Targeting of claudin-4 by Clostridium perfringens enterotoxin-conjugated polysialic acid nanoparticles for pancreatic cancer therapy

Abstract

Despite recent advances in chemotherapy, pancreatic cancer remains a leading cause of cancer-related deaths. Moreover, although targeted therapy has shown promising therapeutic efficacy in many types of cancers, no such effective targeting strategy for treatment of pancreatic cancer, which is in desperate need for new treatment approaches. Here, we developed claudin-4-targeting Clostridium perfringens enterotoxin (CPE) peptide-conjugated polysialic acid nanoparticles (C-SNPs) for pancreatic cancer-targeted therapy. Doxorubicin-loaded C-SNPs (DOX-C-SNPs) higly accumulated in the targeted pancreatic cancer via enhanced peameability and retention (EPR) effect, targeting claudin-4 in pancreatic cancer that becomes superficially exposed owing to the disruption of tight junctions. Notably, DOX-C-SNP accumulation in the non-targeted, normal pancreas was significantly reduced because of hindered access to claudin-4 in tight junctions. As a result, DOX-C-SNPs substantially suppressed tumor growth in an orthotopic pancreatic cancer model while exerting minimal toxicity against non-targeted, normal tissues. Collectively, these findings indicate that claudin-4-targeting DOX-C-SNPs may have promise in treating pancreatic cancers through targeting of exposed claudin-4.

Keywords: Claudin-4; Clostridium perfringens enterotoxin (CPE); Pancreatic cancer; Targeted therapy.