Development of pH-sensitive liposomes that efficiently retain encapsulated doxorubicin (DXR) in blood
Development of pH-sensitive liposomes that efficiently retain encapsulated doxorubicin (DXR) in blood
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DOI：
10.1016/j.ijpharm.2005.11.010
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发表时间：
2006-02-17
影响因子：
5.8
通讯作者：
Kiwada, H
中科院分区：
文献类型：
--
作者：
Ishida, T;Okada, Y;Kiwada, H
我们报道了靶向、pH敏感的空间稳定脂质体能够在体外增加DXR对B淋巴瘤细胞的细胞毒性，但DXR在血浆中的释放速率太快，无法将结果扩展到体内应用。这里报告的研究有两个目的。首先，了解 DXR 从人血浆中 pH 敏感的空间稳定脂质体 (PSL) 中快速释放的机制。其次，重新配制上述脂质体以提高其药物保留，同时保留其pH敏感性。通过比较封装的 DXR 与 HPTS（一种水溶性荧光标记物）的释放速率来评估 PSL 制剂在人血浆中的稳定性。由于 DXR 而不是 HPTS（一种水溶性不溶性膜渗透性荧光标记物）在血浆存在下从脂质体中快速释放，因此 DXR 的快速释放可能是由于 DXR 分子通过脂双层的扩散引起的，而不是由膜的破坏引起的。为了开发更稳定的 PSL 制剂，将不同摩尔比的膜硬化脂质、氢化大豆 HSPC 和/或 CHOL 添加到脂质组合物中，并评估包封溶质的释放速率和 pH 敏感性。显示出最佳药物保留和pH敏感性的组合物是摩尔比为4:2:2:2:0.3的DOPE/HSPC/CHEMS/CHOL/mPEG(2000)-DSPE和摩尔比为4:2:2:2的DOPE/HSPC/CHEMS/CHOL的混合物。我们的制剂如果针对癌细胞上的内化抗原，可能会增加酸性室内的细胞内药物释放速率，从而进一步提高含有靶向抗癌药物的脂质体的治疗效果。 (c) 2005 Elsevier B.V. 保留所有权利。
We have reported that targeted, pH-sensitive sterically stabilized liposomes are able to increase the cytotoxicity of DXR in vitro against B lymphoma cells, but the rate of release of DXR in plasma was too rapid to permit the results to be extended to in vivo applications. The purpose of the study reported here is two-fold. First, to understand the mechanism of the rapid release of DXR from pH-sensitive sterically stabilized liposomes (PSL) in human plasma. Second, to reformulate the above liposomes to improve their drug retention, while retaining their pH sensitivity. The stability of the PSL formulations in human plasma was evaluated by comparing the rate of release of encapsulated DXR with that of HPTS, a water-soluble fluorescent marker. Since DXR, but not HPTS, a water soluble-less membrane permeable fluorescence marker, was rapidly released from liposomes in the presence of plasma, the rapid release of DXR is likely caused by the diffusion of DXR molecules through the lipid bilayer, not by the disruption of the membrane. In order to develop more stable PSL formulations, various molar ratios of the membrane rigidifying lipid, hydrogenated soy HSPC and/or CHOL, were added to the lipid composition and the rate of release of encapsulated solutes and pH-sensitivity were evaluated. The compositions that showed the best drug retention and pH-sensitivity were a mixture of DOPE/HSPC/CHEMS/CHOL/mPEG(2000)-DSPE at a molar ratio of 4:2:2:2:0.3 and DOPE/HSPC/CHEMS/CHOL at a molar ratio of 4:2:2:2. Our formulations, if targeted to internalizing antigens on cancer cells, may increase intracellular drug release rates within acidic compartment, resulting in a further increase in the therapeutic efficacy of targeted anticancer drug-containing liposomes. (c) 2005 Elsevier B.V. All rights reserved.