Determination of the optimal route of administration of Salmonella typhimurium A1-R to target breast cancer in nude mice

Abstract

We have developed the genetically-modified Salmonella typhimurium A1-R strain that selectively targets tumors. S. typhimurium A1-R is auxotrophic for Leu and Arg, which precludes it from growing continuously in normal tissues but allows high tumor virulence. We report here the efficacy and safety of three different routes of S. typhimurium A1-R administration: oral (p.o.), intravenous (i.v.), and intra-tumoral (i.t.) in nude mice with orthotopic human breast cancer. Nude mice with MDA-MB-435 human breast cancer, expressing red fluorescent protein (RFP), were administered S. typhimurium A1-R by one of the three routes: [p.o.: 2×10(8) colony forming units (CFU)/200 μl; i.v.: 2.5×10(7) CFU/100 μl; i.t.: 2.5×10(7) CFU/50 μl] twice a week. Tumor growth was monitored by fluorescence imaging and caliper measurement in two dimensions. S. typhimurium A1-R targeted tumors at much higher levels than normal organs after all three routes of administration. The fewest bacteria were detected in normal organs after p.o. administration, which suggests that p.o. administration has the highest safety. The i.v. route had the greatest antitumor efficacy. There were no obvious toxic effects on the host with any of the routes of administration. The results of this study suggest that p.o. administration was the most safe to the host and the i.v. route was most effective for tumor targeting with S. typhimurium A1-R.