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Diffusion MRI (dMRI) explores tissue microstructures by analyzing diffusion-weighted signal decay measured at different b-values. While relatively low b-values are used for most dMRI models, high b-value diffusion-weighted imaging (DWI) techniques have gained interest given that the non-Gaussian water diffusion behavior observed at high b-values can yield potentially valuable information. In this study, we investigated anomalous diffusion behaviors associated with degeneration of spinal cord tissue using a continuous time random walk (CTRW) model for DWI data acquired across an extensive range of ultrahigh b-values. The diffusion data were acquired in situ from the lumbar level of spinal cords of wild-type and age-matched transgenic SOD1G93A mice, a well-established animal model of amyotrophic lateral sclerosis (ALS) featuring progressive degeneration of axonal tracts in this tissue. Based on the diffusion decay behaviors at low and ultrahigh b-values, we applied the CTRW model using various combinations of b-values and compared diffusion metrics calculated from the CTRW model between the experimental groups. We found that diffusion-weighted signal decay curves measured with ultrahigh b-values (up to 858,022 s/mm2 in this study) were well represented by the CTRW model. The anomalous diffusion coefficient obtained from lumbar spinal cords was significantly higher in SOD1G93A mice compared with control mice (14.7 × 10-5 ± 5.54 × 10-5  vs. 7.87 × 10-5 ± 2.48 × 10-5  mm2 /s, p = 0.01). We believe this is the first study to illustrate the efficacy of the CTRW model for analyzing anomalous diffusion regimes at ultrahigh b-values. The CTRW modeling of ultrahigh b-value dMRI can potentially present a novel approach for noninvasively evaluating alterations in spinal cord tissue associated with ALS pathology.

Asunto(s)

Esclerosis Amiotrófica Lateral , Ratones , Animales , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/patología , Superóxido Dismutasa-1 , Médula Espinal/diagnóstico por imagen , Médula Espinal/patología , Ratones Transgénicos , Imagen de Difusión por Resonancia Magnética , Modelos Animales de Enfermedad

RESUMEN

Purpose To demonstrate the feasibility of using chemical shift fat-water MRI methods to visualize and measure intrahepatic delivery of ethiodized oil to liver tumors following conventional transarterial chemoembolization (cTACE). Materials and Methods Twenty-eight participants (mean age, 66 years ± 8 [SD]; 22 men) with hepatocellular carcinoma (HCC) treated with cTACE were evaluated with follow-up chemical shift MRI in this Health Insurance Portability and Accountability Act-compliant prospective, institutional review board-approved study. Uptake of ethiodized oil was evaluated at 1-month follow-up chemical shift MRI. Measurements of tumor size (MRI and CT), attenuation and enhancement (CT), fat content percentage, and tumor:normal ratio (MRI) were compared by lesion for responders versus nonresponders, as assessed with modified Response Evaluation Criteria in Solid Tumors and European Association for the Study of the Liver (EASL) criteria. Adverse events and overall survival by the Kaplan-Meier method were secondary end points. Results Focal tumor ethiodized oil retention was 46% (12 of 26 tumors) at 24 hours and 47% (18 of 38 tumors) at 1 month after cTACE. Tumor volume at CT did not differ between EASL-defined responders and nonresponders (P = .06). Tumor ethiodized oil volume measured with chemical shift MRI was statistically significantly higher for EASL-defined nonresponders (P = .02). Doxorubicin dosing (P = .53), presence of focal fat (P = .83), and a combined end point of focal fat and low doxorubicin dosing (P = .97) did not stratify overall survival after cTACE. Conclusion Chemical shift MRI allowed for assessment of tumor delivery of ethiodized oil out to 1 month after cTACE in participants with HCC and demonstrated tumor ethiodized oil volume as a potential tool for stratification of tumor response by EASL criteria. Keywords: MRI, Chemical Shift Imaging, CT, Hepatic Chemoembolization, Ethiodized Oil Clinicaltrials.gov registration no.: NCT02173119 Supplemental material is available for this article. © RSNA, 2023.

Asunto(s)

Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Masculino , Humanos , Anciano , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Aceite Etiodizado/efectos adversos , Estudios de Factibilidad , Estudios Prospectivos , Quimioembolización Terapéutica/efectos adversos , Quimioembolización Terapéutica/métodos , Doxorrubicina , Imagen por Resonancia Magnética

RESUMEN

The purpose of this study was to define the optimal infusion parameters and operator radiation exposure for yttrium-90 (90Y) radioembolization in the VX2 rabbit model of liver cancer. Forty-one rabbits with VX2 were treated with glass microspheres with vial sizes of 1, 3, and 5 GBq. The mean administered activity was 51.5 MBq (95% CI, 39.1-63.9). Delivery efficiency improved with 1 GBq versus with 3 GBq (residual 11.0% vs 46.4%, respectively; P = .0013) and improved with 1 GBq versus with 5 GBq (residual 11.0% vs 33.8%, respectively; P = .0060). The mean operator extremity exposure was 41.7 µSv/infusion. The optimal minimum infusion volume and rate was 49 mL and 21 mL/min, respectively. Fecal elimination occurred with microsphere uptake in the gallbladder at 1 and 2 weeks. 90Y radioembolization can be safely and efficiently performed in the VX2 rabbit model. Methodological considerations as a "how-to" for the setup of a preclinical 90Y laboratory are included to support future translational research.

Asunto(s)

Embolización Terapéutica , Neoplasias Hepáticas , Exposición a la Radiación , Animales , Embolización Terapéutica/efectos adversos , Neoplasias Hepáticas/radioterapia , Microesferas , Conejos , Radioisótopos de Itrio/efectos adversos

RESUMEN

Purpose: To validate the therapeutic efficacy of sorafenib-eluting embolic microspheres (SOR-EMs) used in combination with transarterial chemoembolization (TACE) for treatment of hepatocellular carcinoma (HCC) in a preclinical animal model. Materials and Methods: SOR-EMs were prepared with poly(d,l-lactide-co-glycolide), iron oxide nanoparticles, and sorafenib. The morphology of the prepared SOR-EMs was confirmed by using optical microscopy. Drug release from the SOR-EMs was quantified in vitro by using high-performance liquid chromatography. In an orthotopic rat model of HCC, embolic doxorubicin-Lipiodol (ethiodized oil) emulsion (DLE) and SOR-EMs were sequentially injected into the hepatic artery of the rats: The rats in group 1 were injected with DLE; group 2 was injected with DLE plus unloaded embolic microspheres (DLE + EM); group 3, with DLE plus SOR-EMs (DLE + SOR-EM); and group 4, with saline solution. The SOR-EM and tumor size changes in each group (of six rats each) over time were measured by using MRI. Tissues were assessed by using immunohistochemistry, with hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated dUTP (2'-deoxyuridine 5'-triphosphate) nick-end labeling staining used for dead cells and CD34 staining used for new microvessel formation. Results: The SOR-EMs were a mean size of 6.6 µm ± 2.3 (standard deviation) and showed 53.7% ± 8.3 sorafenib loading efficiency with T2-weighted MRI capability. In the HCC rat model, the intra-arterially injected SOR-EMs were successfully monitored by using MRI. The DLE + SOR-EM-treated rats showed a superior tumor growth-inhibitory effect compared with the rats treated with DLE only (P < .05). Immunohistochemical assessment of tissue specimens showed that compared with the other treatment groups, the DLE + SOR-EM treatment group had the lowest number of microvessels, as quantified by using the percentage of CD34-positive stained area (P < .01 for all comparisons). Conclusion: In a preclinical rat HCC model, SOR-EMs used in combination with DLE TACE were effective in treating HCC.Keywords: Chemoembolization, Experimental Investigations, Laboratory Tests, Liver, Technology Assessment Supplemental material is available for this article. © RSNA, 2021See also the commentary by Yamada and Gayed in this issue.

Asunto(s)

Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Microesferas , Ratas , Sorafenib

RESUMEN

Degradable embolic agents that provide transient arterial occlusion during embolization procedures have been of interest for many years. Ideally, embolic agents are visible with standard imaging modalities and offer on-demand degradability, permitting physicians to achieve desired arterial occlusion tailored to patient and procedure indication. Subsequent arterial recanalization potentially enhances the overall safety and efficacy of embolization procedures. Here, we report on-demand degradable and MRI-visible microspheres for embolotherapy. Embolic microspheres composed of calcium alginate and USPIO nanoclusters were synthesized with an air spray atomization and coagulation reservoir equipped with a vacuum suction. An optimized distance between spray nozzle and reservoir allowed uniform size and narrow size distribution of microspheres. The fabricated alginate embolic microspheres crosslinked with Ca2+ demonstrated highly responsive on-demand degradation properties in vitro and in vivo. Finally, the feasibility of using the microspheres for clinical embolization and recanalization procedures was evaluated with interventional radiologists in rabbits. Digital subtraction angiography (DSA) guided embolization of hepatic arteries with these embolic microspheres was successfully performed and the occlusion of artery was confirmed with DSA images and contrast enhanced MRI. T2 MRI visibility of the microspheres allowed to monitor the distribution of intra-arterial (IA) infused embolic microspheres. Subsequent on-demand image-guided recanalization procedures were also successfully performed with rapid degradation of microspheres upon intra-arterial infusion of an ion chelating agent. These instant degradable embolic microspheres will permit effective on-demand embolization/recanalization procedures offering great promise to overcome limitations of currently available permanent and biodegradable embolic agents.

Asunto(s)

Embolización Terapéutica , Alginatos , Animales , Arterias , Humanos , Imagen por Resonancia Magnética , Microesferas , Conejos

RESUMEN

RATIONALE AND OBJECTIVES: To use a rapid gas-challenge blood oxygen-level dependent magnetic resonance imaging exam to evaluate changes in tumor hypoxia after 90Y radioembolization (Y90) in the VX2 rabbit model. MATERIALS AND METHODS: White New Zealand rabbits (n = 11) provided a Y90 group (n = 6 rabbits) and untreated control group (n = 5 rabbits). R2* maps were generated with gas-challenges (O2/room air) at baseline, 1 week, and 2 weeks post-Y90. Laboratory toxicity was evaluated at baseline, 24 hours, 72 hours, 1 hours, and 2 weeks. Histology was used to evaluate tumor necrosis on hematoxylin and eosin and immunofluorescence imaging was used to assess microvessel density (CD31) and proliferative index (Ki67). RESULTS: At baseline, median tumor volumes and time to imaging were similar between groups (p = 1.000 and p = 0.4512, respectively). The median administered dose was 50.4 Gy (95% confidence interval:44.8-55.9). At week 2, mean tumor volumes were 5769.8 versus 643.7 mm3 for control versus Y90 rabbits, respectively (p = 0.0246). At two weeks, ΔR2* increased for control tumors to 12.37 ± 12.36sec-1 and decreased to 4.48 ± 9.00sec-1 after Y90. The Pearson correlation coefficient for ΔR2* at baseline and percent increase in tumor size by two weeks was 0.798 for the Y90 group (p = 0.002). There was no difference in mean microvessel density for control versus Y90 treated tumors (p = 0.6682). The mean proliferative index was reduced in Y90 treated tumors at 30.5% versus 47.5% for controls (p = 0.0071). CONCLUSION: The baseline ΔR2* of tumors prior to Y90 may be a predictive imaging biomarker of tumor response and treatment of these tumors with Y90 may influence tumor oxygenation over time.

Asunto(s)

Carcinoma Hepatocelular , Embolización Terapéutica , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Conejos , Hipoxia Tumoral , Radioisótopos de Itrio/uso terapéutico

RESUMEN

PURPOSE: To demonstrate a stronger correlation and agreement of yttrium-90 (90Y) positron emission tomography (PET)/computed tomography (CT) measurements with explant liver tumor dosing compared with the standard model (SM) for radioembolization. MATERIALS AND METHODS: Hepatic VX2 tumors were implanted into New Zealand white rabbits, with growth confirmed by 7 T magnetic resonance imaging. Seventeen VX2 rabbits provided 33 analyzed tumors. Treatment volumes were calculated from manually drawn volumes of interest (VOI) with three-dimensional surface renderings. Radioembolization was performed with glass 90Y microspheres. PET/CT imaging was completed with scatter and attenuation correction. Three-dimensional ellipsoid VOI were drawn to encompass tumors on fused images. Tumors and livers were then explanted for inductively coupled plasma (ICP)-optical emission spectroscopy (OES) analysis of microsphere content. 90Y PET/CT and SM measurements were compared with reference standard ICP-OES measurements of tumor dosing with Pearson correlation and Bland-Altman analyses for agreement testing with and without adjustment for tumor necrosis. RESULTS: The median infused activity was 33.3 MBq (range, 5.9-152.9). Tumor dose was significantly correlated with 90Y PET/CT measurements (r = 0.903, P < .001) and SM estimates (r = 0.607, P < .001). Bland-Altman analyses showed that the SM tended to underestimate the tumor dosing by a mean of -8.5 Gy (CI, -26.3-9.3), and the degree of underestimation increased to a mean of -18.3 Gy (CI, -38.5-1.9) after the adjustment for tumor necrosis. CONCLUSIONS: 90Y PET/CT estimates were strongly correlated and had better agreement with reference measurements of tumor dosing than SM estimates.

Asunto(s)

Embolización Terapéutica , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/radioterapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Dosis de Radiación , Radiofármacos/administración & dosificación , Radioisótopos de Itrio/administración & dosificación , Animales , Femenino , Necrosis , Valor Predictivo de las Pruebas , Conejos , Interpretación de Imagen Radiográfica Asistida por Computador , Carga Tumoral

RESUMEN

Purpose: The aim of this study was to develop and evaluate a liposome formulation that deliver oxaliplatin under magnetic field stimulus in high concentration to alleviate the off-target effects in a rat model of colorectal liver metastases (CRLM). Materials and Methods: Hybrid liposome-magnetic nanoparticles loaded with Cy5.5 dye and oxaliplatin (L-NIR- Fe3O4/OX) were synthesized by using thermal decomposition method. CRLM (CC-531) cell viability was assessed and rats orthotopically implanted with CC-531 cells were treated with L-NIR-Fe3O4/OX or by drug alone via different routes, up to 3 cycles of alternating magnetic field (AMF). Optical and MR imaging was performed to assess the targeted delivery. Biodistribution and histology was performed to determine the distribution of oxaliplatin. Results: L-NIR-Fe3O4/OX presented a significant increase of oxaliplatin release (~18%) and lower cell viability after AMF exposure (p<0.001). Optical imaging showed a significant release of oxaliplatin among mesenteric vein injected (MV) group of animals. MR imaging on MV injected animals showed R2* changes in the tumor regions at the same regions immediately after infusion compared to the surrounding liver (p<0.001). Biodistribution analysis showed significantly higher levels of oxaliplatin in liver tissues compared to lungs (p<0.001) and intestines (p<0.001) in the MV animals that received AMF after L-NIR- Fe3O4/OX administration. Large tumor necrotic zones and significant improvement in the survival rates were noted in the MV animals treated with AMF. Conclusion: AMF triggers site selective delivery of oxaliplatin at high concentrations and improves survival outcomes in colorectal liver metastasis tumor bearing rats.

RESUMEN

PURPOSE: Portal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass 90Y microspheres (Y90 PVE) in Sprague-Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy. METHODS: Twenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8 MBq; n = 2), high- (99.9 MBq; n = 10), medium- (48.1 MBq; n = 5), and low-dose (14.8 MBq; n = 5). An untreated control group included seven rats. 90Y PET/CT of 90Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide). RESULTS: Ex vivo measurements confirmed 91-97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was - 5.0% (95% CI - 17.0-6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6-29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2 µm2 for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively. CONCLUSION: Y90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12 weeks. The onset of imaging-based volumetric changes was 8-12 weeks.

Asunto(s)

Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas Experimentales/terapia , Animales , Hígado/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas Experimentales/diagnóstico , Imagen por Resonancia Magnética , Masculino , Microesferas , Estadificación de Neoplasias/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Radioisótopos de Itrio

RESUMEN

PURPOSE: To develop bile acid-stabilized multimodal magnetic resonance (MR) imaging and computed tomography (CT)-visible doxorubicin eluting lipiodol emulsion for transarterial chemoembolization of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Ferumoxytol, a US Food and Drug Administration-approved iron oxide nanoparticle visible under MR imaging was electrostatically complexed with doxorubicin (DOX). An amphiphilic bile acid, sodium cholate (SC), was used to form a stable dispersion of ferumoxytol-DOX complex in lipiodol emulsion. Properties of the fabricated emulsion were characterized in various component ratios. Release kinetics of DOX were evaluated for the chemoembolization applications. Finally, in vivo multimodal MR imaging/CT imaging properties and potential therapeutic effects upon intra-arterial (IA) infusion bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion were evaluated in orthotopic McA-Rh7777 HCC rat models. RESULTS: DOX complexed with ferumoxytol through electrostatic interaction. Amphiphilic SC bile acid at the interface between the aqueous ferumoxytol-DOX complexes and lipiodol enabled a sustained DOX release (17.2 ± 1.6% at 24 hours) at an optimized component ratio. In McA Rh7777 rat HCC model, IA-infused emulsion showed a significant contrast around tumor in both T2-weighted MR imaging and CT images (P = .044). Hematoxylin and eosin and Prussian blue staining confirmed the local deposition of IA-infused SC bile acid-stabilized emulsion in the tumor. The deposited emulsion induced significant increases in TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) stain-positive cancer cell apoptosis compared to those in a group treated with the nonstabilized emulsion. CONCLUSIONS: SC bile acid-stabilized ferumoxytol-DOX-lipiodol emulsion demonstrated sustained drug release and multimodal MR imaging/CT imaging capabilities. The new lipiodol-based formulation may enhance the therapeutic efficacy of chemoembolization in HCC.

Asunto(s)

Antibióticos Antineoplásicos/administración & dosificación , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica , Medios de Contraste/administración & dosificación , Doxorrubicina/administración & dosificación , Aceite Etiodizado/administración & dosificación , Óxido Ferrosoférrico/administración & dosificación , Neoplasias Hepáticas Experimentales/terapia , Colato de Sodio/administración & dosificación , Animales , Antibióticos Antineoplásicos/química , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Medios de Contraste/química , Doxorrubicina/química , Liberación de Fármacos , Estabilidad de Medicamentos , Emulsiones , Óxido Ferrosoférrico/química , Infusiones Intraarteriales , Cinética , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/patología , Imagen por Resonancia Magnética , Imagen Multimodal , Ratas Sprague-Dawley , Colato de Sodio/química , Tomografía Computarizada por Rayos X

RESUMEN

PURPOSE: To evaluate the combination of 90Y radioembolization (Y90) and drug-eluting bead irinotecan (DEBIRI) microspheres in the VX2 rabbit model. MATERIALS AND METHODS: An initial dose finding study was performed in 6 White New Zealand rabbits to identify a therapeutic but subcurative dose of Y90. In total, 29 rabbits were used in four groups: Y90 treatment (n = 8), DEBIRI treatment (n = 6), Y90 + DEBIRI treatment (n = 7), and an untreated control group (n = 8). Hepatic toxicity was evaluated at baseline, 24 h, 72 h, 1 week, and 2 weeks. MRI tumor volume (TV) and enhancing tumor volume were assessed baseline and 2 weeks. Tumor area and necrosis were evaluated on H&E for pathology. RESULTS: Infused activities of 84.0-94.4 MBq (corresponding to 55.1-72.7 Gy) were selected based on the initial dose finding study. Infusion of DEBIRI after Y90 was technically feasible in all cases (7/7). Overall, 21/29 animals survived to 2 weeks, and the remaining animals had extrahepatic disease on necropsy. Liver transaminases were elevated with Y90, DEBIRI, and Y90 + DEBIRI compared to control at 24 h, 72 h, and 1 week post-treatment and returned to baseline by 2 weeks. By TV, Y90 + DEBIRI was the only treatment to show statistically significant reduction at 2 weeks compared to the control group (p = 0.012). The change in tumor volume (week 2-baseline) for both Y90 + DEBIRI versus control (p = 0.002) and Y90 versus control (p = 0.014) was significantly decreased. There were no statistically significant differences among groups on pathology. CONCLUSION: Intra-arterial Y90 + DEBIRI was safe and demonstrated enhanced antitumor activity in rabbit VX2 tumors. This combined approach warrants further investigation.

Asunto(s)

Antineoplásicos/administración & dosificación , Quimioembolización Terapéutica , Irinotecán/administración & dosificación , Neoplasias Hepáticas Experimentales/terapia , Microesferas , Radioisótopos de Itrio/administración & dosificación , Animales , Antineoplásicos/efectos adversos , Quimioembolización Terapéutica/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Irinotecán/efectos adversos , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Imagen por Resonancia Magnética , Necrosis , Conejos , Radioisótopos de Itrio/efectos adversos

RESUMEN

The microstructure changes associated with degeneration of spinal axons in amyotrophic lateral sclerosis (ALS) may be reflected in altered water diffusion properties, potentially detectable with diffusion-weighted (DW) MRI. Prior work revealed the classical mono-exponential model fails to precisely depict decay in DW signal at high b-values. In this study, we aim to investigate signal decay behaviors at ultra-high b-values for non-invasive assessment of spinal cord alterations in the transgenic SOD1G93A mouse model of ALS. A multiexponential diffusion analysis using regularized non-negative least squares (rNNLS) algorithm was applied to a series of thirty DW MR images with b-values ranging from 0 to 858,022 s/mm2 on ex vivo spinal cords of transgenic SOD1G93A and age-matched control mice. We compared the distributions of measured diffusion coefficient fractions between the groups. The measured diffusion weighted signals in log-scale showed non-linear decay behaviors with increased b-values. Faster signal decays were observed with diffusion gradients applied parallel to the long axis of the spinal cord compared to when oriented in the transverse direction. Multiexponential analysis at the lumbar level in the spinal cord identified ten subintervals. A significant decrease of diffusion coefficient fractions was found in the ranges of [1.63×10-8,3.70×10-6] mm2/s (P = 0.0002) and of [6.01×10-6,4.20×10-5] mm2/s (P = 0.0388) in SOD1G93A mice. Anisotropic diffusion signals persisted at ultra-high b-value DWIs of the mouse spinal cord and multiexponential diffusion analysis offers the potential to evaluate microstructural alterations of ALS-affected spinal cord non-invasively.

Asunto(s)

Algoritmos , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Axones/patología , Imagen de Difusión por Resonancia Magnética/métodos , Médula Espinal/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Masculino , Ratones , Médula Espinal/patología , Superóxido Dismutasa-1/genética

Asunto(s)

Medios de Contraste/administración & dosificación , Portadores de Fármacos/administración & dosificación , Técnicas de Transferencia de Gen/tendencias , Nanopartículas/administración & dosificación , Radiografía Intervencional/tendencias , Nanomedicina Teranóstica/tendencias , Animales , Medios de Contraste/efectos adversos , Difusión de Innovaciones , Portadores de Fármacos/efectos adversos , Técnicas de Transferencia de Gen/efectos adversos , Humanos , Nanopartículas/efectos adversos , Valor Predictivo de las Pruebas , Pronóstico , Radiografía Intervencional/efectos adversos , Factores de Riesgo

RESUMEN

Colorectal cancer (CRC) is diagnosed with colonoscopy and treated with focal therapies. CRC is a good candidate for nanoparticle-mediated photothermal ablation (PTA) therapy. Herein, we developed a near-infrared fluorescent (NIRF) endoscopic image-guided PTA approach using a nanoparticle capable of simultaneously diagnosing and treating CRC. Dual-modal NIR heating and fluorescent gold nanorods (dual-modal GNRs) were synthesized by conjugation of GNRs to an NIRF probe. To validate the translational potential of our approach, a well-characterized transgenic TS4 CRE/APC loxΔ468 colon cancer mouse model was used to carry out NIRF image-guided PTA using our dual-modal GNRs under clinically relevant conditions. Intravenously infused dual-modal GNRs were effectively targeted at colon polyps by immunogenic capturing of the GNRs within tumor-infiltrating innate immune cells. NIRF endoscopic image-guided PTA using the GNRs permitted successful detection and ablation of inflammatory colon polyps. NIRF endoscopy image-guided PTA using dual-modal GNRs can be utilized for diagnosis and treatment of CRC and various inflammatory diseases.

Asunto(s)

Técnicas de Ablación/métodos , Neoplasias Colorrectales/terapia , Oro/química , Nanotubos/química , Fototerapia/métodos , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Inmunidad Innata/fisiología , Ratones , Ratones Transgénicos , Espectroscopía Infrarroja Corta

RESUMEN

PURPOSE: To label Clostridium novyi-NT spores (C. novyi-NT) with iron oxide nanoclusters and track distribution of bacteria during magnetic resonance (MR) imaging-monitored locoregional delivery to liver tumors using intratumoral injection or intra-arterial transcatheter infusion. MATERIALS AND METHODS: Vegetative state C. novyi-NT were labeled with iron oxide particles followed by induction of sporulation. Labeling was confirmed with fluorescence microscopy and transmission electron microscopy (TEM). T2 and T2* relaxation times for magnetic clusters and magnetic microspheres were determined using 7T and 1.5T MR imaging scanners. In vitro assays compared labeled bacteria viability and oncolytic potential to unlabeled controls. Labeled spores were either directly injected into N1-S1 rodent liver tumors (n = 24) or selectively infused via the hepatic artery in rabbits with VX2 liver tumors (n = 3). Hematoxylin-eosin, Prussian blue, and gram staining were performed. Statistical comparison methods included paired t-test and ANOVA. RESULTS: Both fluorescence microscopy and TEM studies confirmed presence of iron oxide labels within the bacterial spores. Phantom studies demonstrated that the synthesized nanoclusters produce R2 relaxivities comparable to clinical agents. Labeling had no significant impact on overall growth or oncolytic properties (P >.05). Tumor signal-to-noise ratio (SNR) decreased significantly following intratumoral injection and intra-arterial infusion of labeled spores (P <.05). Prussian blue and gram staining confirmed spore delivery. CONCLUSIONS: C. novyi-NT spores can be internally labeled with iron oxide nanoparticles to visualize distribution with MR imaging during locoregional bacteriolytic therapy involving direct injection or intra-arterial transcatheter infusion.

Asunto(s)

Terapia Biológica/métodos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Clostridium/metabolismo , Medios de Contraste/administración & dosificación , Compuestos Férricos/administración & dosificación , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/terapia , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita/administración & dosificación , Imagen Molecular/métodos , Esporas Bacterianas , Animales , Carcinoma Hepatocelular/microbiología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Clostridium/genética , Clostridium/patogenicidad , Medios de Contraste/metabolismo , Compuestos Férricos/metabolismo , Neoplasias Hepáticas Experimentales/microbiología , Neoplasias Hepáticas Experimentales/patología , Valor Predictivo de las Pruebas , Conejos , Ratas Sprague-Dawley

RESUMEN

PURPOSE: To investigate the differences in immune responses between cryoablation and irreversible electroporation (IRE) in a preclinical mouse model. MATERIAL AND METHODS: A mouse pancreatic cancer cell line (PANC-2) was implanted in the bilateral flanks of mice, and tumor-bearing mice were divided into 6 groups. One of the tumors was ablated either with contact cryoablation using an argon-cooled cryoablation probe for 1 minute at 5% power or by IRE for a total of 64 100-µs-duration, 1250-V/cm2 pulses with 100-ms spacing. The contralateral tumors in the same animal served as controls. At immediate, 6, 12, and 24 hours after ablation, the tumors were processed for immunostaining with F480 (macrophages), CD3 (T cells), and CD-56 (natural killer cells) antibodies. RESULTS: CD3 staining demonstrated significantly more T cells in the IRE group than in the cryoablation group at 6 hours (45 vs 16; P = .027), 12 hours (67 vs 33; P = .020), and 24 hours (161 vs 94; p = .003), with almost a 2-fold increase at every time point. Although the mean number of natural killer cells in the treated tumors was higher, no significant differences were observed between the 2 groups at any of the time points. A significant difference was observed in F480 positivity between the cryoablation group and the IRE group at 12 hours (210 vs 356; P = .0004) and 24 hours (220 vs 328; P = .04), respectively. CONCLUSIONS: In a mouse model of pancreatic cancer, IRE evokes a more robust infiltration of macrophages and T cells than cryoablation within 24 hours.

Asunto(s)

Criocirugía , Electroporación , Neoplasias Experimentales/terapia , Neoplasias Pancreáticas/terapia , Animales , Antígenos de Diferenciación/metabolismo , Complejo CD3/metabolismo , Antígeno CD56/metabolismo , Línea Celular Tumoral , Criocirugía/efectos adversos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones Endogámicos C57BL , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Factores de Tiempo

RESUMEN

The purpose of this work is to explore the potential contribution of diffusion MRI to predict the effects of irreversible electroporation (IRE) in a pancreatic ductal adenocarcinoma (PDAC) mouse model. Thirteen mice were injected with Panc-02 PDAC cells in both flanks. One tumor was treated with IRE when it reached a diameter of about 5 mm. T2- and diffusion-weighted MRI sequences were acquired before IRE treatment and 1, 3 and 7 days later. The mice were euthanized 1 day (n = 6) or 2 weeks (n = 7) after treatment. The tumors were excised and stained with H&E, caspase-3, CD-3, F4/80. The volume and the mean and standard deviation of the apparent diffusion coefficient (ADC) were compared between treated and untreated lesions and correlated with histology-derived measures. At 1-day post-treatment, a dramatic ADC increase (+50.81%, P < 0.05) was found in ablated lesions, strongly correlated with apoptosis (τ = 0.90). At later time points the ADC returned to pre-treatment values, though histopathology showed a quite different scenario compared to the untreated controls. The ADC standard deviation measured within the treated tumors 1 day after IRE treatment had a strong negative correlation with the number of tumor cells found 14 days later (τ = 0.80). There was also a strong correlation between 1-day ADC and 14-day apoptosis in untreated tumors (τ = 0.95). In conclusion, diffusion MRI is sensitive to the short-term effects of IRE in PDAC tumors, and can help predict the long-term treatment outcome.

Asunto(s)

Investigación Biomédica , Radiología Intervencionista , Comités Consultivos , Consenso , Humanos , Sociedades Médicas

RESUMEN

While natural killer (NK) cell-based adoptive transfer immunotherapy (ATI) provides only modest clinical success in cancer patients. This study was hypothesized that MRI-guided transcatheter intra-hepatic arterial (IHA) infusion permits local delivery to liver tumors to improve outcomes during NK-based ATI in a rat model of hepatocellular carcinoma (HCC). Mouse NK cells were labeled with clinically applicable iron nanocomplexes. Twenty rat HCC models were assigned to three groups: transcatheter IHA saline infusion as the control group, transcatheter IHA NK infusion group, and intravenous (IV) NK infusion group. MRI studies were performed at baseline and at 24 h, 48 h, and 8 days postinfusion. There was a significant difference in tumor R2* values between baseline and 24 h following the selective transcatheter IHA NK delivery to the tumors (P = 0.039) when compared to IV NK infusion (P = 0.803). At 8 days postinfusion, there were significant differences in tumor volumes between the control, IV, and IHA NK infusion groups (control vs. IV, P = 0.196; control vs. IHA, P < 0.001; and IV vs. IHA, P = 0.001). Moreover, there was a strong correlation between tumor R2* value change (∆R2*) at 24 h postinfusion and tumor volume change (∆volume) at 8 days in IHA group (R2  = 0.704, P < 0.001). Clinically applicable labeled NK cells with 12-h labeling time can be tracked by MRI. Transcatheter IHA infusion improves NK cell homing efficacy and immunotherapeutic efficiency. The change in tumor R2* value 24 h postinfusion is an important early biomarker for prediction of longitudinal response.

Asunto(s)

Carcinoma Hepatocelular/terapia , Células Asesinas Naturales/trasplante , Neoplasias Hepáticas/terapia , Imagen por Resonancia Magnética Intervencional/métodos , Administración Intravenosa , Animales , Línea Celular Tumoral , Inmunoterapia Adoptiva , Infusiones Parenterales , Masculino , Ratones , Ratas , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

PURPOSE: Biodegradable polylactic-co-glycolic acid (PLGA) nanoparticles can adsorb at the water/oil interface to stabilize the emulsion (forming Pickering-emulsion). The purpose of this study was to compare the release profiles of oxaliplatin from Pickering-emulsion and Lipiodol-emulsion. MATERIALS/METHODS: Pickering-emulsions and Lipiodol-emulsions were both formulated with oxaliplatin (5 mg/mL) and Lipiodol (water/oil ratio: 1/3). For Pickering-emulsion only, PLGA nanoparticles (15 mg/mL) were dissolved into oxaliplatin before formulation. In vitro release of oxaliplatin from both emulsions was evaluated. Then, oxaliplatin was selectively injected into left hepatic arteries of 18 rabbits bearing VX2 liver tumors using either 0.5 mL Pickering-emulsion (n = 10) or 0.5 mL Lipiodol-emulsion (n = 8). In each group, half of the rabbits were killed at 1 h and half at 24 h. Mass spectrometry was used to quantify drug pharmacokinetics in blood and resulting tissue (tumors, right, and left livers) oxaliplatin concentrations. RESULTS: Pickering-emulsion demonstrated a slow oxaliplatin release compared to Lipiodol-emulsion (1.5 ± 0.2 vs. 12.0 ± 6% at 1 h and 15.8 ± 3.0 vs. 85.3 ± 3.3% at 24 h) during in vitro comparison studies. For animal model studies, the plasmatic peak (Cmax) and the area under the curve (AUC) were significantly lower with Pickering-emulsion compared to Lipiodol-emulsion (Cmax = 0.49 ± 0.14 vs. 1.08 ± 0.41 ng/mL, p = 0.01 and AUC = 19.8 ± 5.9 vs. 31.8 ± 14.9, p = 0.03). This resulted in significantly lower oxaliplatin concentrations in tissues at 1 h with Pickering-emulsion but higher ratio between tumor and left liver at 24 h (43.4 vs. 14.5, p = 0.04). CONCLUSION: Slow release of oxaliplatin from Pickering-emulsion results in a significant decrease in systemic drug exposure and higher ratio between tumor and left liver oxaliplatin concentration at 24 h.

Asunto(s)

Antineoplásicos/uso terapéutico , Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas/terapia , Compuestos Organoplatinos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Emulsiones , Aceite Etiodizado/uso terapéutico , Oxaliplatino , Conejos