Ryu Beom-Young, Sohn Jeong-Sun, Hess Michael, Choi Soo-Kyung, Choi Jae-Kon, Jo Byung-Wook
Department of Polymer Science & Engineering, Chosun University, Gwang Ju, South Korea.
J Biomater Sci Polym Ed. 2008;19(3):311-24. doi: 10.1163/156856208783720994.
A new series of poly(ethylene glycol)(PEG)-paclitaxel conjugates that increases water solubility of paclitaxel was synthesized. We developed well-designed self-immolating linkers between a drug and a water-soluble polymer moiety which gave an extremely rapid hydrolysis rate to convert a pro-drug into a parent drug without any reduction in drug efficacy. The self-immolating spacer groups were introduced between the solubilizing PEG and C7-OH of paclitaxel in order to control the rate of enzymatic hydrolysis. All these pro-drugs had a water-solubility of 400 mg/ml or more compared with a solubility of about 0.01 mg/ml. The rate of hydrolysis for the pro-drugs in rat plasma showed considerable variation of t((1/2)) ranging from 0.94 min to 42.7 min. To evaluate the anti-tumor efficacy of the pro-drug which had the fastest enzymatic hydrolysis rate, the growth inhibitory effect (IC(50)), the anti-tumor activity and the anti-metastatic potential of the pro-drug were examined. The pro-drug was potent to inhibit the growth of various cancer cell lines, such as human lung, ovarian, colon and melanoma cancer cells. On the development of melanoma lung colonies in C57B/6 mice following intravenous administration of metastatic murine B16/F10 melanoma cells, the pro-drug seems to be more efficacious than paclitaxel. The reduction of the number of melanoma lung colonies was 46.9% (dose: 5 mg/kg) with pure paclitaxel, and 24.5%, and 40.0% with the pro-drug in the dose of 0.71 mg paclitaxel equivalent/kg and 1.42 mg paclitaxel equivalent/kg, respectively.
合成了一系列新型的聚乙二醇（PEG）-紫杉醇缀合物，该缀合物提高了紫杉醇的水溶性。我们在药物与水溶性聚合物部分之间设计了精心设计的自裂解连接子，其水解速率极快，能将前药转化为原药，且药物疗效没有任何降低。在增溶PEG与紫杉醇的C7-OH之间引入自裂解间隔基团，以控制酶促水解速率。与约0.01mg/ml的溶解度相比，所有这些前药的水溶性均达到400mg/ml或更高。前药在大鼠血浆中的水解速率显示t((1/2))有相当大的变化，范围从0.94分钟到42.7分钟。为了评估酶促水解速率最快的前药的抗肿瘤疗效，检测了该前药的生长抑制作用（IC(50)）、抗肿瘤活性和抗转移潜力。该前药能有效抑制多种癌细胞系的生长，如人肺癌、卵巢癌、结肠癌和黑色素瘤癌细胞。在静脉注射转移性小鼠B16/F10黑色素瘤细胞后，C57B/6小鼠中黑色素瘤肺集落的形成情况表明，该前药似乎比紫杉醇更有效。纯紫杉醇（剂量：5mg/kg）使黑色素瘤肺集落数量减少46.9%，而前药在0.71mg紫杉醇当量/kg和1.42mg紫杉醇当量/kg的剂量下，分别使集落数量减少24.5%和40.0%。
