Suppression of pancreatic ductal adenocarcinoma growth by intratumoral delivery of attenuated Salmonella typhimurium using a dual fluorescent live tracking system

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis among all malignancies and is resistant to almost all current therapies. Attenuated Salmonella typhimurium strain VNP20009 has been deployed as powerful anticancer agent in a variety of animal cancer models, and previous phase 1 clinical trials have proven its safety profiles. However, thus far, little is known about its effect on PDAC. Here, we established CFPAC-1 cell lines expressing an mKate2 protein and thus emitting far-red fluorescence in the subsequent xenograft implant. VNP20009 strain was further engineered to carry a luciferase cDNA, which catalyzes the light-emitting reaction to allow the observation of salmonella distribution and accumulation within tumor with live imaging. Using such VNP20009 strain and intratumoral delivery, we could reduce the growth of pancreatic cancer by inducing apoptosis and severe necrosis in a dosage dependent manner. Consistent with this finding, intratumoral delivery of VNP20009 also increase caspase-3 activity and the expression of Bax protein. In summary, we revealed that VNP20009 is a promising bacterial agent for the treatment of PDAC, and that we have established a dual fluorescent imaging system as a valuable tool for noninvasive live imaging of solid tumor and engineered bacterial drug.

KEYWORDS:

• Attenuated Salmonella typhimurium
• bacteria therapy
• far-red fluorescence
• imaging
• intratumoral delivery
• pancreatic ductal adenocarcinoma
• VNP20009

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

This work was supported by grants from the National Program on Key Basic Research Project of China (973 Program) (No. 2013CB945202, to AZZ and FL), the National Natural Science foundation of China (NSFC, No. 81170780 to AZZ; No. 81372798 to FL, No. 81200570 to XXL, No. 81502587 to ZG), the Ph.D. Programs Foundation of Ministry of Education of China (No. 20113234110005 to AZZ), the Scientific Support Program of Jiangsu Province (BE2012756 to AZZ), the Natural Science Foundation of Jiangsu Province of China (JSNFC, No. BK20130059 to AZZ, No. 2011766 to XXL), and the High-level Innovative Talents Reward from Jiangsu Province (to FL).