Liposome-based therapy of human ovarian cancer: parameters determining potency of negatively charged and antibody-targeted liposomes.
Liposome-based therapy of human ovarian cancer: parameters determining potency of negatively charged and antibody-targeted liposomes.
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发表时间：
1988-09
期刊：
影响因子：
11.2
通讯作者：
R. Straubinger;N. G. Lopez;R. J. Debs;Keelung Hong;Demetrios Papahadjopoulos
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文献类型：
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作者：
R. Straubinger;N. G. Lopez;R. J. Debs;Keelung Hong;Demetrios Papahadjopoulos
含有细胞毒性剂的脂质体对于恶性肿瘤如卵巢癌的腔内治疗可能是高度有效的，卵巢癌主要存在于腹膜腔中。我们已经在体外研究了各种脂质体药物制剂对OVCAR-3（一种人卵巢癌细胞系）的细胞毒性。测试的两种药物，甲氨蝶呤-γ-天冬氨酸和5-氟乳清酸，在脂质体中包封后对各种培养的细胞系显示出增加的细胞毒性，并且可以被认为是脂质体依赖性药物。对于本研究中使用的最佳脂质组成，对OVCAR-3的效力的最大增加对于甲氨蝶呤-γ-天冬氨酸为2.6倍，对于5-氟乳清酸为5.2倍。对脂质体-细胞缔合的研究表明OVCAR-3结合和内化磷脂囊泡的能力低，这限制了脂质体对这些细胞的体外效力。OC-125是一种识别许多人卵巢癌（CA-125）共同抗原的单克隆抗体，已与脂质体表面共价偶联。在96小时生长抑制试验中，携带OC-125并含有蛋氨酸-γ-天冬氨酸的脂质体显示出对OVCAR-3细胞的效力增加8倍。肿瘤细胞对治疗的更短暴露突出了靶向脂质体的优势。暴露于OC-125脂质体1小时的细胞抑制作用比暴露于游离药物的等效作用大100倍，等于游离药物96小时达到的最大细胞抑制作用。OC-125抗体的附着还赋予脂质体识别在裸鼠中作为腹水肿瘤生长的OVCAR-3细胞的能力。腹膜内注射后，对照脂质体以相对低的数量结合肿瘤细胞，而荧光OC-125脂质体可以观察到特异性结合肿瘤细胞团达数天。
Liposomes containing cytotoxic agents may be highly efficacious for intracavitary therapy of malignancies such as ovarian carcinoma, which resides principally in the peritoneal cavity. We have examined in vitro the cytotoxicity of a variety of liposome-drug formulations against OVCAR-3, a human ovarian cancer cell line. Two drugs tested, methotrexate-gamma-aspartate and 5-fluoroorotate, show increased cytotoxicity on various cultured cell lines following encapsulation in liposomes and can be considered liposome-dependent agents. With the optimal lipid composition used in this study, the maximal increase in potency on OVCAR-3 is 2.6-fold for methotrexate-gamma-aspartate and 5.2-fold for 5-fluoroorotate. Studies on liposome-cell association suggest a low capacity of OVCAR-3 to bind and internalize phospholipid vesicles, which limits the in vitro potency of liposomes for these cells. OC-125, a monoclonal antibody recognizing an antigen common to a number of human ovarian cancers (CA-125), has been coupled covalently to the liposome surface. Liposomes bearing OC-125 and containing methotrexate-gamma-aspartate show an 8-fold increase in potency against OVCAR-3 cells in a 96-h growth inhibition assay. Briefer exposure of tumor cells to treatment accentuates the advantage of targeted liposomes. The cytostatic effect of 1 h exposure to OC-125 liposomes is 100-fold greater than the equivalent exposure to free drug and equal to the maximal cytostatic effect achieved with free drug for 96 h. Attachment of OC-125 antibody also confers upon liposomes the capacity to recognize OVCAR-3 cells growing as an ascites tumor in nude mice. After i.p. injection, control liposomes bind tumor cells in relatively low numbers, while fluorescent OC-125 liposomes can be observed bound specifically to tumor cell masses for periods of days.