Laboratory of Analytical Chemistry and Biopolymer Structure Analysis, Department of Chemistry, University of Konstanz, 78457 Konstanz, Germany.
J Control Release. 2011 Dec 10;156(2):170-8. doi: 10.1016/j.jconrel.2011.08.005. Epub 2011 Aug 12.
To increase the selectivity and consequently to minimize the side effects of chemotherapeutic agents, receptor mediated tumor targeting approaches have been developed. In the present work, various anthracycline-GnRH derivative bioconjugates were synthesized with the aim of investigating the influence of (i) different anthracycline anticancer drugs, (ii) different linkages between the targeting moiety and the anticancer drug, and (iii) different targeting moieties (e.g., GnRH-III and [D-Lys⁶]-GnRH-I) on their in vitro drug release and cytostatic effect. The anthracyclines, daunorubicin or doxorubicin, were attached to the ε-amino group of Lys of GnRH-III or [D-Lys⁶]-GnRH-I through oxime, hydrazone or ester bonds. In another bioconjugate, a self-immolative p-aminobenzyloxycarbonyl spacer was used to link daunorubicin to GnRH-III. The in vitro degradation of the bioconjugates was investigated in the presence of rat liver lysosomal homogenate and cathepsin B. The cellular uptake of the compounds was evaluated by flow cytometry and their in vitro cytostatic effect was determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. The results indicate that on the tested cancer cell lines there is no significant difference in the cellular uptake and in vitro cytostatic effect of bioconjugates containing GnRH-III or [D-Lys⁶]-GnRH-I as a targeting moiety. The bioconjugates containing ester bond, hydrazone bond and the self-immolative spacer exert the highest cytostatic effect, followed by oxime bond-linked compounds.
为了提高选择性，从而最大限度地减少化疗药物的副作用，已经开发了受体介导的肿瘤靶向方法。在本工作中，合成了各种蒽环类药物-GnRH 衍生物缀合物，目的是研究（i）不同的蒽环类抗癌药物、（ii）靶向部分与抗癌药物之间的不同连接、和（iii）不同的靶向部分（例如，GnRH-III 和 [D-Lys⁶]-GnRH-I）对其体外药物释放和细胞抑制作用的影响。通过肟、腙或酯键，将蒽环类药物柔红霉素或阿霉素连接到 GnRH-III 或 [D-Lys⁶]-GnRH-I 的 Lys 的 ε-氨基上。在另一种缀合物中，使用自毁的对氨基苄氧羰基间隔物将柔红霉素连接到 GnRH-III。在存在大鼠肝溶酶体匀浆和组织蛋白酶 B 的情况下，研究了缀合物的体外降解情况。通过流式细胞术评估了化合物的细胞摄取，并通过 3-(4,5-二甲基噻唑基-2)-2,5-二苯基四氮唑溴盐测定法测定了它们的体外细胞抑制作用。结果表明，在所测试的癌细胞系中，含有 GnRH-III 或 [D-Lys⁶]-GnRH-I 作为靶向部分的缀合物的细胞摄取和体外细胞抑制作用没有显著差异。含有酯键、腙键和自毁间隔物的缀合物表现出最高的细胞抑制作用，其次是肟键连接的化合物。
