Bacterial genotoxin-coated nanoparticles for radiotherapy sensitization in prostate cancer

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). It has been found to be abundantly expressed in cancer stem cells (CSCs) that often exhibit a radioresistant phenotype. Cytolethal distending toxin (CDT), produced by Campylobacter jejuni, is a tripartite genotoxin composed of CdtA, CdtB, and CdtC sub-units. Among the three, CdtB acts as a type I deoxyribonuclease (DNase I), which creates 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. In this study, HA-decorated nanoparticle-encapsulated CdtB (HA-CdtB-NPs) were prepared and their targeted therapeutic activity in radioresistant PCa cells was evaluated. Our 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. HA-CdtB-NPs possess maximum target specificity and delivery efficiency of CdtB into the nucleus and enhance the effect of radiation in radioresistant PCa cells. These findings demonstrate that HA-CdtB-NPs exert target specificity accompanied with radiomimetic activity and can be developed as an effective strategy against ra-dioresistant PCa.