Novel bacterial genotoxin-loaded nanoparticles for targeting therapy of radioresistant prostate cancer

Yu-An Chen, Yi-Ru Lai, Ho Lin, J. Hsieh, Yu-Hsin Lin, Chih-Ho Lai
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Abstract

Background: Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and usually becomes refractory because of recurrence and metastasis. CD44, a transmembrane glycoprotein, serves as a receptor for hyaluronic acid (HA) and has been found to be abundantly expressed in cancer stem cells (CSCs) that often exhibit a radioresistant phenotype. Cytolethal distending toxin subunit B (CdtB), produced by Campylobacter jejuni, is a genotoxin acts as a type I deoxyribonuclease (DNase I), which is responsible for creating DNA double-strand breaks (DSBs). Nanoparticles loaded with antitumor drugs and specific ligands that recognize cancerous cell receptors are promising methods to overcome the therapeutic challenges. Results: Our results showed that administration of bacterial genotoxin significantly improved the efficacy of radiotherapy in a xenograft mouse model. We further prepared HA-decorated nanoparticles-encapsulated CdtB (HA-CdtB-NPs) and investigated the targeted therapeutic activity in radioresistant PCa cells. The results showed that HA-CdtB-NPs sensitized radioresistant PCa cells by enhancing DSB and causing G2/M cell-cycle arrest, without affecting the normal prostate epithelial cells. Our results demonstrate that HA-CdtB-NPs possess maximum target-specificity and delivery efficiency of CdtB into the nucleus, thereby enhancing the effect of radiation in radioresistant PCa cells. Conclusions: These findings indicate that HA-loaded CdtB nanoparticles exert target-specificity accompanied with radiomimetic activity, which can be developed as an effective agent for overcoming radioresistance in PCa.
新型细菌基因毒素纳米颗粒靶向治疗放射耐药前列腺癌
背景:前列腺癌(PCa)是男性最常见的癌症之一,由于其复发和转移而变得难治性。CD44是一种跨膜糖蛋白,作为透明质酸(HA)的受体,已被发现在经常表现出放射抗性表型的癌症干细胞(CSCs)中大量表达。空肠弯曲杆菌(Campylobacter jejuni)产生的细胞致死膨胀毒素亚基B (CdtB)是一种基因毒素,作为I型脱氧核糖核酸酶(DNase I),负责产生DNA双链断裂(DSBs)。纳米颗粒装载抗肿瘤药物和识别癌细胞受体的特异性配体是克服治疗挑战的有希望的方法。结果:我们的研究结果表明,在异种移植小鼠模型中,细菌基因毒素的施用显著提高了放射治疗的疗效。我们进一步制备了ha修饰的纳米颗粒包封CdtB (HA-CdtB-NPs),并研究了其对放射耐药PCa细胞的靶向治疗活性。结果表明,HA-CdtB-NPs通过增强DSB和引起G2/M细胞周期阻滞而致敏放射耐药PCa细胞,而不影响正常前列腺上皮细胞。我们的研究结果表明,HA-CdtB-NPs具有最大的靶向特异性和CdtB进入细胞核的递送效率,从而增强了放射耐药PCa细胞的辐射作用。结论:这些研究结果表明,ha负载的CdtB纳米颗粒具有靶向特异性并具有放射模拟活性,可作为克服前列腺癌放射耐药的有效药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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