title: Enhanced bacterial tumor delivery by modulating the EPR effect and therapeutic potential of Lactobacillus casei.
abstract: Bacteria of micrometer size could accumulate in tumor based on enhanced permeability and retention (EPR) effect. We report here Lactobacillus casei (L. casei), a nonpathogenic facultatively anaerobic bacterium, preferentially accumulated in tumor tissues after intravenously (i.v.) injection; at 24 h, live bacteria were found more in the tumor, whereas the bacteria in normal tissues including the liver and spleen were cleared rapidly. The tumor-selective accumulation and growth of L. casei is probably due to the EPR effect and the hypoxic tumor environment. Moreover, the bacterial tumor delivery was significantly increased by a nitric oxide (NO) donor nitroglycerin (NG, 10-70 times) and an angiotensin II converting enzyme inhibitor, enalapril (6-18 times). Consequently significant suppression of tumor growth was found in a colon cancer C26 model, and more remarkable antitumor effect was achieved when L. casei was combined with NG, probably by modulating the host nonspecific immune responses; tumor necrosis factor-α significantly increased in tumor after the treatment, as well as NO synthase activity and myleoperoxidase activity. These findings suggest the potential of L. casei as a candidate for targeted bacterial antitumor therapy, especially in combine with NG or other vascular mediators.
authors.affiliation: Institute of Drug Delivery Science, Sojo University, Ikeda 4-22-1, Kumamoto, 860-0082, Japan; Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Kumamoto, 860-0082, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Long
authors.initials: L
authors.lastname: Liao
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Yin
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Shin
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
mesh_terms: D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D004656:Enalapril / Q000008:administration & dosage; D005260:Female; D007780:Lacticaseibacillus casei; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000628:therapy*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D005996:Nitroglycerin / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D014409:Tumor Necrosis Factor-alpha; D004656:Enalapril; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin
keywords: ACE inhibitor; Cancer; Distribution; EPR effect; Lactobacillus casei; Nanotechnology; Permeability; Targeted drug delivery; nitroglycerin; vascular permeability