title: Bacterial Carriers for Glioblastoma Therapy.
abstract: Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro-apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, UA Whitaker Building, 313 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: Nalini
authors.initials: N
authors.lastname: Mehta
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, UA Whitaker Building, 313 Ferst Drive, Atlanta, GA 30332, USA; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, 101 Science Drive, Durham, NC 27708-0271, USA.
authors.forename: Johnathan G
authors.initials: JG
authors.lastname: Lyon
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, UA Whitaker Building, 313 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: Ketki
authors.initials: K
authors.lastname: Patil
authors.affiliation: Department of Biomedical Engineering, Pratt School of Engineering, Duke University, 101 Science Drive, Durham, NC 27708-0271, USA.
authors.forename: Nassir
authors.initials: N
authors.lastname: Mokarram
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, UA Whitaker Building, 313 Ferst Drive, Atlanta, GA 30332, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Biomedical Engineering, Pratt School of Engineering, Duke University, 101 Science Drive, Durham, NC 27708-0271, USA.
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Bellamkonda
keywords: Azurin; RNU rats; Salmonella typhimurium; VNP 20009; bacteria; brain cancer; drug delivery; glioblastoma; p53; tumor targeting