxantrone survival rates of 40% were observed.