木瓜蛋白酶介导合成的金纳米粒子进一步增强了生物共轭氟他胺的效力。

Papain Mediated Synthesized Gold Nanoparticles Encore the Potency of Bioconjugated Flutamide.

机构信息

Department of Urology, Beijing Jishuitan Beijing, 100096, China.

出版信息

Curr Pharm Biotechnol. 2021;22(4):557-568. doi: 10.2174/1389201021666200227121144.

DOI:10.2174/1389201021666200227121144

PMID:32106799

Abstract

BACKGROUND

Prostate cancer is the second most common cause of male cancer death after lung cancer in the US. Therefore, there is an urgent need for a highly effective therapeutic drug at substantially low doses.

OBJECTIVE

Anti-androgen drug flutamide was delivered to the prostate cancer cells using Papain Mediated Synthesized Gold Nanoparticles (PGNPs) as the drug delivery system. PGNPs and flutamide worked synergistically against cancer cells.

METHODS

Flutamide was used to bioconjugate with PGNPs to improve its efficacy against prostate cancer. The synthesis and bioconjugation of flutamide with PGNPs (F-PGNPs) were characterized by various characterization techniques such as UV-vis spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and zeta potential to ensure the synthesis, size, shape, size distribution, and stability. The drug loading efficiency of flutamide in F-PGNPs was confirmed and validated by UV-vis spectroscopy. Eventually, in vitro studies were performed to determine the potency of F-PGNPs, changes in nuclear morphology, and generation of Reactive Oxygen Species (ROS).

RESULTS

The efficacy of F-PGNPs (IC is 46.54 μg/mL) was found to be improved significantly over pure flutamide (IC50 is 64.63 μg/mL) against human prostate cancer PC-3 cell line whereas F-PGNPs did not show any significant toxicity up to a fairly high concentration toward normal mouse macrophage J774A.1 cells. The apoptotic effects and ROS generation of F-PGNPs were analyzed by increased permeability of the cell membrane and condensed chromatin with deep blue and green fluorescent nucleus, respectively.

DISCUSSION

The results clearly showed that F-PGNPs significantly improved the potency of flutamide by delivering it directly into the nucleus of cancer cells through caveolae-dependent endocytosis.

CONCLUSION

Thus, the greater inhibitory effect of F-PGNPs over the pure drug would be of great advantage during prostate cancer treatment.

摘要

背景

在美国，前列腺癌是继肺癌之后导致男性癌症死亡的第二大常见原因。因此，迫切需要一种高效的治疗药物，且剂量要低得多。

目的

使用木瓜蛋白酶介导合成的金纳米粒子（PGNPs）作为药物递送系统将抗雄激素药物氟他胺递送到前列腺癌细胞中。PGNPs 和氟他胺协同作用于癌细胞。

方法

使用氟他胺与 PGNPs 进行生物缀合，以提高其对前列腺癌的疗效。通过各种表征技术，如紫外-可见光谱、透射电子显微镜（TEM）、动态光散射（DLS）和 Zeta 电位，对 PGNPs 与氟他胺的合成和生物缀合（F-PGNPs）进行了表征，以确保合成、尺寸、形状、尺寸分布和稳定性。通过紫外-可见光谱证实和验证了 F-PGNPs 中氟他胺的载药效率。最终，进行了体外研究以确定 F-PGNPs 的效力、核形态变化和活性氧（ROS）的产生。

结果

与纯氟他胺（IC50 为 64.63μg/mL）相比，F-PGNPs（IC 为 46.54μg/mL）对人前列腺癌 PC-3 细胞系的疗效显著提高，而 F-PGNPs 对正常小鼠巨噬细胞 J774A.1 细胞的毒性在相当高的浓度下也没有明显增加。通过细胞膜通透性增加和染色质浓缩，分别用深蓝色和绿色荧光核分析 F-PGNPs 的凋亡作用和 ROS 生成。