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首页> 外文期刊>Anti-Cancer Drug Design >Camptothecin delivery systems: the utility of amino acid spacers for the conjugation of camptothecin with polyethylene glycol to create prodrugs.
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Camptothecin delivery systems: the utility of amino acid spacers for the conjugation of camptothecin with polyethylene glycol to create prodrugs.

机译：喜树碱递送系统：氨基酸间隔基用于喜树碱与聚乙二醇缀合以产生前药的用途。

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The primary purpose of this study was to screen individual amino acid spacers in polyethylene glycol (PEG) conjugated camptothecin for their impact on the conjugates' antitumor activity. Secondly, an active member of this series was used to assess the PEG-camptothecin conjugate's efficacy against a battery of solid tumor types. PEG-camptothecin is a novel water soluble transport form (macromolecular prodrug) of the naturally derived antitumor drug, 20-(S)-camptothecin (CPT). Rates of hydrolysis were studied in phosphate buffered saline (PBS) and the plasma of both rats and humans. In vivo efficacy screens were performed against P388/0 murine leukemia and LS174T human colon solid tumor xenograft models. The results showed that while all the derivatives had considerable stability in PBS, their rates of hydrolysis varied in both rat and human plasma according to the amino acid spacer employed. Not surprisingly, changing the amino acid also affected in vivo toxicity and efficacy in the treatment of ascites and solid tumors. A representative of this amino acid series, PEG-alanine-CPT, which showed moderate activity in the solid tumor screen, was chosen for evaluation of efficacy across a wide range of solid tumor types and demonstrated significant antitumor activity (% T/C < 30%) in all tested xenograft models (colon, ovarian, mammary, lung, pancreatic and prostate). Therefore, this study showed that the use of specific amino acid spacers affected both the PEG-camptothecin conjugates' breakdown and biological activity. We anticipate that using these insights, this soluble macromolecular transport technology could be successfully employed with a number of antitumor drugs.
机译：这项研究的主要目的是筛选聚乙二醇（PEG）缀合喜树碱中的各个氨基酸间隔基，以了解它们对缀合物的抗肿瘤活性的影响。其次，该系列的活跃成员用于评估PEG-喜树碱偶联物对一系列实体瘤类型的功效。 PEG-喜树碱是天然衍生的抗肿瘤药20-（S）-喜树碱（CPT）的新型水溶性转运形式（大分子前药）。在磷酸盐缓冲盐水（PBS）和大鼠和人类血浆中研究了水解速率。针对P388 / 0鼠白血病和LS174T人结肠实体瘤异种移植模型进行了体内功效筛选。结果表明，尽管所有衍生物在PBS中都具有相当的稳定性，但它们的水解速率在大鼠和人血浆中均会根据所用氨基酸间隔物而变化。毫不奇怪，改变氨基酸还影响了腹水和实体瘤治疗的体内毒性和功效。选择该氨基酸系列的代表-在实体瘤筛选中显示中等活性的PEG-丙氨酸-CPT，用于评估各种实体瘤类型的疗效并显示出显着的抗肿瘤活性（％T / C <30 ％）在所有测试的异种移植模型（结肠，卵巢，乳腺，肺，胰腺和前列腺）中进行。因此，这项研究表明，使用特定的氨基酸间隔子会影响PEG-喜树碱偶联物的分解和生物学活性。我们预计，利用这些见解，这种可溶性大分子转运技术可以成功地与多种抗肿瘤药物一起使用。

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