Methoxypoly(ethylene glycol)-conjugated carboxypeptidase A for solid tumor targeting: part II: pharmacokinetics and biodistribution in normal and tumor-bearing rodents.
Methoxypoly(ethylene glycol)-conjugated carboxypeptidase A for solid tumor targeting: part II: pharmacokinetics and biodistribution in normal and tumor-bearing rodents.
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用于实体瘤靶向的甲氧基聚（乙二醇）缀合的羧肽酶 A：第二部分：正常和荷瘤啮齿动物中的药代动力学和生物分布。
DOI：
10.1016/j.jconrel.2005.01.015
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Kwon,GlenS
中科院分区：
文献类型：
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作者：
Ton,GiangthyN;Weichert,JameyP;Longino,MarcA;Fine,JasonP;Kwon,GlenS
我们评价了mpeg修饰对羧基肽酶A(CPA)在正常大鼠体内药代动力学特性的影响。将两条或三条mpeg链连接到CPA上会导致MPEG2-CPA和mPEG3-CPA类似物的产生，其血浆半衰期显著增加，特别是在分布阶段。此外，对CT26荷瘤小鼠的实时全身动力学评估表明，MPEG2-CPA和mPEG3-CPA在注射后48小时均表现出较高的体内滞留。此外，mPEG3-CPA在72h的肿瘤定位通过γ-闪烁成像和MicroCT数据集的融合而被可视化和确认。影像研究的结果支持了我们的假设，即肿瘤摄取与增强的循环半衰期之间存在相关性。组织分布数据显示，在给药后48h，MPEG2-CPA观察到的肿瘤渗出增加和有效的肾脏消除相结合，导致肿瘤与血液的最高比率为4.8：1。虽然在预定的时间间隔内，mPEG3-CPA在肿瘤中的累积总浓度高于MPEG2-CPA和CPA，但由于血液活性水平较高，并未获得更高的肿瘤与血液比率。显然，连接适当数量的mpeg链可以像使用肿瘤特异性抗体一样有效地促进肿瘤的定位。
We have evaluated effects of mPEG modification on pharmacokinetic properties of carboxypeptidase A (CPA) in normal rats. Attachment of two or three mPEG chains to CPA resulted in the generation of mPEG2–CPA and mPEG3–CPA analogs with significantly enhanced plasma half-lives, especially during the distribution phase. Moreover, the assessment of real-time whole-body kinetics in CT26 tumor-bearing mice showed both mPEG2–CPA and mPEG3–CPA exhibited increased body retention at 48 h post-injection. In addition, tumor localization of mPEG3–CPA at 72 h was visualized and confirmed by fusion of the γ-scintigraphy and microCT data sets. Results from the imaging studies support our hypothesis of a correlation between tumor uptake and enhanced circulatory half-life. Tissue distribution data indicated the combination of increased tumor extravasation and effective renal elimination observed with mPEG2–CPA at 48 h following administration led to the highest observed tumor-to-blood ratio of 4.8:1. Although the total concentration of mPEG3–CPA accumulated in tumor was higher than that of mPEG2–CPA and CPA at predetermined time intervals, a higher tumor-to-blood ratio was not obtained owing to a higher level of blood activity. Clearly, the attachment of an appropriate number of mPEG chains can facilitate tumor localization as effectively as can the use of a tumor-specific antibody.