title: 32-Phosphorus selectively delivered by listeria to pancreatic cancer demonstrates a strong therapeutic effect.
abstract: Our laboratory has developed a novel delivery platform using an attenuated non-toxic and non-pathogenic bacterium Listeria monocytogenes that infects tumor cells and selectively survives and multiplies in metastases and primary tumors with help of myeloid-derived suppressor cells (MDSC) and immune suppression in the tumor microenvironment (TME). 32P was efficiently incorporated into the Listeria bacteria by starvation of the bacteria in saline, and then cultured in phosphorus-free medium complemented with 32P as a nutrient. Listeria-32P kills tumor cells through both 32P-induced ionizing radiation and Listeria-induced reactive oxygen species (ROS). The levels of 32P and Listeria were studied in various normal and tumor tissues, at sequential time points after injection of mice with pancreatic cancer (syngeneic model Panc-02). We found that 32P and Listeria predominantly accumulated in tumors and metastases, with their highest accumulation 4 hrs (32P) and 3 days (Listeria) after injection. Listeria also penetrated the transgenic KPC (conditionally express endogenous Kras-G12D and p53-R172H mutant alleles) pancreatic tumors and metastases. This is remarkable since KPC tumors, like human tumors, exhibit a stromal barrier, which prevents most drugs from penetrating the pancreatic tumors. Therapeutic treatment with Listeria -32P resulted in a strong reduction of the growth of pancreatic cancer at early and late stages in Panc-02 and KPC mice. These results highlight the power of Listeria as new delivery platform of anticancer agents to the TME. Not only were therapeutic levels of radioactive Listeria reached in tumors and metastases but the selective delivery also led to minimal side effects.
authors.affiliation: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Chandra
authors.affiliation: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461, USA.
authors.forename: Benson Chellakkan
authors.initials: BC
authors.lastname: Selvanesan
authors.affiliation: Montefiore Medical Center, Medical Arts Pavilion, MMC-MAP, Bronx, NY 10467, USA.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Montefiore Medical Center, Medical Arts Pavilion, MMC-MAP, Bronx, NY 10467, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
authors.affiliation: Albert Einstein College of Medicine, Department of Radiology, MRRC, Bronx, NY 10461, USA.
authors.forename: Wade
authors.initials: W
authors.lastname: Koba
authors.affiliation: Albert Einstein College of Medicine, Department of Pathology, Michael F. Price Center, Bronx, NY 10461, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Beck
authors.affiliation: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Baltimore, MD 21205, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
authors.affiliation: Albert Einstein College of Medicine, Department of Radiology/Department of Microbiology and Immunology, Bronx, NY 10461, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Dadachova
authors.affiliation: Albert Einstein College of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gravekamp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D008089:Listeria monocytogenes; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010761:Phosphorus Radioisotopes / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D010761:Phosphorus Radioisotopes
keywords: 32P; KPC; Panc-02; delivery platform; listeria monocytogenes; pancreatic cancer