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首页> 外文期刊>Journal of pharmaceutical sciences. >Increase of doxorubicin sensitivity for folate receptor positive cells when given as the prodrug N-(phenylacetyl) doxorubicin in combination with folate-conjugated PGA.
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Increase of doxorubicin sensitivity for folate receptor positive cells when given as the prodrug N-(phenylacetyl) doxorubicin in combination with folate-conjugated PGA.

机译：当将前药N-（苯基乙酰基）阿霉素与叶酸偶联的PGA联合使用时，阿霉素对叶酸受体阳性细胞的敏感性增加。

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Folate receptor (FR) has been proposed as a promising target for tumor drug targeting. The aim of this study was to increase the chemo-sensitivity of FR-positive cells to doxorubicin by folate-directed enzyme prodrug therapy (FDEPT). Folate conjugated penicillin-G amidase was prepared and its ability to hydrolyze N-(phenylacetyl) doxorubicin was measured by HPLC. Fluorescence and confocal image analysis revealed that Folate-PGA can be specifically delivered into FR-positive HeLa and SKOV3 tumor cells. In vitro cytotoxity assays, IC50 was reduced with N-(phenylacetyl) doxorubicin versus doxorubicin for HeLa (3.1-fold reduction; p<0.001) and SKOV3 (3.3-fold reduction; p<0.001) when Folate-PGA was specifically bound to the cells. Complete activation was confirmed in HeLa and SKOV3 cells pretreated with free folic acid (1 mM), where the combination of N-(phenylacetyl) doxorubicin with Folate-PGA did not show any significant cell toxicity to the IC50 of doxorubicin. Pharmacokinetic clearance and biodistribution studies in vivo showed that 125I-Folate-PGA was cleared from blood within 24 h and had significantly higher tumor uptake compared to 125I-PGA (p<0.05). These results demonstrate that the FDEPT approach may be a potential promising strategy to improve chemotherapy-resistant cancers therapeutic ratio and warranted future studies. Association
机译：叶酸受体（FR）已被提议作为肿瘤药物靶向的有希望的靶标。这项研究的目的是通过叶酸定向酶前药治疗（FDEPT）来提高FR阳性细胞对阿霉素的化学敏感性。制备叶酸偶联的青霉素-G酰胺酶，并通过HPLC测定其水解N-（苯乙酰基）阿霉素的能力。荧光和共聚焦图像分析表明，叶酸-PGA可以特异性地递送到FR阳性HeLa和SKOV3肿瘤细胞中。在体外细胞毒性试验中，当叶酸-PGA特异性结合到HeLa上时，N-（苯乙酰基）阿霉素相对于阿霉素对ICLa的IC50降低（降低3.1倍; p <0.001）和SKOV3（降低3.3倍; p <0.001）。细胞。在用游离叶酸（1 mM）预处理的HeLa和SKOV3细胞中证实了完全激活，其中N-（苯基乙酰基）阿霉素与叶酸-PGA的组合对阿霉素的IC50没有明显的细胞毒性。体内药代动力学清除和生物分布研究表明，与125I-PGA相比，125I-Folate-PGA在24小时内从血液中清除，并且肿瘤摄取显着更高（p <0.05）。这些结果表明，FDEPT方法可能是提高化疗耐药性癌症治疗率的潜在有前途的策略，值得今后进行研究。协会

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