Development of Chitosan/Heparin Nanoparticle-Encapsulated Cytolethal Distending Toxin for Gastric Cancer Therapy

Abstract

Aim: The aim of this work was to develop pH-responsive nanoparticles encapsulating CdtB and to demonstrate that these particles represent a potential therapeutic agent for gastric cancer. Materials & methods: Chitosan/heparin nanoparticle-encapsulated CdtB was prepared and the delivery efficiency was monitored by confocal laser scanning microscopy. The molecular basis of the nanoparticle-encapsulated CdtB-mediated p53 activation pathway was explored by immunoblot analysis. Antitumoral activities were investigated by analyzing the cell cycle and apoptosis. Results: Chitosan/heparin nanoparticle-encapsulated CdtB preferentially inhibited the proliferation of cells derived from gastric cancer, but not in primary gastric epithelial cells. Treatment of cells with nanoparticle-encapsulated CdtB enhanced cell-cycle arrest at G2/M, followed by apoptosis. Moreover, our data showed that the mechanism for nanoparticle-encapsulated CdtB-induced cell death was mediated by ATM-dependent DNA damage checkpoint responses. Conclusion: These findings indicate that chitosan/heparin nanoparticle-encapsulated CdtB could represent a new CdtB delivery strategy for the treatment of gastric cancer.

Keywords::

• apoptosis
• cell cycle
• chitosan
• cytolethal distending toxin
• heparin
• nanoparticle

Financial & competing interests disclosure

This work was supported by the National Science Council, Taiwan (NSC100-2628-E-039-003-MY3, NSC100-2918-I-039-003 and NSC101-2313-B-039-004-MY3), China Medical University, Taiwan (CMU100-S-23, CMU101-S-13 and CMU101-S-22) and the Tomorrow Medicine Foundation. The confocal microscopy SP2 experiment and Zetasizer apparatus use were supported by the Medical Research Core Facilities Center, Office of Research and Development, China Medical University, and are gratefully acknowledged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

Experiments and data analysis were performed in part through the use of the microscopic facility at Scientific Instrument Center of Academia Sinica and with the assistance of S-C Shen.

Additional information

Funding

This work was supported by the National Science Council, Taiwan (NSC100-2628-E-039-003-MY3, NSC100-2918-I-039-003 and NSC101-2313-B-039-004-MY3), China Medical University, Taiwan (CMU100-S-23, CMU101-S-13 and CMU101-S-22) and the Tomorrow Medicine Foundation. The confocal microscopy SP2 experiment and Zetasizer apparatus use were supported by the Medical Research Core Facilities Center, Office of Research and Development, China Medical University, and are gratefully acknowledged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.