Computed Tomography Imaging of Primary Lung Cancer in Mice Using a Liposomal-Iodinated Contrast Agent

To investigate the utility of a liposomal-iodinated nanoparticle contrast agent and computed tomography (CT) imaging for characterization of primary nodules in genetically engineered mouse models of non-small cell lung cancer.Primary lung cancers with mutations in K-ras alone (Kras(LA1)) or in combination with p53 (LSL-Kras(G12D);p53(FL/FL)) were generated. A liposomal-iodine contrast agent containing 120 mg Iodine/mL was administered systemically at a dose of 16 µl/gm body weight. Longitudinal micro-CT imaging with cardio-respiratory gating was performed pre-contrast and at 0 hr, day 3, and day 7 post-contrast administration. CT-derived nodule sizes were used to assess tumor growth. Signal attenuation was measured in individual nodules to study dynamic enhancement of lung nodules.A good correlation was seen between volume and diameter-based assessment of nodules (R(2)>0.8) for both lung cancer models. The LSL-Kras(G12D);p53(FL/FL) model showed rapid growth as demonstrated by systemically higher volume changes compared to the lung nodules in Kras(LA1) mice (p<0.05). Early phase imaging using the nanoparticle contrast agent enabled visualization of nodule blood supply. Delayed-phase imaging demonstrated significant differential signal enhancement in the lung nodules of LSL-Kras(G12D);p53(FL/FL) mice compared to nodules in Kras(LA1) mice (p<0.05) indicating higher uptake and accumulation of the nanoparticle contrast agent in rapidly growing nodules.The nanoparticle iodinated contrast agent enabled visualization of blood supply to the nodules during the early-phase imaging. Delayed-phase imaging enabled characterization of slow growing and rapidly growing nodules based on signal enhancement. The use of this agent could facilitate early detection and diagnosis of pulmonary lesions as well as have implications on treatment response and monitoring

CT scan images of orthotopic tumor in mouse abdomen.

<p>Yellow line outlines the tumor. (a) Pre contrast injection. (b) immediately post contrast injection, showing the abdominal vasculature including vessels within the tumor. (c) 5 days post contrast injection, showing extravasated contrast within the tumor margin, and highlighting the liver and spleen, organs of the reticulo-endothelial system (RES) involved in clearance of the contrast agent. (d) After a 2^nd dose of contrast, thus depicting both the vasculature and the intratumoral extravasate.</p

Heterogeneous Uptake of Nanoparticles in Mouse Models of Pediatric High-Risk Neuroblastoma - Fig 5

<p>(a) Normalized cumulative leak volume as a function of normalized radial position for 15 individual NGP tumors ranging in age from 2 to 4 weeks post inoculation, and ranging in volume from 150 to 8500 mm3. (b) Normalized cumulative iodine uptake as a function of normalized radial position for 15 individual NGP tumors ranging in age from 2 to 4 weeks post inoculation, and ranging in volume from 150 to 8500mm3.</p

Maximum intensity projections of three segmented tumors, of similar tumor weight and size (~ 1.2 g, ~1cm major axis), showing iodine deposition in the tumors as a color map (top row).

<p>Thresholding the iodine signal at 3σ renders the locations of high iodine deposition (white) and the rest of the tumor (dark). The high iodine deposition locations are designated as extravascular leak.</p

Radial discretization of tumor volume into 140μm thick concentric sections.

<p>The process begins at the periphery of the tumor and creating a sub-volume that penetrates 140μm into the interior of the tumor. The process is repeated for the remaining portion of the tumor until the remaining portion has a dimension less than 140μm.</p

Representative coronal micro-CT images of LSL-Kras^G12D;p53^FL/FL and Kras^LA1 mice before liposomal contrast-agent injection and at 0 hr, Day 3 and Day 7 post-contrast injection.

<p>Note the differential enhancement of tumors at Day 7 post-contrast time point in the LSL-Kras^G12D;p53^FL/FL lesions only.</p

Orthgonal thick slab maximum intensity projection (MIP) images demonstrating visualization of nodule blood supply in the lung cancer models.

<p>The images were acquired immediately after administration of liposomal contrast agent.</p

Correlation between nodule volume and diameter in LSL-Kras^G12D;p53^FL/FL (•) and Kras^LA1 (×) models.

<p>(<b>a</b>)<b>.</b> Solid lines indicate cubic fit to the data points. An R² value of 0.93 and 0.81 was obtained for LSL-Kras^G12D;p53^FL/FL and Kras^LA1 models, respectively. Percentage change in nodule volume in the two lung cancer models as a function of nodule diameter (* indicates p<0.05) (b). CT-derived fractional blood volume as a function of nodule diameter (c).</p

Hematoxylin and eosin staining showing characteristics of high-grade lung cancer in LSL-Kras^G12D;^p53FL/FL mice with pleomorphic nuclei (a,b) and low-grade Kras^LA1 lung tumors in Kras^LA1 mice with regular nuclei and minimal cytologic atypia (c,d).

<p>Images were acquired at 10× (a,c) and 40× magnification (c,d). Scale bars: 200 um in a and c; 100 um in b and d.</p

Differential signal enhancement on day 7 in the two primary lung cancer nodules.

<p>(* indicates p<0.05).</p