INVITRO CYTOTOXICITY OF LIPOSOME-ENCAPSULATED DOXORUBICIN - DEPENDENCE ON LIPOSOME COMPOSITION AND DRUG RELEASE
INVITRO CYTOTOXICITY OF LIPOSOME-ENCAPSULATED DOXORUBICIN - DEPENDENCE ON LIPOSOME COMPOSITION AND DRUG RELEASE
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DOI：
10.1016/0005-2736(92)90084-y
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发表时间：
1992-08-24
期刊：
影响因子：
--
通讯作者：
GABIZON, AA
中科院分区：
文献类型：
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作者：
HOROWITZ, AT;BARENHOLZ, Y;GABIZON, AA
用比色法研究了游离阿霉素(DOX)和脂质体包裹的DOX(L-DOX)对人卵巢癌细胞株OV-1063的体外细胞毒作用。DOX通过硫酸铵产生的质子梯度被包裹在脂质体的内水相中。脂质体的磷脂组成不同，但大小相似。研究发现，当使用含有高相变温度(T(M))磷脂的脂质体时，L DOX的细胞毒活性显著降低。带负电荷的头基类型对观察到的细胞毒性没有任何显著影响。使用与游离和蛋白质结合的DOX，但不与L-DOX相互作用的树脂珠进行的实验表明，细胞毒作用是通过药物从脂质体释放到细胞外介质中介导的；没有发现直接细胞摄取脂质体药物的证据。使用黑色离子载体诱导DOX从高T(M)脂质体中释放，将细胞毒性提高到与游离DOX相当的水平，这表明“远程释放”技术可以显著提高脂质体介导的药物输送效率，并允许充分利用特定高T(M)制剂的良好药代动力学特性。
We have investigated the in vitro cytotoxicity of free doxorubicin (DOX) and liposome-entrapped DOX (L-DOX) against a human ovarian carcinoma cell line (OV-1063) using a colorimetric assay. DOX was encapsulated in the inner water phase of liposomes by an ammonium sulfate-generated proton gradient. Liposomes varied in phospholipid composition but were of a similar size. It was found that the cytotoxic activity of L-DOX is substantially decreased when liposomes containing phospholipids of high phase-transition temperature (T(m)) are used. The type of negatively charged headgroup did not have any significant influence on the cytotoxicity observed. Experiments using resin beads that bind free and protein-bound DOX, but do not interact with L-DOX, indicated that the cytotoxic effect is mediated by the release of drug from the liposomes into the extracellular medium; no evidence was found for direct cellular uptake of liposome-encapsulated drug. The use of the ionophore nigericin to induce the release of DOX from high-T(m) liposomes increased cytotoxicity to a level comparable to free DOX, suggesting that 'remote release' techniques may substantially improve the efficiency of liposome-mediated drug delivery and allow for the full exploitation of the favorable pharmacokinetic properties of specific high-T(m) formulations.