MRI-monitored intra-tumoral injection of iron-oxide labeled Clostridium novyi-NT anaerobes in pancreatic carcinoma mouse model

Linfeng Zheng, Zhuoli Zhang, Khashayarsha Khazaie, Saurabh Saha, Robert J. Lewandowski, Guixiang Zhang, Andrew C. Larson

Research output: Contribution to journalArticle

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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. Intraprocedural 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.

Original languageEnglish (US)
Article numbere116204
JournalPLoS One
Volume9
Issue number12
DOIs
StatePublished - Dec 30 2014

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Clostridium novyi
Clostridium
anaerobes
iron oxides
Magnetic resonance
magnetic resonance imaging
carcinoma
animal models
Magnetic Resonance Imaging
injection
Imaging techniques
Injections
Labeling
Signal-To-Noise Ratio
nanoparticles
Nanoparticles
Signal to noise ratio
Fluorescence
fluorescence
Staining and Labeling

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

MRI-monitored intra-tumoral injection of iron-oxide labeled Clostridium novyi-NT anaerobes in pancreatic carcinoma mouse model. / Zheng, Linfeng; Zhang, Zhuoli; Khazaie, Khashayarsha; Saha, Saurabh; Lewandowski, Robert J.; Zhang, Guixiang; Larson, Andrew C.

In: PLoS One, Vol. 9, No. 12, e116204, 30.12.2014.

Research output: Contribution to journalArticle

Zheng, Linfeng ; Zhang, Zhuoli ; Khazaie, Khashayarsha ; Saha, Saurabh ; Lewandowski, Robert J. ; Zhang, Guixiang ; Larson, Andrew C. / MRI-monitored intra-tumoral injection of iron-oxide labeled Clostridium novyi-NT anaerobes in pancreatic carcinoma mouse model. In: PLoS One. 2014 ; Vol. 9, No. 12.
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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. Intraprocedural 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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AU - Zheng, Linfeng

AU - Zhang, Zhuoli

AU - Khazaie, Khashayarsha

AU - Saha, Saurabh

AU - Lewandowski, Robert J.

AU - Zhang, Guixiang

AU - Larson, Andrew C.

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N2 - 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. Intraprocedural 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.

AB - 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. Intraprocedural 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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