title: Engineering and visualization of bacteria for targeting infarcted myocardium.
abstract: Optimization of the specific affinity of cardiac delivery vector could significantly improve the efficiency of gene/protein delivery, yet no cardiac vectors to date have sufficient target specificity for myocardial infarction (MI). In this study, we explored bacterial tropism for infarcted myocardium based on our previous observations that certain bacteria are capable of targeting the hypoxic regions in solid tumors. Out of several Escherichia coli or Salmonella typhimurium strains, the S. typhimurium defective in the synthesis of ppGpp (ΔppGpp S. typhimurium) revealed accumulation and selective proliferation in the infarcted myocardium without spillover to noncardiac tissue. The Salmonellae that were engineered to express a variant of Renilla luciferase gene (RLuc8), under the control of the E. coli arabinose operon promoter (P(BAD)), selectively targeted and delivered RLuc8 in the infarcted myocardium only upon injection of L-arabinose. An examination of the infarct size before and after infection, and estimations of C-reactive protein (CRP) and procalcitonin indicated that intravenous injection of ΔppGpp S. typhimurium did not induce serious local or systemic immune reactions. This current proof-of-principle study demonstrates for the first time the capacity of Salmonellae to target infarcted myocardium and to serve as a vehicle for the selective delivery of therapeutic agents in MI.
authors.affiliation: Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Uyenchi N
authors.initials: UN
authors.lastname: Le
authors.forename: Hyung-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Kwon
authors.forename: Mi Yeon
authors.initials: MY
authors.lastname: Kim
authors.forename: Vu H
authors.initials: VH
authors.lastname: Nguyen
authors.forename: Sheng Nan
authors.initials: SN
authors.lastname: Jiang
authors.forename: Byeong-Il
authors.initials: BI
authors.lastname: Lee
authors.forename: Yeongjin
authors.initials: Y
authors.lastname: Hong
authors.forename: Myung Geun
authors.initials: MG
authors.lastname: Shin
authors.forename: Joon Haeng
authors.initials: JH
authors.lastname: Rhee
authors.forename: Hee-Seung
authors.initials: HS
authors.lastname: Bom
authors.forename: Youngkeun
authors.initials: Y
authors.lastname: Ahn
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.forename: Hyon E
authors.initials: HE
authors.lastname: Choy
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Min
mesh_terms: D000818:Animals; D001089:Arabinose / Q000494:pharmacology; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000032:analysis; D002939:Ciprofloxacin / Q000494:pharmacology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004926:Escherichia coli / Q000302:isolation & purification*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006321:Heart / Q000382:microbiology*; D008025:Ligases / Q000172:deficiency / Q000235:genetics; D049410:Luciferases, Renilla / Q000235:genetics / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology / Q000628:therapy; D015202:Protein Engineering; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000302:isolation & purification*; D018523:Tropism
chemical_list: D002939:Ciprofloxacin; D002097:C-Reactive Protein; D001089:Arabinose; D049410:Luciferases, Renilla; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases