Hyung-Jun Im

Radionanomedicine: Widened perspectives of molecular theragnosis

UNLABELLED Despite of promising preclinical results in the fields of in vivo theragnostics of nanomedicine, a majority of attempt for clinical translation has been blocked by unsolved concerns about possible hazards to human body. Theragnosis of nanomedicine relies on the property of huge surface area to volume ratio of nanomaterials, which can offer potential for multi-functionality. Radionanomedicine has a hybrid characteristic of tracer technology and multi-functionality. Thus, key advantage of radionanomedicine is a possibility of using low amount of nanomaterials for theragnosis. This review article focuses on the concept and advantages of radionanomedicine in theragnosis, formulation of radionanomaterials (particularly encapsulation method), in vivo biodistribution and excretion of radionanomaterials, and immune responses to radionanomaterials. FROM THE CLINICAL EDITOR The expansion of nanomedicine has recently seen the development of a new branch - radionanomedicine. The core concept of radionanomedicine relies on the labeling of radionuclides onto nanomaterials for use both in diagnosis and therapy. In this article, the authors gave a comprehensive review on the current status of radionanomedicine. This should provide interesting reading for practicing clinicians.

In vivo imaging of mGluR5 changes during epileptogenesis using [11C]ABP688 PET in pilocarpine-induced epilepsy rat model.

Introduction Metabotropic glutamate receptor 5 (mGluR5) that regulates glutamatergic neurotransmission contributes to pathophysiology of epilepsy. In this study, we monitored the changes of mGluR5 in vivo using [11C]ABP688 PET during the epileptogenesis in a pilocarpine-induced epilepsy rat model. Methods In vivo mGluR5 images were acquired using [11C]ABP688 microPET/CT in pilocarpine-induced chronic epilepsy rat models and controls. We also acquired microPET/CT at acute, subacute as well as chronic periods after status epilepticus. Non-displaceable binding potential (BPND) of [11C]ABP688 was calculated using simplified reference tissue model in a voxel-based manner. mGluR5 BPND of the rat brains of epilepsy models and controls were compared. Results Status epilepticus developed after pilocarpine administration and was followed by recurrent spontaneous seizures for more than 3 weeks. In chronic epilepsy rat model, BPND in hippocampus and amygdala was reduced on a voxel-based analysis. Temporal changes of mGluR5 BPND was also found. In acute period after status epilepticus, mGluR5 BPND was reduced in the whole brain. BPND of caudate-putamen was restored in subacute period, while BPND of the rest of the brain was still lower. In chronic period, global BPND was normalized except in hippocampus and amygdala. Conclusions In vivo imaging of mGluR5 using [11C]ABP688 microPET/CT could successfully reveal the regional changes of mGluR5 binding potential of the rat brain in a pilocarpine-induced epilepsy model. The temporal and spatial changes in mGluR5 availability suggest [11C]ABP688 PET imaging in epilepsy provide abnormal glutamatergic network during epileptogenesis.

Rapid Hepatobiliary Excretion of Micelle-Encapsulated/Radiolabeled Upconverting Nanoparticles as an Integrated Form

In the field of nanomedicine, long term accumulation of nanoparticles (NPs) in the mononuclear phagocyte system (MPS) such as liver is the major hurdle in clinical translation. On the other hand, NPs could be excreted via hepatobiliary excretion pathway without overt tissue toxicity. Therefore, it is critical to develop NPs that show favorable excretion property. Herein, we demonstrated that micelle encapsulated 64Cu-labeled upconverting nanoparticles (micelle encapsulated 64Cu-NOTA-UCNPs) showed substantial hepatobiliary excretion by in vivo positron emission tomography (PET) and also upconversion luminescence imaging (ULI). Ex vivo biodistribution study reinforced the imaging results by showing clearance of 84% of initial hepatic uptake in 72 hours. Hepatobiliary excretion of the UCNPs was also verified by transmission electron microscopy (TEM) examination. Micelle encapsulated 64Cu-NOTA-UCNPs could be an optimal bimodal imaging agent owing to quantifiability of 64Cu, ability of in vivo/ex vivo ULI and good hepatobiliary excretion property.

Evaluation of a silicon photomultiplier PET insert for simultaneous PET and MR imaging

PURPOSE In this study, the authors present a silicon photomultiplier (SiPM)-based positron emission tomography (PET) insert dedicated to small animal imaging with high system performance and robustness to temperature change. METHODS The insert consists of 64 LYSO-SiPM detector blocks arranged in 4 rings of 16 detector blocks to yield a ring diameter of 64 mm and axial field of view of 55 mm. Each detector block consists of a 9 × 9 array of LYSO crystals (1.2 × 1.2 × 10 mm(3)) and a monolithic 4 × 4 SiPM array. The temperature of each monolithic SiPM is monitored, and the proper bias voltage is applied according to the temperature reading in real time to maintain uniform performance. The performance of this PET insert was characterized using National Electrical Manufacturers Association NU 4-2008 standards, and its feasibility was evaluated through in vivo mouse imaging studies. RESULTS The PET insert had a peak sensitivity of 3.4% and volumetric spatial resolutions of 1.92 (filtered back projection) and 0.53 (ordered subset expectation maximization) mm(3) at center. The peak noise equivalent count rate and scatter fraction were 42.4 kcps at 15.08 MBq and 16.5%, respectively. By applying the real-time bias voltage adjustment, an energy resolution of 14.2% ± 0.3% was maintained and the count rate varied ≤1.2%, despite severe temperature changes (10-30 °C). The mouse imaging studies demonstrate that this PET insert can produce high-quality images useful for imaging studies on the small animals. CONCLUSIONS The developed MR-compatible PET insert is designed for insertion into a narrow-bore magnetic resonance imaging scanner, and it provides excellent imaging performance for PET/MR preclinical studies.

Functional evaluation of parathyroid adenoma using 99mTc-MIBI parathyroid SPECT/CT: correlation with functional markers and disease severity.

ObjectivesIn parathyroid adenoma, uptake of technetium-99m-methoxyisobutylisonitrile (99mTc-MIBI) has been suggested to have a correlation with functional markers. The purpose of this study was to evaluate the feasibility of 99mTc-MIBI parathyroid single photon emission computed tomography/computed tomography (SPECT/CT) in evaluating the function and disease severity of parathyroid adenoma. Patients and methodsTwenty-three patients with surgically confirmed parathyroid adenoma were retrospectively enrolled. A parathyroid planar scan and SPECT/CT were performed before parathyroidectomy. Functional and clinical makers reflecting the disease severity of parathyroid adenoma were also evaluated, including serum intact parathyroid hormone, calcium, bone mineral density, and creatinine clearance. The pathologic volume (VP) of the adenoma was measured after parathyroidectomy. On parathyroid SPECT/CT, metabolic volume (VM) was measured using an isocontour method. Maximum uptakes of parathyroid adenoma and mean uptakes of contralateral thyroid tissue were measured to calculate the parathyroid adenoma-to-background ratio on parathyroid SPECT/CT (PBRSCT) and planar scan (PBRPL). ResultsVM significantly correlated with VP (r=0.669, P=0.0005). Serum intact parathyroid hormone level significantly correlated with PBRPL, PBRSCT, VM, and VP (P=0.0004, 0.005, 0.003, and 0.025, respectively). However, serum calcium level correlated only with VM (P=0.012). Regarding the surgical indication criteria, PBRSCT and PBRPL were significantly higher in the young-aged group (P=0.0004 and 0.024, respectively) and VM was significantly higher in the high calcium level group (P=0.049), whereas VP was not different between groups on the basis of any criteria. ConclusionQuantitative indices of parathyroid SPECT/CT closely correlate with laboratory functional markers and disease severity of parathyroid adenoma. Thus, parathyroid SPECT/CT could be used for evaluation of the underlying functional state and disease severity of parathyroid adenoma, particularly for decision pertaining to surgical treatment.

Prognostic Implications of the SUVmax of Primary Tumors and Metastatic Lymph Node Measured by 18F-FDG PET in Patients With Uterine Cervical Cancer: A Meta-analysis.

Purpose We conducted a meta-analysis to evaluate the prognostic value of the SUVmax measured in pretreatment primary lesions and metastatic lymph nodes (LNs) on 18F-FDG PET scans in patients with uterine cervical cancer. Methods A systematic search of EMBASE and MEDLINE was performed using the keywords “positron emission tomography (PET),” “uterine cervical cancer,” and “prognosis.” Event-free survival and overall survival were evaluated as outcomes. The impact of SUVmax on survival was measured by the effect size of the hazard ratio (HR). Results Fourteen eligible studies including 1150 patients were analyzed. Patients with a high primary SUVmax showed a worse prognosis, with an HR of 2.66 (95% confidence interval [CI], 1.90–3.74; P < 0.00001) for adverse events and an HR of 2.45 (95% CI, 1.74–3.45; P < 0.00001) for death. Patients with high SUVmax in metastatic pelvic LN (PLN) showed a worse prognosis, with an HR of 2.92 (95% CI, 1.94–4.39; P < 0.00001) for adverse events and an HR of 2.66 (95% CI, 1.60–4.43; P = 0.0002) for SUVmax in PLN for death. In addition, high SUVmax in metastatic para-aortic LN was associated with a worse prognosis, with an HR of 4.41 (95% CI, 2.32–8.38; P < 0.00001) for death. Conclusions Patients with uterine cervical cancer and a high SUVmax primary lesion, PLN, or para-aortic LN are at higher risk of adverse events or death.

In Vivo Visualization and Monitoring of Viable Neural Stem Cells Using Noninvasive Bioluminescence Imaging in the 6-Hydroxydopamine-Induced Mouse Model of Parkinson Disease

Transplantation of neural stem cells (NSCs) has been proposed as a treatment for Parkinson disease (PD). The aim of this study was to monitor the viability of transplanted NSCs expressing the enhanced luciferase gene in a mouse model of PD in vivo. The PD animal model was induced by unilateral injection of 6-hydroxydopamine (6-OHDA). The behavioral test using apomorphine-induced rotation and positron emission tomography with [18F]N-(3-fluoropropyl)-2′-carbomethoxy-3′-(4-iodophenyl)nortropane ([18F]FP-CIT) were conducted. HB1.F3 cells transduced with an enhanced firefly luciferase retroviral vector (F3-effLuc cells) were transplanted into the right striatum. In vivo bioluminescence imaging was repeated for 2 weeks. Four weeks after transplantation, [18F]FP-CIT PET and the rotation test were repeated. All 6-OHDA-injected mice showed markedly decreased [18F]FP-CIT uptake in the right striatum. Transplanted F3-effLuc cells were visualized on the right side of the brain in all mice by bioluminescence imaging. The bioluminescence intensity of the transplanted F3-effLuc cells gradually decreased until it was undetectable by 10 days. The behavioral test showed that stem cell transplantation attenuated the motor symptoms of PD. No significant change was found in [18F]FP-CIT imaging after cell transplantation. We successfully established an in vivo bioluminescence imaging system for the detection of transplanted NSCs in a mouse model of PD. NSC transplantation induced behavioral improvement in PD model mice.

Prognostic Value of Metabolic and Volumetric Parameters of Preoperative FDG-PET/CT in Patients With Resectable Pancreatic Cancer

AbstractIn this study, we aimed to evaluate prognostic value of metabolic and volumetric parameters measured from 18F fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with resectable pancreatic cancer.Fifty-one patients with resectable pancreatic cancer who underwent FDG-PET/CT and curative operation were retrospectively enrolled. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured from FDG-PET/CT. Association between FDG-PET/CT and clinicopathologic parameters was evaluated. The prognostic values of the FDG-PET/CT and clinicopathologic parameters for recurrence-free survival (RFS) and overall survival (OS) were assessed by univariate and multivariate analyses.The 51 enrolled patients were followed up for a median of 21 months (mean ± SD: 23 ± 16 months, range: 1–78 months) with 33 (65%) recurrences and 30 (59%) deaths during the period. SUVmax, MTV, and TLG were associated with Tumor node metastasis (TNM) stage and presence of lymph node metastasis. MTV and TLG were associated with presence of lymphovascular invasion, whereas SUVmax was not. On the univariate analysis, SUVmax, MTV, and TLG were associated with RFS and OS. Also, lymph node metastasis and TNM stage were associated with OS on the univariate analysis. On multivariate analysis, MTV and TLG were independent prognostic factors for RFS and OS. SUVmax was an independent prognostic factor for OS, but not for RFS.Metabolic tumor volume and TLG were independently predictive of RFS and OS in resectable pancreatic cancer. SUVmax was an independent factor for OS, but not for RFS.

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using 68Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

The diagnosis of myocarditis traditionally relies on invasive endomyocardial biopsy but none of the imaging studies so far are specific for infiltration of the inflammatory cells itself. We synthesized 68Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA) by conjugating human serum albumin with mannose, followed by conjugation with NOTA and labeling it with 68Ga. The efficacy of 68Ga-NOTA-MSA positron emission tomography (PET) for imaging myocardial inflammation was tested in a rat myocarditis model. A significant number of mannose receptor-positive inflammatory cells infiltrated the myocardium in both human and rat myocarditis tissue. 68Ga-NOTA-MSA uptake was upregulated in organs of macrophage accumulation, such as liver, spleen, bone marrow and myocardium (0.32 (0.31~0.33) for normal versus 1.02 (0.86~1.06) for myocarditis (median (range), SUV); n=4~6 per group, p-value=0.01). 68Ga-NOTA-MSA uptake in the left ventricle was upregulated in myocarditis compared with normal rats (2.29 (1.42~3.40) for normal versus 4.18 (3.43~6.15) for myocarditis (median (range), average standard uptake value ratio against paraspinal muscle); n=6 per group, p-value<0.01), which was downregulated in rats with cyclosporine-A treated myocarditis (3.69 (2.59~3.86) for myocarditis versus 2.28 (1.76~2.60) for cyclosporine-A treated myocarditis; n=6 per group, p-value<0.01). The specificity of the tracer was verified by administration of excess non-labeled MSA. 68Ga-NOTA-MSA uptake was significantly enhanced earlier in the evolution of myocarditis before any signs of inflammation could be seen on echocardiography. These results demonstrate the potential utility of visualizing infiltration of mannose receptor-positive macrophages with 68Ga-NOTA-MSA PET in the early diagnosis of as well as in the monitoring of treatment response of myocarditis.

[11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome: A pilot study.

Abstract Complex regional pain syndrome (CRPS) is characterized by severe and chronic pain, but the pathophysiology of this disease are not clearly understood. The primary aim of our case–control study was to explore neuroinflammation in patients with CRPS using positron emission tomography (PET), with an 18-kDa translocator protein specific radioligand [11C]-(R)-PK11195. [11C]-(R)-PK11195 PET scans were acquired for 11 patients with CRPS (30–55 years) and 12 control subjects (30–52 years). Parametric image of distribution volume ratio (DVR) for each participant was generated by applying a relative equilibrium-based graphical analysis. The DVR of [11C]-(R)-PK11195 in the caudate nucleus (t(21) = −3.209, P = 0.004), putamen (t(21) = −2.492, P = 0.022), nucleus accumbens (t(21) = −2.218, P = 0.040), and thalamus (t(21) = −2.395, P = 0.026) were significantly higher in CRPS patients than in healthy controls. Those of globus pallidus (t(21) = −2.045, P = 0.054) tended to be higher in CRPS patients than in healthy controls. In patients with CRPS, there was a positive correlation between the DVR of [11C]-(R)-PK11195 in the caudate nucleus and the pain score, the visual analog scale (r = 0.661, P = 0.026, R2 = 0.408) and affective subscales of McGill Pain Questionnaire (r = 0.604, P = 0.049, R2 = 0.364). We demonstrated that neuroinflammation of CRPS patients in basal ganglia. Our results suggest that microglial pathology can be an important pathophysiology of CRPS. Association between the level of caudate nucleus and pain severity indicated that neuroinflammation in this region might play a key role. These results may be essential for developing effective medical treatments.