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Non-invasive monitoring of therapeutic response in sorafenib-treated orthotopic hepatocellular carcinoma mouse models using photoacoustic and fluorescence imaging

S. Lee, J. Kim, J. Lee, J. Han; Seoul/KR


Purpose: To investigate the changes in oxygen saturation (sO2) and radiant efficiency (RE) in sorafenib-treated hepatocellular carcinoma (HCC) mouse models using photoacoustic (PI) and fluorescence imaging (FI).
Methods and Materials: BALB/c nude mice, implanted with human HepG2-RFP cells in left lobe of the liver, were randomized to the sorafenib-treated group (n = 21), or the control group (n = 20). Sorafenib (30 mg/kg) was administered orally to the treated group during 1-week. The changes in tumour volume, sO2 of HCC and liver parenchyma, and RE were measured at baseline and after 1-week. Pathologic changes including necrotic fraction and microvessel density were compared using unpaired t-test and correlation analysis.
Results: In the sorafenib-treated group, tumour volume and RE showed lower values than those in the control group at 1-week (94.77 ± 42.24 vs. 159.10 ± 77.32 mm3 and 4.89 ± 2.57 vs. 7.02 ± 3.89 x 1011 [p/sec/cm2/sr]/ [µW/cm2], P = .003 and P = .044). The sO2 of HCC and liver parenchyma were also lower in the treated group than in the control group at 1-week (42.89 ± 8.16% vs. 49.40 ± 8.52% and 54.16 ± 7.91% vs. 59.14 ± 5.29%, P = .017 and P = .023). The sO2 change in HCC showed a significant correlation with higher necrotic fraction (r = .427, P = .005) and lower microvessel density (r = -.421, P = .006) in the treated group.
Conclusion: The changes in sO2 and RE by sorafenib can be useful markers for non-invasive monitoring of therapeutic response in orthotopic HCC mouse models.


Hyperpolarised MRS using 13-C-pyruvate reveals alterations in the metabolic phenotype of DEN-induced HCC in a rat model not revealed by 18F-FDG-PET

G. Kaissis, E. Bliemsrieder, D. Keim, L. S. Gebrekidan, G. Topping, F. Schilling, M. Schwaiger, E. J. Rummeny, R. Braren; Munich/DE


Purpose: The propensity of tumour cells for aerobic glycolysis as opposed to mitochondrial oxidative phosphorylation, termed the “Warburg-Effect”, is a potential target for oncologic pharmacotherapy in HCC. Magnetic Resonance Spectroscopy (MRS) with hyperpolarized substances such as C-13-Pyruvate allows non-invasive evaluation of tumour metabolism to identify candidate tumours.
Methods and Materials: HCC was induced in Wistar rats with oral Diethyl Nitrosamine. 20 HCCs were imaged using high-resolution T2w imaging and Free Induction Decay-Chemical Shift Imaging (FID-CSI) after i.v. injection of Hyperpolarised 13-C-Pyruvate. 6 healthy control animals were also imaged. A subset of 5 tumours was also examined with 18F-FDG-PET. Tumours and livers were excised and histologically examined. Tumour-ROI and liver spectra were generated and label exchange between C13-pyruvate, lactate and alanine was evaluated.
Results: Ratios of 13-C-pyruvate to lactate and 13-C-pyruvate to alanine label exchange (lac/ala-ratio) were significantly higher in HCC than in normal liver tissue (1.69±0.44 in HCC vs 1.05±0.12 in normal liver, p=0.002). There was marked intertumoural heterogeneity in lac/ala-ratio (σ2=0.19) compared to normal liver (σ2=0.016). Tumours with similar standardised uptake values in PET demonstrated markedly different lac/ala ratios.
Conclusion: C-13-Pyruvate-MRS allows in vivo visualisation of HCC metabolics and offers an imaging correlate to the “Warburg-phenotype” by directly demonstrating increased lactate production from pyruvate in HCC compared to normal liver. This technique could offer additional information about tumour biology compared to PET, since tumours with similar SUVs were found to demonstrate distinctly heterogeneous lactate/alanine production.


Time-lapse MRI: single-cell tracking in experimental autoimmune encephalomyelitis

M. Masthoff, S. Gran, X. Zhang, L. Wachsmuth, L. Sorokin, J. Roth, M. Eisenblätter, M. Wildgruber, C. Faber; Münster/DE


Purpose: Time-lapse MRI was recently introduced for MRI cell tracking studies. Here, via repetitive acquisition of the region of interest not only a static, single impression but also dynamic observation of cell migration can be obtained. Our purpose was to optimise the temporal resolution of time-lapse MRI and evaluate this technique in a specific disease model.
Methods and Materials: After inducing experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice via myelin oligodendrocyte glycoprotein injection, iron nanoparticles (Resovist®, 1.3ml per kg/BW) were injected i.v. 24h prior to MRI scan. MRI of the brain was performed on a 9.4T small animal MRI at different EAE disease levels (symptomatic n=8, presymptomatic n=2, healthy control n=3) using a T2* multi-gradient echo sequence with following scan parameters: TR 649ms, TE: 8.0ms, FA: 60°, averages 4, slice thickness 300µm, scan time 8min 12s (single time frame), respectively, 2h 44min with 20 repetitions. After MRI mice were sacrificed and brains prepared for histology.
Results: Time-lapse MRI sequence was improved to a temporal resolution of 8 minutes per time frame covering the entire brain. The technique allowed for tracking of patrolling leukocytes labelled with iron nanoparticles. The number of detected events changed significantly in EAE mice compared to healthy control mice.
Conclusion: By optimising time-lapse MRI towards an improved temporal resolution this technique is now applicable for single-cell tracking in animal models. Application in EAE disease shows the feasibility of detection of alternated immune cell dynamics.


High resolution magnetic resonance imaging of HPF-labelled mouse natural Killer cell

L. Zheng1, Z. Zhang2, A. Larson2; 1 Shanghai/CN 2 Chicago/US


Purpose: To develop and optimise clinically translational protocol using US FDA approved drugs ferumoxytol, heparin and protamine to form HPF nanocomplexes and label specific mouse NK cell line (LNK) and determine in vitro and in vivo quantitative MRI properties.
Methods and Materials: LNK cells were labelled with self-assembled HPF nanocomplexes and optimise by varying the amount of HPF-nanocomplex. Labelling was confirmed the iron uptake with TEM, Prussian blue staining and ICP-MS. Cell viability and function were evaluated with Trypan blue staining and flow cytometry. Using a 7 Tesla MRI scanner, the labelled LNK MRI properties including signal intensity, R2* value and SNR were assessed with T2*W sequence. Finally, in Panc02 C57BL/6 mice model, changes of T2* signal, R2* value and SNR of labelled cells injection area were analysed by serial MRI detection after delivery of these labelled cells via percutaneous and intra-tumoral injection procedures, respectively.
Results: The HPF nancomplexes were internalised and encapsulated in labelled LNK cell as electron-dense nanoparticles. No significant difference between labelled LNK and control(unlabelled) LNK cells(p<0.05, n=6) . No influence of HPF on both dead cell and early apoptosis were observed with exception of 200 µg/ml HPF-labelled LNK cells (p<0.05, compared with control).There is statistical significance between labelled and unlabelled LNK cells for both SNR and R2* in vivo and in vitro, respectively (all p<0.05).
Conclusion: LNK can be labelled with clinical applicable HPF-nanocomplex for MRI imaging in vitro and in vivo and has the potential to translate for longitudinal monitoring during NK cell immunotherapy.


Directing neuronal differentiation of stem cells with a small interfering RNA-complexed MRI-visible cationic polymersome to counteract inhibitory microenvironment in stroke

L. Lu, J. Shen, X. Duan, F. Zhang, W. Young, M. Chen; Guangzhou/CN


Purpose: Poor neural differentiation limits therapeutic prospects of exogenous neural stem cells (NSCs) to stroke,myelin associated inhibitory factors played critical inhibitory roles in axonal regeneration and neuronal differentiation of NSCs. A MRI-visible cationic polymersome system was used to delive siRNA targeting NgR gene, a common receptor of myelin associated inhibitory factors to direct neuronal differentiation of NSCs.
Methods and Materials: Superparamagnetic iron oxide nanoparticles loaded polyethyleneimine polylactic acid polymeric vesicle was synthesized and used to deliver NgR-siRNA into NSCs.Then, we assess the capability of this MRI-visible cationic polymersome to deliver siRNA targeting NgR into NSCs and the consequent effectiveness of directing neuronal differentiation of NSCs. The therapeutic benefits, long-term biological behaviour and safety of such epigenetic modification of NSCs are further tracked by the structural and functional changes of the host brain.
Results: This multifunctional nanocarrier enables efficient and safe blockage of NgR gene and can efficiently direct neuronal differentiation of NSCs both in vitro and in vivo. Meanwhile, this nanosystem can non-invasively monitor the migration and retention of NSCs in real time, without affect their therapeutic benefits.
Conclusion: These results demonstrate that the cationic polymersome-based multifunctional nanocarrier can provide robust epigenetically control over stem cell differentiation via RNA interference to counteract inhibitory microenvironment in stroke. This nanosystem will offer an opportunity for delivery of proneurogenic genes and simultaneous real-time monitoring of dynamics of stem cells, which will facilitate develop new stem cell therapy paradigm for stroke.


Histological correlation of dGEMRIC and T2 mapping in an ovine femoroacetabular impingement model: preliminary results

F. Schmaranzer1, L. Arendt2, N. Wolfer2, C. Zurmühle1, T. Lerch1, K. Nuss2, P. Kircher2, B. von Rechenberg2, M. Tannast1; 1 Berne/CH 2 Zürich/CH


Purpose: DGEMRIC and T2 mapping are increasingly used to judge prearthritic cartilage quality in femoroacetabular impingement (FAI) but the correlation between histology and both techniques is not well established. We asked whether dGEMRIC and T2 indices correlate with histological cartilage degeneration in a validated, experimental ovine FAI model.
Methods and Materials: This experimental, controlled, prospective study on 5 sheep (10 hips) was conducted after IRB approval. Five sheep underwent surgical induction of FAI by varus intertrochanteric osteotomy unilaterally, which rotates the naturally aspherical ovine femoral head into the acetabulum, inducing typical focal chondrolabral damage as seen in humans. Correction of the deformity was performed after 70 days. No surgery was performed in the 5 contralateral hips. Sheeps were sacrificed after further 70 days. One hour before sacrifice sheep received i.v gadolinium-DTPA and roamed free. Hips were dissected to fit into the coil. dGEMRIC and T2 maps were obtained at 3 T using inversion recovery techniques. Histologic samples were stained with toluidine blue and cartilage degeneration was graded with the Mankin score. DGEMRIC and T2 indices of acetabular and femoral cartilage were radially measured at the 12 clock-face positions and correlated to Mankin scores (linear regression analysis; p< 0.05).
Results: Overall and regional (up to R= -0.742; p<0.007) inverse correlation was found between dGEMRIC indices and Mankin scores. No overall correlation was found between T2 indices and Mankin scores.
Conclusion: dGEMRIC correlates well with histological cartilage degradation, while we could not find such a correlation between T2 indices and Mankin scores.


Whole-body imaging of mice using a long circulating blood pool tracer to perform multi-patch MPI

C. S. L. Jung1, J. Salamon1, P. Szwargulski1, M. G. Kaul1, G. Adam1, K. M. Krishnan2, A. Khandahr2, T. Knopp1, H. Ittrich1; 1 Hamburg/DE 2 Seattle/US


Purpose: The purpose was to perform multi-patch MPI using LS-008 as long circulating blood tracer to achieve mice whole body imaging in a high-spatial resolution.
Methods and Materials: MPI Scans of FVB mice (n=4) were carried out using a 3D imaging sequence (2.5T/m gradient strength, 14mT drive-field strength). Ten minutes after the iv injection of 60µl of LS-008 six different drive-field patches (two cranial, two median and two caudal) each taking 1.5min were performed. As MPI delivers no anatomic information, MRI scans at 7T ClinScan (Bruker) were performed using a T2-weighted 2D turbo spin echo sequence. Fiducial markers were used to enable MRI/MPI image fusion. Image reconstruction was performed offline using a custom reconstruction framework developed in the programming language Julia using the join formulation.
Results: The combined MRI/MPI measurements were carried out successfully. The reconstruction of the drive-field patches generated no artefacts at the margins resulting in a whole mice body MP imaging. Compared to previous experiments using a lower gradient strength of 1T/m the multi-patch method with a gradient strength of 2.5T/m resulted in a higher spatial resolution. Therefore we were able not only to visualise the inferior vena cava, the heart and the liver but also the cerebral vessels, the thoracic aorta and the kidneys.
Conclusion: In vivo whole-body imaging of mice using multi-patch MPI is feasible. The long circulating blood tracer enabled us to visualize whole mice without motion artefacts that would occur using short half-life contrast agents.


Insulin-dependent triglyceride-rich lipoprotein uptake into brown adipose tissue visualised by 7T MRI and intravital microscopy

C. S. L. Jung, M. Heine, N. Mangels, M. G. Kaul, G. Adam, H. Ittrich, J. Heeren; Hamburg/DE


Purpose: The aim was to determine the activity of brown adipose tissue (BAT) and its dependence on signalling pathway mediated by insulin using superparamagnetic iron oxide nanoparticles (SPIO) or quantum dots (QD) embedded into triglyceride-rich lipoproteins (TRL).
Methods and Materials: BAT activity of C57BL/6J wild-type was stimulated by treatment with the β3 receptor agonist CL316, 243. Inhibition of insulin secretion was induced using the potassium channel agonist diazoxide. MRI at 7T ClinScan (Bruker) was performed before and 20min after iv injection of TRL-SPIOs using a T2*w Multiecho-GRE sequence (TR/TEfirst 400/2ms, ETL 12, ES 1ms, FA 25°). ΔR2* in BAT was estimated. In addition intravital microscopy (IVM) analysis was performed for real time imaging of TRL-QD uptake. In order to quantify TRL clearance, the fate of radioactively labelled TRLs was analysed.
Results: For control mice no signal difference in BAT before and after the injection of TRL-SPIO was detectable, while a significant signal drop and increase of ∆R2* (82.9s-1; p<0.001) was estimated for CL treated, BAT activated mice. Inhibition of insulin signalling resulted in a significant lower uptake of TRL-SPIO into BAT (∆R2* = 21.1s-1; p<0.001). IVM analysis and quantitative metabolic studies using radioactive lipid tracers confirmed MRI results. In both set-ups inhibition of insulin secretion using diazoxide diminished TRL uptake into BAT.
Conclusion: β3-receptor activation via CL with following acute insulin release lead to BAT activation, which can be visualized in vivo by MRI using TRL-SPIO and estimating ∆R2*. Accordingly, the inhibition of insulin signalling blocks TRL uptake into BAT.

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