Successful translation of the use of nanoparticles from laboratories to clinics requires exhaustive and elaborate studies involving the biodistribution, clearance and biocompatibility of nanoparticles for in vivo biomedical applications. We report here the use of multimodal organically modified silica (ORMOSIL) nanoparticles for in vivo bioimaging, biodistribution, clearance and toxicity studies. We have synthesized ORMOSIL nanoparticles with diameters of 20-25 nm, conjugated with near infra-red (NIR) fluorophores and radiolabelled them with 124 I, for optical and PET imaging in vivo. The biodistribution of the non targeted nanoparticles was studied in non-tumored nude mice by optical fluorescence imaging, as well by measuring the radioactivity from harvested organs. Biodistribution studies showed a greater accumulation of nanoparticles in liver, spleen and stomach than in kidney, heart and lungs. The clearance studies carried out over a period of 15 days indicated hepatobiliary excretion of the nanoparticles. Selected tissues were analyzed for any potential toxicity by histological analysis, which confirmed the absence of any adverse effect or any other abnormalities in the tissues. The results demonstrate that these multimodal nanoparticles have potentially ideal attributes for use as biocompatible probes for in vivo imaging. KeywordsORMOSIL Nanoparticles; optical and PET Imaging; NIR fluorophore; 124 I radiolabeling; Biodistribution; clearance and toxicity Nanomaterials promise to address the current limitations of sensitivity and specificity of medical diagnostics, as well as significantly improve the outcome of existing and emerging therapeutics, via the introduction of new generation of multimodal nanoprobes. [1][2][3][4][5][6] In this regard, it is critical to design nanoprobes with desired composition, size and surface functionalities, and rigorously test them in vitro and in vivo for their safety and efficiency. Also biocompatibility and biodegradation of the nanoprobe materials play an important role in the use of the nanoprobes in the field of diagnostic and therapeutic applications.The rise in nanoprobes development has bolstered the prospects of in vivo optical imaging through the development of a variety of NIR-luminescent nanoformulations, which include quantum dots, 7 upconverting nanophosphors, 8 Herein, we report the synthesis of ultrafine ORMOSIL nanoparticles (diameter ∼20 nm), conjugated with a near-infra-red (NIR) fluorophore, as optical probes. The resulting NIRnanoparticles will facilitate optical bioimaging in the NIR window, with maximum tissue penetration of light and minimum background signal. 23, 24 Furthermore, we have also conjugated the well-known positron emission tomographic (PET) imaging probe Iodine-124 with the nanoparticle, which will allow bioimaging independent of tissue-depth, as well as more accurate quantification of accumulation of nanoparticles in various major organs in vivo. These multimodal nanoprobes have been injected systemically in mice, and their in v...

Objectives The PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) study sought to test the hypothesis that quantifying inhomogeneity in myocardial sympathetic innervation could identify patients at highest risk for sudden cardiac arrest (SCA). Background Left ventricular ejection fraction (LVEF) is the only parameter identifying patients at risk of SCA who benefit from an implantable cardiac defibrillator (ICD). Methods We prospectively enrolled 204 subjects with ischemic cardiomyopathy (LVEF ≤35%) eligible for primary prevention ICDs. Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation (11C-meta-hydroxyephedrine [11C-HED]), perfusion (13N-ammonia) and viability (insulin-stimulated 18F-2-deoxyglucose). The primary endpoint was SCA defined as arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 beats/min. Results After 4.1 years follow-up, cause-specific SCA was 16.2%. Infarct volume (22 ± 7% vs. 19 ± 9% of left ventricle [LV]) and LVEF (24 ± 8% vs. 28 ± 9%) were not predictors of SCA. In contrast, patients developing SCA had greater amounts of sympathetic denervation (33 ± 10% vs. 26 ± 11% of LV; p = 0.001) reflecting viable, denervated myocardium. The lower tertiles of sympathetic denervation had SCA rates of 1.2%/year and 2.2%/year, whereas the highest tertile had a rate of 6.7%/year. Multivariate predictors of SCA were PET sympathetic denervation, left ventricular end-diastolic volume index, creatinine, and no angiotensin inhibition. With optimized cut-points, the absence of all 4 risk factors identified low risk (44% of cohort; SCA <1%/year); whereas ≥2 factors identified high risk (20% of cohort; SCA ~12%/year). Conclusions In ischemic cardiomyopathy, sympathetic denervation assessed using 11C-HED PET predicts cause-specific mortality from SCA independently of LVEF and infarct volume. This may provide an improved approach for the identification of patients most likely to benefit from an ICD. (Prediction of ARrhythmic Events With Positron Emission Tomography [PAREPET]; NCT01400334)

Methyl 3-(1'-m-iodobenzyloxyethyl)-3-devinylpyropheophorbide-a (2), obtained in a sequence of reactions from pyropheophorbide-a (a chlorophyll-a derivative), was found to be a promising imaging agent and a photosensitizer for photodynamic therapy (PDT). The electrophilic aromatic iodination of the corresponding trimethylstannyl intermediate with Na124I in the presence of an Iodogen bead afforded 124I-labeled photosensitizer 4 with >95% radioactive specificity. In addition to drug-uptake, the light fluence and fluence rate that were used for the light treatment had a significant impact in long-term tumor cure. The iodo photosensitizer 2 (nonlabeled analogue of 4) produced 100% tumor cure (5/5 mice were tumor free on day 60) at a dose of 1.5 micromol/kg and a light dose of 128 J/cm2, 14 mW/cm2 for 2.5 h (lambda(max) 665 nm) at 24 h postinjection. The photosensitizer also showed promising tumor fluorescence and PET imaging ability. Our present work demonstrates the utility of the first 124I-labeled photosensitizer as a "multimodality agent", which could further be improved by using more tumor-avid and/or target-specific photosensitizers.

It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen’s flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand 11C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.