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

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.