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Novel bacterial genotoxin-loaded nanoparticles for targeting therapy of radioresistant prostate cancer
1 , 2 , 3 , 1 , * 4 , * 5
1  University of Texas Southwestern Medical Center
2  Chang Gung University
3  National Chung Hsing University
4  National Yang-Ming University
5  Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan


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.

Keywords: DNA damage response; genotoxin; hyaluronic acid; nanoparticle; radiosensitizer
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Novel bacterial genotoxin-loaded nanoparticles
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