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Intracellular Delivery of Glucose Oxidase for Enhanced Cytotoxicity toward PSMA-Expressing Prostate Cancer Cells.
Macromolecular Bioscience ( IF 4.4 ) Pub Date : 2019-09-10 , DOI: 10.1002/mabi.201900183
Nicholas Flynn 1 , Ashish Ranjan 2 , Joshua D Ramsey 1
Affiliation  

Reactive oxygen species (ROS) forming enzymes are of significant interest as anticancer agents due to their potent cytotoxicity. A key challenge in their clinical translation is attaining site‐specific delivery and minimizing biodistribution to healthy tissues. Here, complexes composed of the ROS enzyme glucose oxidase (GOX), poly‐l‐lysine‐grafted‐polyethylene glycol (PLL‐g‐PEG), and anti‐prostate specific membrane antigen (anti‐PSMA) monoclonal antibody are synthesized for localized delivery and uptake in prostate cancer cells. Formation of anti‐PSMA‐PLL‐g‐PEG/GOX results in nanoscale complexes ≈30 nm in diameter with a ζ‐potential of 6 mV. The anti‐PSMA‐PLL‐g‐PEG/GOX complexes show significant cytotoxicity (≈60% reduction in cell viability) against PSMA‐expressing LNCaP cells compared to unmodified GOX. Importantly, cytotoxicity in LNCaP cells occurrs concurrently with anti‐PSMA‐PLL‐g‐PEG/GOX uptake and increases in intracellular generation of ROS. These results demonstrate that cytotoxicity of ROS inducing enzymes can be enhanced by intracellular delivery compared to equivalent concentrations of free enzyme, providing a novel means for cancer therapy.

中文翻译:

葡萄糖氧化酶的细胞内传递增强对表达PSMA的前列腺癌细胞的细胞毒性。

活性氧(ROS)形成酶因其强大的细胞毒性而作为抗癌剂受到广泛关注。在临床翻译中的主要挑战是实现针对特定部位的递送并最大程度地减少对健康组织的生物分布。在这里,合成了由ROS酶葡萄糖氧化酶(GOX),聚l赖氨酸接枝的聚乙二醇(PLL g g PEG)和抗前列腺特异性膜抗原(anti-PSMA)单克隆抗体组成的复合物以进行局部定位前列腺癌细胞的转运和摄取。抗PSMA‐ PLL ‐ g ‐ PEG / GOX的形成导致直径约30 nm的纳米级复合物的ζ电位为6 mV。抗PSMA‐PLL‐ g‐PEG / GOX复合物与未修饰的GOX相比,对表达PSMA的LNCaP细胞显示出显着的细胞毒性(细胞活力降低约60%)。重要的是,LNCaP细胞的细胞毒性与抗PSMA‐ PLL ‐ g ‐ PEG / GOX摄取同时发生,并增加了细胞内ROS的产生。这些结果表明,与同等浓度的游离酶相比,通过细胞内递送可以增强ROS诱导酶的细胞毒性,从而为癌症治疗提供了一种新的手段。
更新日期:2019-09-10
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