Oncolytic Adenoviruses Armed with Thymidine Kinase Can Be Traced by PET Imaging and Show Potent Antitumoural Effects by Ganciclovir Dosing

Replication-competent adenoviruses armed with thymidine kinase (TK) combine the concepts of virotherapy and suicide gene therapy. Moreover TK-activity can be detected by noninvasive positron emission-computed tomography (PET) imaging, what could potentially facilitate virus monitoring in vivo. Here, we report the generation of a novel oncolytic adenovirus that incorporates the Tat8-TK gene under the control of the Major Late Promoter in a highly selective backbone thus providing selectivity by targeting the retinoblastoma pathway. The selective oncolytic TK virus, termed ICOVIR5-TK-L, showed reduced potency compared to a non-selective counterpart. However the combination of ICOVIR5-TK-L with ganciclovir (GCV) induced a potent antitumoural effect similar to that of wild type adenovirus in a preclinical model of pancreatic cancer. Although the treatment with GCV provoked a reduction in the viral yield, both in vitro and in vivo, a two-cycle treatment of virus and GCV resulted in an enhanced antitumoral response that correlated with high TK-activity, based on microPET measurements. Thus, TK-expressing oncolytic adenoviruses can be traced by PET imaging providing real time information on the activity of the virus and its antitumoral potency can be optimized by GCV dosing

Comparison of the Performance Evaluation of the MicroPET R4 Scanner According to NEMA Standards NU 4-2008 and NU 2-2001

The purpose of this work was to evaluate the performance of the microPET R4 system for rodents according to the NU 4-2008 standards of the National Electrical Manufacturers Association (NEMA) for small-animal positron emission tomography (PET) systems and to compare it against its previous evaluation according the adapted clinical NEMA NU 2-2001. The performance parameters evaluated here were spatial resolution, sensitivity, scatter fraction, counting rates for rat- and mouse-sized phantoms, and image quality. Spatial resolution and sensitivity were measured with a 22Na point source, while scatter fraction and count rate performance were determined using a mouse and rat phantoms with an 18F line source. The image quality of the system was assessed using the NEMA image quality phantom. Assessment of attenuation correction was performed using γ-ray transmission and computed tomography (CT)-based attenuation correction methods. At the center of the field of view, a spatial resolution of 2.12 mm at full width at half maximum (FWHM) (radial), 2.66 mm FWHM (tangential), and 2.23 mm FWHM (axial) was measured. The absolute sensitivity was found to be 1.9% at the center of the scanner. Scatter fraction for mouse-sized phantoms was 8.5 %, and the peak count rate was 311 kcps at 153.5 MBq. The rat scatter fraction was 22%, and the peak count rate was 117 kcps at 123.24 MBq. Image uniformity showed better results with 2-D filtered back projection (FBP), while an overestimation of the recovery coefficients was observed when using 2-D and 3-D OSEM MAP reconstruction algorithm. All measurements were made for an energy window of 350-650 keV and a coincidence window of 6 ns. Histogramming and reconstruction parameters were used according to the manufacturer's recommendations. The microPET R4 scanner was fully characterized according to the NEMA NU 4-2008 standards. Our results diverge considerably from those previously reported with an adapted version- of the NEMA NU 2-2001 clinical standards. These discrepancies can be attributed to the modifications in NEMA methodology, thereby highlighting the relevance of specific small-animal standards for the performance evaluation of PET systems.This work was supported in part by the Fondo de Investigación Sanitaria (FIS) of the Instituto de Salud Carlos III under Grants PS09/02620 and PS09/02217, the CDTI as part of the CENIT Program (AMIT Project), the Ministerio de Ciencia e Innovación under Project No. SAF2009-08076, and the Spanish Ministry of Economy and Competitivenes

Comparison of the Performance Evaluation of the MicroPET R4 Scanner According to NEMA Standards NU 4-2008 and NU 2-2001

The purpose of this work was to evaluate the performance of the microPET R4 system for rodents according to the NU 4-2008 standards of the National Electrical Manufacturers Association (NEMA) for small-animal positron emission tomography (PET) systems and to compare it against its previous evaluation according the adapted clinical NEMA NU 2-2001. The performance parameters evaluated here were spatial resolution, sensitivity, scatter fraction, counting rates for rat- and mouse-sized phantoms, and image quality. Spatial resolution and sensitivity were measured with a 22Na point source, while scatter fraction and count rate performance were determined using a mouse and rat phantoms with an 18F line source. The image quality of the system was assessed using the NEMA image quality phantom. Assessment of attenuation correction was performed using γ-ray transmission and computed tomography (CT)-based attenuation correction methods. At the center of the field of view, a spatial resolution of 2.12 mm at full width at half maximum (FWHM) (radial), 2.66 mm FWHM (tangential), and 2.23 mm FWHM (axial) was measured. The absolute sensitivity was found to be 1.9% at the center of the scanner. Scatter fraction for mouse-sized phantoms was 8.5 %, and the peak count rate was 311 kcps at 153.5 MBq. The rat scatter fraction was 22%, and the peak count rate was 117 kcps at 123.24 MBq. Image uniformity showed better results with 2-D filtered back projection (FBP), while an overestimation of the recovery coefficients was observed when using 2-D and 3-D OSEM MAP reconstruction algorithm. All measurements were made for an energy window of 350-650 keV and a coincidence window of 6 ns. Histogramming and reconstruction parameters were used according to the manufacturer's recommendations. The microPET R4 scanner was fully characterized according to the NEMA NU 4-2008 standards. Our results diverge considerably from those previously reported with an adapted version- of the NEMA NU 2-2001 clinical standards. These discrepancies can be attributed to the modifications in NEMA methodology, thereby highlighting the relevance of specific small-animal standards for the performance evaluation of PET systems.This work was supported in part by the Fondo de Investigación Sanitaria (FIS) of the Instituto de Salud Carlos III under Grants PS09/02620 and PS09/02217, the CDTI as part of the CENIT Program (AMIT Project), the Ministerio de Ciencia e Innovación under Project No. SAF2009-08076, and the Spanish Ministry of Economy and Competitivenes

Identification of myocardial insulin resistance by using liver tests: a simple approach for clinical practice

Background: We report that myocardial insulin resistance (mIR) occurs in around 60% of patients with type 2 diabetes (T2D) and was associated with higher cardiovascular risk in comparison with patients with insulin-sensitive myocardium (mIS). These two phenotypes (mIR vs. mIS) can only be assessed using time-consuming and expensive methods. The aim of the present study is to search a simple and reliable surrogate to identify both phenotypes. Methods: Forty-seven patients with T2D underwent myocardial [18F]FDG PET/CT at baseline and after a hyperinsulinemic–euglycemic clamp (HEC) to determine mIR were prospectively recruited. Biochemical assessments were performed before and after the HEC. Baseline hepatic steatosis index and index of hepatic fibrosis (FIB-4) were calculated. Furthermore, liver stiffness measurement was performed using transient elastography. Results: The best model to predict the presence of mIR was the combination of transaminases, protein levels, FIB-4 score and HOMA (AUC = 0.95; sensibility: 0.81; specificity: 0.95). We observed significantly higher levels of fibrosis in patients with mIR than in those with mIS (p = 0.034). In addition, we found that patients with mIR presented a reduced glucose uptake by the liver in comparison with patients with mIS. Conclusions: The combination of HOMA, protein, transaminases and FIB-4 is a simple and reliable tool for identifying mIR in patients with T2D. This information will be useful to improve the stratification of cardiovascular risk in T2D

Biodistribution of Amino-Functionalized Diamond Nanoparticles. In Vivo Studies Based on (18)F Radionuclide Emission

[EN] Nanoparticles have been proposed for several biomedical applications; however, in vivo biodistribution studies to con¿rm their potential are scarce. Nanodiamonds are carbon nanoparticles that have been recently proposed as a promising biomaterial. In this study, we labeled nanodiamonds with 18F to study their in vivo biodistribution by positron emission tomography. Moreover, the impact on the biodistribution of their kinetic particle size and of the surfactant agents has been evaluated. Radiolabeled diamond nanoparticles accumulated mainly in the lung, spleen, and liver and were excreted into the urinary tract. The addition of surfactant agents did not lead to signi¿cant changes in this pattern, with the exception of a slight reduction in the urinary excretion rate. On the other hand, after ¿ltration of the radiolabeled diamond nanoparticles to remove those with a larger kinetic size, the uptake in the lung and spleen was completely inhibited and signi¿cantly reduced in the liverThe present work was supported by Spanish MICINN (Grant CTQ-2009-11586); the Fondo de Investigacion Sanitaria (FIS) of the Instituto de Salud Carlos III (Grants PS09/02620, PI10/1195, and PS09/02217), La Marato TV3 Foundation (Grant 090530), and CDTI under the CENIT Programme (AMIT Project) and supported by the Spanish Ministry of Science and Innovation. R.M. thanks the Spanish Ministry for a postgraduate scholarship. V.M.V. is a recipient of Fond de Investigacion Sanitaria (FIS) and Generalitat Valenciana contract (CES10/030)Rojas, S.; Gispert, JD.; Martín González, R.; Abad, S.; Menchón, C.; Pareto, D.; Víctor, VM.... (2011). Biodistribution of Amino-Functionalized Diamond Nanoparticles. In Vivo Studies Based on (18)F Radionuclide Emission. ACS Nano. 5(7):5552-5559. https://doi.org/10.1021/nn200986zS555255595

In Vivo Biodistribution of Amino-Functionalized Ceria Nanoparticles in Rats Using Positron Emission Tomography

A variety of nanoparticles have been proposed for several biomedical applications. To gauge the therapeutic potential of these nanoparticles, in vivo biodistribution is essential and mandatory. In the present study, ceria nanoparticles (5 nm average particle size) were labeled with F-18 to study their in vivo biodistribution in rats by positron emission tomography (PET). The F-18 isotope was anchored by reaction of N-succinimidyl 4-[F-18]fluorobenzoate (F-18-SFB) with a modified nanoparticle surface obtained by silylation with 3-aminopropylsilyl. Radiolabeled ceria nanoparticles accumulated mainly in lungs, spleen, and liver. Metabolic products of the radiolabeled nanoparticulate material were excreted into the urinary tract.The present work was supported by the Spanish MICINN (Grants CTQ-2009-11586, CTQ2006-06785, and CTQ2007-67805-AR07, PI10/1195, AP192/11); the Fondo de Investigacion Sanitaria (FIS) of the Instituto de Salud Carlos III (Grants PS09/02620, PI10/1195, and PS09/02217), the Generalitat Valenciana (Grant ACOMP/2012/045), La Marato Fundation (Grant 090530), and by CDTI under the CENIT Programme (AMIT Project) and the Spanish Ministry of Science and Innovation. V.M.V. is a recipient of a contract from the Regional Ministry of Health of the Valencian Regional Government and Carlos III Health Institute (CES10/030).Rojas, S.; Domingo Gispert, J.; Abad Fuentes, S.; Buaki-Sogo, M.; Victor, VM.; García Gómez, H.; Herance Camacho, JR. (2012). In Vivo Biodistribution of Amino-Functionalized Ceria Nanoparticles in Rats Using Positron Emission Tomography. Molecular Pharmaceutics. 9(12):3543-3550. https://doi.org/10.1021/mp300382nS3543355091