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      • Record: found
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      Is Open Access

      MRI-Monitored Intra-Tumoral Injection of Iron-Oxide Labeled Clostridium novyi-NT Anaerobes in Pancreatic Carcinoma Mouse Model

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          Abstract

          Objectives

          To validate the feasibility of labeling Clostridium novyi-NT ( C.novyi-NT) anaerobes with iron-oxide nanoparticles for magnetic resonance imaging (MRI) and demonstrate the potential to use MRI to visualize intra-tumoral delivery of these iron-oxide labeled C.novyi-NT during percutaneous injection procedures.

          Materials and Methods

          All studies were approved by IACUC. C.novyi-NT were labeled with hybrid iron-oxide Texas red nanoparticles. Growth of labeled and control samples were evaluated with optical density. Labeling was confirmed with confocal fluorescence and transmission electron microscopy (TEM). MRI were performed using a 7 Tesla scanner with T2*-weighted (T2*W) sequence. Contrast-to-noise ratio (CNR) measurements were performed for phantoms and signal-to-noise ratio (SNR) measurements performed in C57BL/6 mice (n = 12) with Panc02 xenografts before and after percutaneous injection of iron-oxide labeled C.novyi-NT. MRI was repeated 3 and 7 days post-injection. Hematoxylin-eosin (HE), Prussian blue and Gram staining of tumor specimens were performed for confirmation of intra-tumoral delivery.

          Results

          Iron-oxide labeling had no influence upon C.novyi-NT growth. The signal intensity (SI) within T2*W images was significantly decreased for iron-oxide labeled C.novyi-NT phantoms compared to unlabeled controls. Under confocal fluorescence microscopy, the iron-oxide labeled C.novyi-NT exhibited a uniform red fluorescence consistent with observed regions of DAPI staining and overall labeling efficiency was 100% (all DAPI stained C.novyi-NT exhibited red fluorescence). Within TEM images, a large number iron granules were observed within the iron-oxide labeled C.novyi-NT; these were not observed within unlabeled controls. Intra-procedural MRI measurements permitted in vivo visualization of the intra-tumoral distribution of iron-oxide labeled C.novyi-NT following percutaneous injection (depicted as punctate regions of SI reductions within T2*-weighted images); tumor SNR decreased significantly following intra-tumoral injection of C.novyi-NT (p<0.05); these SNR reductions were maintained at 3 and 7 day follow-up intervals. Prussian blue and Gram staining confirmed presence of the iron-oxide labeled anaerobes.

          Conclusions

          C.novyi-NT can be labeled with iron-oxide nanoparticles for MRI visualization of intra-tumoral deposition following percutaneous injection during bacteriolytic therapy.

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          Most cited references27

          • Record: found
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          Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium.

          Zhi-Ming Li, Shukuan Li, Eugene Baranov … (2005)
          Here we report a genetically modified bacteria strain, Salmonella typhimurium A1, selected for anticancer activity in vivo. The strain grows in tumor xenografts. In sharp contrast, normal tissue is cleared of these bacteria even in immunodeficient athymic mice. S. typhimurium A1 is auxotrophic (Leu/Arg-dependent) but apparently receives sufficient support from the neoplastic tissue to grow locally. Whether additional genetic lesions are present is not known. In in vitro infection, the GFP-expressing bacteria grew in the cytoplasm of PC-3 human prostate cancer cells and caused nuclear destruction. These effects were visualized in cells labeled with GFP in the nucleus and red fluorescent protein in the cytoplasm. In vivo, the bacteria caused tumor inhibition and regression of xenografts visualized by whole-body imaging. The bacteria, introduced i.v. or intratumorally, invaded and replicated intracellularly in PC-3 prostate cancer cells labeled with red fluorescent protein grafted into nude mice. By day 15, S. typhimurium A1 was undetectable in the liver, lung, spleen, and kidney, but it continued to proliferate in the PC-3 tumor, which stopped growing. When the bacteria were injected intratumorally, the tumor completely regressed by day 20. There were no obvious adverse effects on the host when the bacteria were injected by either route. The S. typhimurium A1 strain grew throughout the tumor, including viable malignant tissue. This result is in marked contrast to bacteria previously tried for cancer therapy that were confined to necrotic areas of the tumor, which may account, in part, for the strain's unique antitumor efficacy.
          Article 0 comments Cited 158 times – based on 0 reviews     Review now
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            Combination bacteriolytic therapy for the treatment of experimental tumors.

            B Vogelstein, C Bettegowda, Nam Dang … (2001)
            Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascular compartments of transplanted tumors. Among 26 different strains tested, one (Clostridium novyi) appeared particularly promising. We created a strain of C. novyi devoid of its lethal toxin (C. novyi-NT) and showed that intravenously injected C. novyi-NT spores germinated within the avascular regions of tumors in mice and destroyed surrounding viable tumor cells. When C. novyi-NT spores were administered together with conventional chemotherapeutic drugs, extensive hemorrhagic necrosis of tumors often developed within 24 h, resulting in significant and prolonged antitumor effects. This strategy, called combination bacteriolytic therapy (COBALT), has the potential to add a new dimension to the treatment of cancer.
            Article 0 comments Cited 136 times – based on 0 reviews     Review now
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              Bacteriolytic therapy can generate a potent immune response against experimental tumors.

              Edward L. Hipkiss, L. Calero Diaz, Nam Dang … (2004)
              When spores of the anaerobic bacterium Clostridium novyi-NT are systemically injected into animals, they germinate exclusively within the hypoxic regions of cancers. The germinated bacteria destroy adjacent tumor cells but spare a rim of well oxygenated tumor cells that subsequently expand. Surprisingly, we found that approximately 30% of mice treated with such spores were cured of their cancers despite the viable tumor rim initially remaining after spore germination. The mechanism underlying this effect was shown to be immune-mediated, because cured animals rejected a subsequent challenge of the same tumor. Similar effects were observed in rabbits with intrahepatic tumors. It was particularly notable that the induced immune response, when combined with the bacteriolytic effects of C. novyi-NT, could eradicate large established tumors.
              Article 0 comments Cited 90 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Bing Xu: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 30 December 2014
                Volume: 9
                Issue: 12
                Electronic Location Identifier: e116204
                Affiliations
                [1 ]Department of Radiology, First People’s Hospital, Shanghai Jiaotong University, Shanghai, China
                [2 ]Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
                [3 ]Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, United States of America
                [4 ]Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
                [5 ]BioMed Valley Discoveries, Kansas City, Missouri, United States of America
                Brandeis University, United States of America
                Author notes

                Competing Interests: The authors have read the journal's policy and have the following competing interests: Co-author Dr. Saurabh Saha is employed by commercial company BioMed Valley Discoveries but this does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. Materials for these studies (C.novyi-NT spores) were provided by Biomed Valley Discoveries to investigators at Northwestern University under a Materials Transfer Agreement (MTA).

                Conceived and designed the experiments: LZ ZZ ACL. Performed the experiments: LZ ZZ KK SS RJL ACL. Analyzed the data: LZ ZZ ACL. Contributed reagents/materials/analysis tools: LZ ZZ SS GZ ACL. Contributed to the writing of the manuscript: LZ ZZ ACL.

                Article
                Publisher ID: PONE-D-14-45425
                DOI: 10.1371/journal.pone.0116204
                PMC ID: 4280207
                PubMed ID: 25549324
                SO-VID: 40a63a32-9c6b-48b7-ac1f-3735cabb294e
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 9 October 2014
                Date accepted : 7 December 2014
                Page count
                Pages: 15
                Funding
                This work was supported by grants (R01CA159178, RO1CA141047 and R21CA173491) from the National Cancer Institute, the State Scholarship Fund by China Scholarship Council (for LZ), the award for the best youth medical scholars by Shanghai First People’s Hospital, Shanghai Jiao Tong University (for LZ). This work was also supported by the Center for Translational Imaging at Northwestern University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Bacterial Pathogens
                Subject: Clostridium
                Subject: Research and analysis methods
                Subject: Imaging Techniques
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: In Vivo Imaging
                Subject: Microscopy
                Subject: Electron Microscopy
                Subject: Transmission Electron Microscopy
                Subject: Light Microscopy
                Subject: Confocal Microscopy
                Subject: Fluorescence Microscopy
                Subject: Specimen preparation and treatment
                Subject: Staining
                Subject: Membrane Staining
                Subject: Gram Staining
                Subject: Nuclear staining
                Subject: DAPI staining
                Custom metadata
                Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

                Comments

                added an editorial note to Cancer Immunotherapy
                This article was selected by ScienceOpen Consulting Editor, Richard Gallagher, to appear in the Collection entitled Cancer Immunotherapy which can be found here http://ow.ly/Jy1HH. 1. Why this article was chosen: this research provides a reliable method to determine the biodistribution of therapeutically administered bacteriolytic anaerobes. 2. What this article shows: bacteria that are useful as tumor lysing agents can be labeled with commercially available iron-oxide nanoparticles and visualized in vivo using magnetic resonance imaging. 3. A key quote from the article: “Given the anticipated importance of C.novyi-NT biodistributions to treatment outcomes, these non-invasive imaging methods are anticipated to offer a valuable means to optimize injection procedures and/or provide early predictions of response.” 4. Corresponding author: Andrew C. Larson is Professor in Radiology at Northwestern University, Chicago, IL, USA. His research focuses on the development and validation of magnetic resonance imaging techniques for optimal delivery and functional guidance of minimally invasive therapies, early prediction of therapy response, and non-invasive staging of carcinogenesis.
                2015-02-24 01:38 UTC
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