title: PSMA-specific theranostic nanoplex for combination of TRAIL gene and 5-FC prodrug therapy of prostate cancer.
abstract: Metastatic prostate cancer causes significant morbidity and mortality and there is a critical unmet need for effective treatments. We have developed a theranostic nanoplex platform for combined imaging and therapy of prostate cancer. Our prostate-specific membrane antigen (PSMA) targeted nanoplex is designed to deliver plasmid DNA encoding tumor necrosis factor related apoptosis-inducing ligand (TRAIL), together with bacterial cytosine deaminase (bCD) as a prodrug enzyme. Nanoplex specificity was tested using two variants of human PC3 prostate cancer cells in culture and in tumor xenografts, one with high PSMA expression and the other with negligible expression levels. The expression of EGFP-TRAIL was demonstrated by fluorescence optical imaging and real-time PCR. Noninvasive (19)F MR spectroscopy detected the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) by bCD. The combination strategy of TRAIL gene and 5-FC/bCD therapy showed significant inhibition of the growth of prostate cancer cells and tumors. These data demonstrate that the PSMA-specific theranostic nanoplex can deliver gene therapy and prodrug enzyme therapy concurrently for precision medicine in metastatic prostate cancer.
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, 21205, USA.
authors.forename: Zhihang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, 21205, USA; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Penet
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, 21205, USA.
authors.forename: Balaji
authors.initials: B
authors.lastname: Krishnamachary
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, 21205, USA; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Banerjee
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, 21205, USA; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, 21205, USA; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. Electronic address: zaver@mri.jhu.edu.
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D000963:Antimetabolites / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D001419:Bacteria / Q000201:enzymology; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D057487:Enzyme Therapy; D005437:Flucytosine / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D015316:Genetic Therapy; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D011355:Prodrugs / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D000068936:Theranostic Nanomedicine
chemical_list: D000954:Antigens, Surface; D000963:Antimetabolites; D011355:Prodrugs; D053221:TNF-Related Apoptosis-Inducing Ligand; D004247:DNA; D005437:Flucytosine; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D043525:Cytosine Deaminase
keywords: Gene therapy; PSMA; Prodrug enzyme therapy; Prostate cancer; TRAIL; Theranostic imaging