Liposomal delivery of doxorubicin to hepatocytes in vivo by targeting heparan sulfate.
Liposomal delivery of doxorubicin to hepatocytes in vivo by targeting heparan sulfate.
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DOI：
10.1016/j.ijpharm.2009.07.030
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发表时间：
2009-12-01
影响因子：
5.8
通讯作者：
Robertson, Richard T.
中科院分区：
文献类型：
--
作者：
Longmuir, Kenneth J.;Haynes, Sherry M.;Baratta, Janie L.;Kasabwalla, Natasha;Robertson, Richard T.
先前的研究表明，脂质体含有与硫酸肝素糖胺聚糖结合的氨基酸序列，可有效靶向肝细胞。对这些脂质体进行了测试，以确定它们是否能在体内选择性地将阿霉素输送到肝脏和肝细胞。液相脂质体含有一种脂质锚定的19氨基酸糖胺聚糖靶向肽。脂质体载有阿霉素，在血清存在下不渗漏。小鼠静脉给药后，取脏器，提取阿霉素含量，荧光强度和荧光显微镜测定。阿霉素脂质体几乎全部从肝脏中回收，仅在心脏、肺和肾脏中检测到微量。荧光显微镜显示多柔比星优先存在于肝细胞中，也存在于肝的非实质细胞中，但不存在于心、肺和肾细胞中。静脉注射后5分钟内，阿霉素可定位于肝细胞核内。这些研究表明，多柔比星脂质体可以通过靶向肝组织的硫酸肝素糖胺聚糖有效地递送到肝细胞。利用本文所述的组合物，阿霉素从脂质体中迅速释放，而不需要外部提供刺激。
Previous work demonstrated that liposomes, containing an amino acid sequence that binds to hepatic heparan sulfate glycosaminoglycan, show effective targeting to liver hepatocytes. These liposomes were tested to determine whether they can deliver doxorubicin selectively to liver and hepatocytes in vivo. Fluid-phase liposomes contained a lipid-anchored 19-amino acid glycosaminoglycan targeting peptide. Liposomes were loaded with doxorubicin and were non-leaky in the presence of serum. After intravenous administration to mice, organs were harvested and the doxorubicin content extracted and measured by fluorescence intensity and by fluorescence microscopy. The liposomal doxorubicin was recovered almost entirely from liver, with only trace amounts detectable in heart, lung, and kidney. Fluorescence microscopy demonstrated doxorubicin preferentially in hepatocytes, also in non-parenchymal cells of the liver, but not in cells of heart, lung or kidney. The doxorubicin was localized within liver cell nuclei within five minutes after intravenous injection. These studies demonstrated that liposomal doxorubicin can be effectively delivered to hepatocytes by targeting the heparan sulfate glycosaminoglycan of liver tissue. With the composition described here, the doxorubicin was rapidly released from the liposomes without the need for an externally supplied stimulus.
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