Transarterial Radioembolization with Yttrium-90 for the Treatment of Hepatocellular Carcinoma

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

<div><p>Objectives</p><p>To validate the feasibility of labeling <i>Clostridium novyi-NT</i> (<i>C.novyi-NT</i>) 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 <i>C.novyi-NT</i> during percutaneous injection procedures.</p><p>Materials and Methods</p><p>All studies were approved by IACUC. <i>C.novyi-NT</i> 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 <i>C.novyi-NT.</i> 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.</p><p>Results</p><p>Iron-oxide labeling had no influence upon <i>C.novyi-NT</i> growth. The signal intensity (SI) within T2*W images was significantly decreased for iron-oxide labeled <i>C.novyi-NT</i> phantoms compared to unlabeled controls. Under confocal fluorescence microscopy, the iron-oxide labeled <i>C.novyi-NT</i> exhibited a uniform red fluorescence consistent with observed regions of DAPI staining and overall labeling efficiency was 100% (all DAPI stained <i>C.novyi-NT</i> exhibited red fluorescence). Within TEM images, a large number iron granules were observed within the iron-oxide labeled <i>C.novyi-NT</i>; these were not observed within unlabeled controls. Intra-procedural MRI measurements permitted <i>in</i><i>vivo</i> visualization of the intra-tumoral distribution of iron-oxide labeled <i>C.novyi-NT</i> following percutaneous injection (depicted as punctate regions of SI reductions within T2*-weighted images); tumor SNR decreased significantly following intra-tumoral injection of <i>C.novyi-NT</i> (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.</p><p>Conclusions</p><p><i>C.novyi-NT</i> can be labeled with iron-oxide nanoparticles for MRI visualization of intra-tumoral deposition following percutaneous injection during bacteriolytic therapy.</p></div

Tumor SNR measurements within T2*-weighted images before and after percutaneous injection of iron-oxide labeled <i>C.novyi-NT</i> into cystic Panc02 tumors with extensive zones of liquefactive necrosis (a, n = 6) and into solid Panc02 tumors (b, n = 6) with follow-up measurements performed immediately after injection and at 3-day and 7-day intervals post-injection.

<p>*p<0.05 for all pre- <i>vs</i> post-injection SNR measurements.</p

Representative confocal fluorescence microscopy and TEM images of Texas Red iron-oxide labeled <i>C.novyi-NT</i>.

<p>Texas Red particles were observed within the <i>C.novyi-NT</i> (a). <i>C.novyi-NT</i> were stained blue with DAPI (b). Merged image (c) demonstrates the co-registration of Texas Red and DAPI staining. TEM of control unlabeled <i>C.novyi-NT</i> (d) with inset depicting the bacterial wall (1), light plasma membrane (2), and relatively homogeneous dark-stained cytoplasm and nucleoid core (3). Within TEM image of iron-oxide labeled <i>C.novyi-NT</i> (e), a large number of punctate dark-stained iron granules were observed within the bacteria (white arrowheads within inset). Scale bars: a, b, and c = 6 µm; d, e, and inset in d and e = 60 µm.</p

MRI measurements following percutaneous injection of iron-oxide labeled <i>C.novyi-NT</i> into a Panc02 tumor with an expansive central zone of liquefactive necrosis.

<p>Axial T2*-weighted images acquired pre-injection (a) and immediately post-injection (b). The red dashed zones in (a) and (b) indicate the tumor position. Hematoxylin-eosin (HE) staining (c), Gram staining (d) and Prussian blue staining (e) from tissue sample at border between solid viable tumor and necrotic region depict the broad distribution of the iron-oxide labeled anaerobes with the necrotic zones. Size bar for MRI image a and b = 2 mm. Scale bars within c, d and e = 50 µm.</p

Parameters for T1W, T2W and T2*W Sequences.

<p>Note: T1W = T1-weighted, T2W = T2-weighted, T2*W = T2*-weighted, GRE = Gradient echo, TSE = Turbo spine echo, TR = Repetition time, TE = Echo time, FOV = Field of view, FA = Flip angle.</p><p>Parameters for T1W, T2W and T2*W Sequences.</p

OD₆₀₀ of <i>C.novyi-NT</i> at different time points after iron-oxide labeling.

<p>There was no significance between iron-oxide labeled and unlabeled <i>C.novyi-NT</i> OD₆₀₀ measurements (p>0.05 for comparisons at each time point, n = 3).</p