Biodistribution and pharmacokinetics of [89Zr]-anti-VEGF mAbs using PET in glioblastoma rat models.

INTRODUCTION: Glioblastomas present intensive angiogenesis, thus anti-Vascular Endothelial Growth Factor (VEGF) antibodies (mAbs) have been proposed as promising therapies. However, the results of clinical trials reported moderate toxicity and limited effectiveness. This study evaluates the in vivo pharmacokinetics and biodistribution of these mAbs in a growing model of glioblastoma in rats using Positron Emission Tomography (PET). MATERIAL: &Methods: mAbs were radiolabeled with zirconium-89. Four days after the model induction, animals were injected with 2.33 ± 1.3 MBq of [89Zr]-DFO-bevacizumab (n = 8) or 2.35 ± 0.26 MBq of [89Zr]-DFO-aflibercept (n = 6). PETs were performed at 0H, 48H, 168H, 240H, and 336H post-injection. Tumor induction was confirmed using [18F]-Fluorodeoxyglucose-PET and immunohistochemistry. Radiotracer uptake was estimated in all pre-defined Volumes-of-Interest. RESULTS: Anti-VEGF mAbs showed 100 % Radiochemical-Purity. [89Zr]-DFO-bevacizumab showed a significantly higher bioavailability in whole-blood. A significant increase in the tumor uptake was detectable at 168H PET with [89Zr]-DFO-bevacizumab meanwhile with [89Zr]-DFO-aflibercept it was only detectable at 336H. [89Zr]-DFO-bevacizumab tumor uptake was significantly higher than that of [89Zr]-DFO-aflibercept in all the scans. Tumor induction was confirmed in all animal models. CONCLUSION: MAbs detect VEGF-expression in glioblastoma models. Tumors were earlier targeted by Bevacizumab. The lower blood availability of aflibercept resulted in a lower tumor uptake than bevacizumab in all the scans.

PET study of intravitreal adalimumab pharmacokinetics in a uveitis rat model.

Adalimumab is an anti-TNFα drug approved for uveitis treatment by subcutaneous injection. This administration route exposes patients to systemic adverse effects and makes difficult to obtain therapeutic drug concentrations in the site of action due to the anatomical and physiological barriers of the eye. These inconveniences could be avoided by intravitreal injection. The aim of this study is to evaluate the pharmacokinetic profile and the biodistribution of the intravitreal administration of 89Zr-adalimumab in a uveitis rat model using PET imaging. Adalimumab was radiolabelled to 89Zr with a maximum specific activity of 10 MBq/mg. Four µL containing ≃1.74 MBq of 89Zr-labelled adalimumab were injected into the vitreous. A microPET acquisition was carried out immediately after the injection and at different time points through a 10-day study and blood samples were obtained through the tail vein. Radiolabelling was successfully performed with a radiochemical purity after ultrafiltration of 99.69 %. The antibody ocular pharmacokinetics followed a one-compartment model, showing an intraocular elimination half-life of 15.57 h for healthy rats and  33.64 h for rats with uveitis, implying that 89Zr-adalimumab remains around two times longer in rats with the disease compared to healthy ones. However, blood concentration half-life had similar values in both groups. In conclusion, this study shows for the first time the ocular and blood pharmacokinetic analysis of adalimumab in a uveitis model in rats.

Development and Characterization of Inhaled Ethanol as a Novel Pharmacological Strategy Currently Evaluated in a Phase II Clinical Trial for Early-Stage SARS-CoV-2 Infection.

Inhaled administration of ethanol in the early stages of COVID-19 would favor its location on the initial replication sites, being able to reduce the progression of the disease and improving its prognosis. Before evaluating the efficacy and safety of this novel therapeutic strategy in humans, its characterization is required. The developed 65° ethanol formulation is stable at room temperature and protected from light for 15 days, maintaining its physicochemical and microbiological properties. Two oxygen flows have been tested for its administration (2 and 3 L/min) using an automated headspace gas chromatographic analysis technique (HS-GC-MS), with that of 2 L/min being the most appropriate one, ensuring the inhalation of an ethanol daily dose of 33.6 ± 3.6 mg/min and achieving more stable concentrations during the entire treatment (45 min). Under these conditions of administration, the formulation has proven to be safe, based on histological studies of the respiratory tracts and lungs of rats. On the other hand, these results are accompanied by the first preclinical molecular imaging study with radiolabeled ethanol administered by this route. The current ethanol formulation has received approval from the Spanish Agency of Medicines and Medical Devices for a phase II clinical trial for early-stage COVID-19 patients, which is currently in the recruitment phase (ALCOVID-19; EudraCT number: 2020-001760-29).

Is FDG-PET texture analysis related to intratumor biological heterogeneity in lung cancer?

OBJECTIVES: We aimed at investigating the origin of the correlations between tumor volume and 18F-FDG-PET texture indices in lung cancer. METHODS: Eighty-five consecutive patients with newly diagnosed non-small cell lung cancer (NSCLC) underwent a 18F-FDG-PET/CT scan before treatment. Seven phantom spheres uniformly filled with 18F-FDG, and covering a range of activities and volumes similar to that found in lung tumors, were also scanned. Established texture indices were computed for lung tumors and homogeneous spheres. The dependence between textural indices and volume in homogeneous spheres was modeled and then used to predict texture indices in lung tumors. Correlation analyses were carried out between predicted and texture features measured in lung tumors. Cox proportional hazards regression was used to investigate the associations between overall survival and volume-adjusted textural features. RESULTS: All textural features showed strong, non-linear correlations with volume, both in tumors and homogeneous spheres. Correlations between predicted versus measured texture features were very high for contrast (r2 = 0.91), dissimilarity (r2 = 0.90), ZP (r2 = 0.90), GLNN (r2 = 0.86), and homogeneity (r2 = 0.82); high for entropy (r2 = 0.50) and HILAE (r2 = 0.53); and low for energy (r2 = 0.30). Cox regressions showed that among volume-adjusted features, only HILAE was associated with overall survival (b = - 0.35, p = 0.008). CONCLUSION: We have shown that texture indices previously found to be correlated with a number of clinically relevant outcomes might not provide independent information apart from that driven by their correlation with tumor volume, suggesting that these metrics might not be suitable as intratumor heterogeneity markers. KEY POINTS: • Associations between texture FDG-PET indices and overall survival have been widely reported in lung cancer, with tumor volume also being associated with overall survival, and therefore, it is still unclear whether the predictive power of textural indices is simply driven by this correlation. • Our results demonstrated strong non-linear correlations between textural indices and volume, showing an analogous behavior for lung tumors from patients and homogeneous spheres inserted in phantoms. • Our findings showed that texture FDG-PET indices might not provide independent information apart from that driven by their correlation with tumor volume.

Feasibility of Longitudinal Brain PET with Real-Time Arterial Input Function in Rats.

PURPOSE: Preclinical dynamic brain PET studies remain hampered by the limitations related to the measurement of the arterial input function (AIF). In this regard, the use of an arterial-venous shunt is a promising method for the generation of real-time AIFs, but its application in longitudinal studies is still impeded by the cumbersome surgeries and high failure rates. We studied the feasibility and reproducibility of double arterial-venous shunt strategies for conducting longitudinal PET studies with real-time AIFs in rats. PROCEDURES: We studied the feasibility of double arterial-venous shunts in rats in the right/left inguinal region and evaluated inter-animal and intra-animal AIF reproducibilities. Image-derived input function (IDIF) was also obtained for comparison. Dynamic brain FDG PET studies were conducted to estimate kinetic constants and Cerebral Metabolic Rate of Glucose (CMRglc) obtained from standard 2-tissue compartment (2TCM) and Patlak analysis. RESULTS: We showed that longitudinal AIFs from double arterial-venous shunts can be obtained with very high success rate of the surgeries (88 %). Our results provided highly reproducible AIF measurements with low inter-animal variabilities (11 %) and intra-animal variabilities (5-10 %) that were included into the kinetic models, such that longitudinal rate constants and CMRglc can be efficiently estimated without bias associated to the double shunt. Our results indicated that longitudinal IDIF can be also generated without bias along time but showing higher intra-animal uncertainties. CONCLUSIONS: We have demonstrated the feasibility and high reproducibility of conducting longitudinal AIF measurements and consequently accurate kinetic modeling using arterial shunt method.

White matter hyperintensities are associated with subthreshold amyloid accumulation.

The association between white matter hyperintensities (WMH) and amyloid accumulation over time in cognitively normal, amyloid-negative elderly people remains largely unexplored. In order to study whether baseline WMH were associated with longitudinal subthreshold amyloid accumulation, 159 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative who were amyloid-negative at baseline were examined. All the participants underwent a T1 and a Fluid-Attenuated Inversion Recovery MRI scan at baseline. Amyloid PET imaging was performed at baseline and follow-up visits in 2-year intervals for up to 8 years. Partial volume correction was applied for quantifying cortical Standardised Uptake Value Ratios (SUVR). The associations between global and regional WMH burden and amyloid accumulation were assessed using linear mixed models adjusted by demographic characteristics and baseline SUVR. Partial volume correction increased the measured annual rate of change (+2.4%) compared to that obtained from non-corrected data (+0.5%). There were no significant correlations between baseline WMHs and baseline subthreshold cortical amyloid uptake. In a longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p â€‹= â€‹0.006), frontal (p â€‹= â€‹0.006), and parietal WMH (p â€‹= â€‹0.003) were associated with faster amyloid accumulation. WMH-related amyloid accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs. This is the first study to identify a specific spatial distribution of WMH which is associated with future amyloid accumulation in cognitively normal elderly subjects without PET-detectable amyloid pathology. These findings may have important implications in prevention trials for the early identification of amyloid accumulation.

Evaluation of the therapeutic activity of melatonin and resveratrol in Inflammatory Bowel Disease: A longitudinal PET/CT study in an animal model.

Inflammatory Bowel Disease (IBD) is a group of chronic disorders of the gastrointestinal tract, which two main types are Crohn's disease and ulcerative colitis. Although conventional therapeutic strategies have demonstrated to be effective in the IBD treatment, it is necessary to incorporate novel therapeutic agents that target other mechanisms involved in the pathogenesis of the disease, such as oxidative stress. For this reason, the efficacy in vivo of two antioxidant compounds, melatonin and resveratrol, has been investigated in an animal model of TNBS (2, 4, 6-trinitrobenzenesulfonic acid) induced colitis. PET/CT (Positron emission tomography/Computer Tomography) scans were performed to assess disease activity and evaluate treatment response. SUVmax (Standardized Uptake Value) values, body weight changes and histological evaluation were used as inflammatory indices to measure the efficacy of both treatments. SUVmax values increased rapidly after induction of colitis, but after the beginning of the treatment (day 3) a statistically significant decrease was observed on days 7 and 10 in treated animals compared to the non-treated group. This remission of the disease was also confirmed by histological analysis of the colon tissue using the Nancy histological index (p value < 0.05 for differences between non-treated and both groups of treated animals). Moreover, statistical analysis showed a correlation (R2 = 65.52%) between SUVmax values and weight changes throughout the treatment. Overall, this study demonstrates the potential of resveratrol, and melatonin in lower extent, as therapeutic agents in the IBD treatment.