In vitro cytotoxicity and in vivo distribution after direct delivery of PEG-camptothecin conjugates to the rat brain
In vitro cytotoxicity and in vivo distribution after direct delivery of PEG-camptothecin conjugates to the rat brain
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DOI：
10.1021/bc034180o
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发表时间：
2004-11-01
影响因子：
4.7
通讯作者：
Saltzman, WM
中科院分区：
文献类型：
--
作者：
Fleming, AB;Haverstick, K;Saltzman, WM
低水溶性和从大脑的快速消除抑制了大多数治疗药物通过植入物和其他输送系统局部输送到大脑。我们已经将化疗药物喜树碱（CPT）偶联到分子量为3400的聚乙二醇（PEG）上。这些新的缀合物具有很强的水溶性，并以ph依赖的速率水解以释放活性母药。我们在体外研究了细胞对这些缀合物的摄取，并量化了它们对胶质肉瘤细胞的细胞毒性。将这些缀合物装入可生物降解的聚合物控释植入物中，并对其体外释放特性进行了研究。我们将类似的聚合磁盘植入大鼠脑内，并使用一种新的切片方案来确定CPT在1、7、14和28天后与共轭CPT在脑内的浓度分布。我们发现，与CPT与PEG共释放相比，PEGylation极大地提高了CPT可达到的最大药物浓度，并极大地增强了CPT的分布特性。虽然在缀合体系中只有1%的CPT以水解的活性形式存在，但对于缀合体系来说，在更远的距离上，药物浓度仍然显著高于细胞毒性水平。基于这些结果，我们相信PEGylation在增加药物在大脑中直接局部递送后的分布以提高药物治疗效果方面具有很大的前景。
Low water solubility and rapid elimination from the brain inhibits local delivery via implants and other delivery systems of most therapeutic drugs to the brain. We have conjugated the chemotherapy drug, camptothecin (CPT), to poly(ethylene glycol) (PEG) of molecular weight 3400 using previously established protocols. These new conjugates are very water-soluble and hydrolyze at a pH-dependent rate to release the active parent drug. We have studied the uptake of these conjugates by cells in vitro and quantified their cytotoxicity toward gliosarcoma cells. These conjugates were loaded into biodegradable polymeric controlled-release implants, and their release characteristics were studied in vitro. We implanted similar polymeric disks into rat brains and used a novel sectioning scheme to determine the concentration profile of CPT in comparison to conjugated CPT in the brain after 1, 7, 14, and 28 days. We have found that PEGylation greatly increases the maximum achievable drug concentration and greatly enhances the distribution properties of CPT, compared to corelease of CPT with PEG. Although only one percent of CPT in the conjugate system was found in the hydrolyzed, active form, drug concentrations were still significantly above cytotoxic levels over a greater distance for the conjugate system. On the basis of these results, we believe that PEGylation shows great promise toward increasing drug distribution after direct, local delivery in the brain for enhanced efficacy in drug treatment.