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Proton-hyperpolarized contrast agents are attractive because they can be imaged on virtually any clinical MRI scanner, which is typically equipped to scan only protons rather than heteronuclei (i.e., anything besides protons, e.g., 13C, 15N, 129Xe, 23Na, etc.). Even though the lifetime of the proton spin hyperpolarization is only a few seconds, it is sufficient for inhalation and scanning of proton-hyperpolarized gas media. We demonstrate the utility of producing hyperpolarized propane gas via heterogeneous parahydrogen-induced polarization for the purpose of ventilation imaging in an excised rabbit lung model. The magnetization of protons in hyperpolarized propane gas is similar to that of tissue water protons, making it possible to rapidly perform lung ventilation imaging with a 0.35 T clinical MRI scanner. Here, we demonstrate the feasibility of rapid (2 s) lung ventilation MRI in excised rabbit lungs using hyperpolarized propane gas with a 1 × 1 mm2 pixel size using a 50 mm slice thickness, and a 1.7 × 1.7 mm2 pixel size using a 9 mm slice thickness. [ABSTRACT FROM AUTHOR]

Over the past two decades, epigenetic regulation has become a rapidly growing and influential field in biology and medicine. One key mechanism involves the acetylation and deacetylation of lysine residues on histone core proteins and other critical proteins that regulate gene expression and cellular signaling. Although histone deacetylases (HDACs) have received significant attention, the roles of individual HDAC isoforms in the pathogenesis of psychiatric diseases still require further research. This is particularly true with regard to the sirtuins, class III HDACs. Sirtuins have unique functional activity and significant roles in normal neurophysiology, as well as in the mechanisms of addiction, mood disorders, and other neuropsychiatric abnormalities. This review aims to elucidate the differences in catalytic structure and function of the seven sirtuins as they relate to psychiatry. [ABSTRACT FROM AUTHOR]

In the past two decades, the research community has focused on defining reliable molecular biomarkers for the early diagnosis of Alzheimer's disease (AD). Several positron emission tomography (PET) radiopharmaceuticals have been developed and gained regulatory approval for the non-invasive detection of amyloid-ß (Aß) amyloid deposits in the brain. Nowadays, there are several PET imaging radiopharmaceuticals available in Thailand for amyloid imaging including [11C]-labeled Pittsburgh compound B ([11C]PiB), [18F]Florbetapir, and [18F]Florbetaben. This review provides a summary of commonly used amyloid PET radiopharmaceuticals, focusing on the available radiopharmaceuticals in Thailand and the experiences of using amyloid PET radiopharmaceuticals and imaging for clinical and research applications at Siriraj Hospital. [ABSTRACT FROM AUTHOR]

A high incidence and prevalence of neurodegenerative diseases and neurodevelopmental disorders justify the necessity of well-defined criteria for diagnosing these pathologies from brain imaging findings. No easy-to-apply quantitative markers of abnormal brain development and ageing are available. We aim to find the characteristic features of non-pathological development and degeneration in distinct brain structures and to work out a precise descriptive model of brain morphometry in age groups. We will use four biomedical databases to acquire original peer-reviewed publications on brain structural changes occurring throughout the human life-span. Selected publications will be uploaded to Covidence systematic review software for automatic deduplication and blinded screening. Afterwards, we will manually review the titles, abstracts, and full texts to identify the papers matching eligibility criteria. The relevant data will be extracted to a 'Summary of findings' table. This will allow us to calculate the annual rate of change in the volume or thickness of brain structures and to model the lifelong dynamics in the morphometry data. Finally, we will adjust the loss of weight/thickness in specific brain areas to the total intracranial volume. The systematic review will synthesise knowledge on structural brain change across the life-span. [ABSTRACT FROM AUTHOR]

The onset of intracerebral hemorrhage and its progression toward acute brain injury have been correlated with the concentration of unconjugated bilirubin (BR). In addition, BR has been considered a novel predictor of outcome from intracranial hemorrhage. Since the existing invasive approach for determining localized BR and biliverdin (BV) concentration within the hemorrhagic brain lesion is not feasible, the predictive capability of BR in terms of determining the onset of hemorrhage and understanding the consequences of its progression (age) is unknown. In this study, we have demonstrated a photoacoustic (PA) approach to the noninvasive measurement of BR–BV ratio that can be utilized longitudinally to approximate the onset of the hemorrhage. The PA imaging‐based measurements of BV and BR in tissues and fluids can potentially be used to determine hemorrhage "age," quantitatively evaluate the hemorrhage resorption or detect a rebleeding, and assess responses to therapy and prognosis. [ABSTRACT FROM AUTHOR]

Coronavirus 2019 (COVID-19) spreads an extremely infectious disease where there is no specific treatment. COVID-19 virus had a rapid and unexpected spread rate which resulted in critical difficulties for public health and unprecedented daily life disruption. Thus, accurate, rapid, and early diagnosis of COVID-19 virus is critical to maintain public health safety. A graphite oxide-based field-effect transistor (GO-FET) was fabricated and functionalized with COVID-19 antibody for the purpose of real-time detection of COVID-19 spike protein antigen. Thermal evaporation process was used to deposit the gold electrodes on the surface of the sensor substrate. Graphite oxide channel was placed between the gold electrodes. Bimetallic nanoparticles of platinum and palladium were generated via an ultra-high vacuum (UHV) compatible system by sputtering and inert-gas condensation technique. The biosensor graphite oxide channel was immobilized with specific antibodies against the COVID-19 spike protein to achieve selectivity and specificity. This technique uses the attractive semiconductor characteristics of the graphite oxide-based materials resulting in highly specific and sensitive detection of COVID-19 spike protein. The GO-FET biosensor was decorated with bimetallic nanoparticles of platinum and palladium to investigate the improvement in the sensor sensitivity. The in-house developed biosensor limit of detection (LOD) is 1 fg/mL of COVID-19 spike antigen in phosphate-buffered saline (PBS). Moreover, magnetic labelled SARS-CoV-2 spike antibody were studied to investigate any enhancement in the sensor performance. The results indicate the successful fabrication of a promising field effect transistor biosensor for COVID-19 diagnosis. [ABSTRACT FROM AUTHOR]

Biomolecular detection methods have evolved from simple chemical processes to laboratory sensors capable of acquiring accurate measurements of various biological components. Recently, silicon nanowire field-effect transistors (SiNW-FETs) have been drawing enormous interest due to their potential in the biomolecular sensing field. SiNW-FETs exhibit capabilities such as providing real-time, label-free, highly selective, and sensitive detection. It is highly critical to diagnose infectious diseases accurately to reduce the illness and death spread rate. In this work, a novel SiNW-FET sensor is designed using a semiempirical approach, and the electronic transport properties are studied to detect the COVID-19 spike protein. Various electronic transport properties such as transmission spectrum, conductance, and electronic current are investigated by a semiempirical modeling that is combined with a nonequilibrium Green's function. Moreover, the developed sensor selectivity is tested by studying the electronic transport properties for other viruses including influenza, rotavirus, and HIV. The results indicate that SiNW-FET can be utilized for accurate COVID-19 identification with high sensitivity and selectivity. [ABSTRACT FROM AUTHOR]

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. The ability to predict patients at risk for preterm birth remains a major health challenge. The currently available clinical diagnostics such as cervical length and fetal fibronectin may detect only up to 30% of patients who eventually experience a spontaneous preterm birth. This paper reviews ongoing efforts to improve the ability to conduct a risk assessment for preterm birth. In particular, this work focuses on quantitative methods of imaging using ultrasound-based techniques, magnetic resonance imaging, and optical imaging modalities. While ultrasound imaging is the major modality for preterm birth risk assessment, a summary of efforts to adopt other imaging modalities is also discussed to identify the technical and diagnostic limits associated with adopting them in clinical settings. We conclude the review by proposing a new approach using combined photoacoustic, ultrasound, and elastography as a potential means to better assess cervical tissue remodeling, and thus improve the detection of patients at-risk of PTB. [ABSTRACT FROM AUTHOR]

Background: The mechanism by which immune cells regulate metastasis is unclear. Understanding the role of immune cells in metastasis will guide the development of treatments improving patient survival.Methods: We used syngeneic orthotopic mouse tumour models (wild-type, NOD/scid and Nude), employed knockout (CD8 and CD4) models and administered CXCL4. Tumours and lungs were analysed for cancer cells by bioluminescence, and circulating tumour cells were isolated from blood. Immunohistochemistry on the mouse tumours was performed to confirm cell type, and on a tissue microarray with 180 TNBCs for human relevance. TCGA data from over 10,000 patients were analysed as well.Results: We reveal that intratumoral immune infiltration differs between metastatic and non-metastatic tumours. The non-metastatic tumours harbour high levels of CD8+ T cells and low levels of platelets, which is reverse in metastatic tumours. During tumour progression, platelets and CXCL4 induce differentiation of monocytes into myeloid-derived suppressor cells (MDSCs), which inhibit CD8+ T-cell function. TCGA pan-cancer data confirmed that CD8lowPlatelethigh patients have a significantly lower survival probability compared to CD8highPlateletlow.Conclusions: CD8+ T cells inhibit metastasis. When the balance between CD8+ T cells and platelets is disrupted, platelets produce CXCL4, which induces MDSCs thereby inhibiting the CD8+ T-cell function. [ABSTRACT FROM AUTHOR]

NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This enormous sensitivity gain enables new applications ranging from studies of small molecules by using high‐resolution NMR spectroscopy to real‐time metabolic imaging in vivo. Several hyperpolarization techniques exist for hyperpolarization of a large repertoire of nuclear spins, although the 13C and 15N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their long T1 allows hyperpolarized states to be retained for up to tens of minutes. Signal amplification by reversible exchange (SABRE) is a low‐cost and ultrafast hyperpolarization technique that has been shown to be versatile for the hyperpolarization of 15N nuclei. Although large sensitivity gains are enabled by hyperpolarization, 15N natural abundance is only ∼0.4 %, so isotopic labeling of the molecules to be hyperpolarized is required in order to take full advantage of the hyperpolarized state. Herein, we describe selected advances in the preparation of 15N‐labeled compounds with the primary emphasis on using these compounds for SABRE polarization in microtesla magnetic fields through spontaneous polarization transfer from parahydrogen. Also, these principles can certainly be applied for hyperpolarization of these emerging contrast agents using dynamic nuclear polarization and other techniques. [ABSTRACT FROM AUTHOR]

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy. [ABSTRACT FROM AUTHOR]

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decisionmaking. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy. [ABSTRACT FROM AUTHOR]

Many MRI contrast agents formed with the parahydrogen‐induced polarization (PHIP) technique exhibit biocompatible profiles. In the context of respiratory imaging with inhalable molecular contrast agents, the development of nonflammable contrast agents would nonetheless be highly beneficial for the biomedical translation of this sensitive, high‐throughput and affordable hyperpolarization technique. To this end, we assess the hydrogenation kinetics, the polarization levels and the lifetimes of PHIP hyperpolarized products (acids, ethers and esters) at various degrees of fluorine substitution. The results highlight important trends as a function of molecular structure that are instrumental for the design of new, safe contrast agents for in vivo imaging applications of the PHIP technique, with an emphasis on the highly volatile group of ethers used as inhalable anesthetics. [ABSTRACT FROM AUTHOR]

Nimorazole belongs to the imidazole‐based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [15N3]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next‐generation MRI‐LINAC systems. Herein, we report the first steps to create long‐lasting (for tens of minutes) hyperpolarized state on three 15N sites of [15N3]nimorazole with T1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000‐fold at 1.4 T (corresponding to P15N of 3.2 %) by 15N−15N spin‐relayed SABRE‐SHEATH hyperpolarization technique, relying on simultaneous exchange of [15N3]nimorazole and parahydrogen on polarization transfer Ir‐IMes catalyst. The presented results pave the way to efficient spin‐relayed SABRE‐SHEATH hyperpolarization of a wide range of imidazole‐based antibiotics and chemotherapeutics. [ABSTRACT FROM AUTHOR]

Nimorazole belongs to the imidazole‐based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [15N3]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next‐generation MRI‐LINAC systems. Herein, we report the first steps to create long‐lasting (for tens of minutes) hyperpolarized state on three 15N sites of [15N3]nimorazole with T1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000‐fold at 1.4 T (corresponding to P15N of 3.2 %) by 15N−15N spin‐relayed SABRE‐SHEATH hyperpolarization technique, relying on simultaneous exchange of [15N3]nimorazole and parahydrogen on polarization transfer Ir‐IMes catalyst. The presented results pave the way to efficient spin‐relayed SABRE‐SHEATH hyperpolarization of a wide range of imidazole‐based antibiotics and chemotherapeutics. [ABSTRACT FROM AUTHOR]

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy. [ABSTRACT FROM AUTHOR]

The growing interest in magnetic resonance imaging (MRI) for assessing regional lung function relies on the use of nuclear spin hyperpolarized gas as a contrast agent. The long gas‐phase lifetimes of hyperpolarized 129Xe make this inhalable contrast agent acceptable for clinical research today despite limitations such as high cost, low throughput of production and challenges of 129Xe imaging on clinical MRI scanners, which are normally equipped with proton detection only. We report on low‐cost and high‐throughput preparation of proton‐hyperpolarized diethyl ether, which can be potentially employed for pulmonary imaging with a nontoxic, simple, and sensitive overall strategy using proton detection commonly available on all clinical MRI scanners. Diethyl ether is hyperpolarized by pairwise parahydrogen addition to vinyl ethyl ether and characterized by 1H NMR spectroscopy. Proton polarization levels exceeding 8 % are achieved at near complete chemical conversion within seconds, causing the activation of radio amplification by stimulated emission radiation (RASER) throughout detection. Although gas‐phase T1 relaxation of hyperpolarized diethyl ether (at partial pressure of 0.5 bar) is very efficient, with T1 of ca. 1.2 second, we demonstrate that, at low magnetic fields, the use of long‐lived singlet states created via pairwise parahydrogen addition extends the relaxation decay by approximately threefold, paving the way to bioimaging applications and beyond. [ABSTRACT FROM AUTHOR]

15N spin–lattice relaxation dynamics in metronidazole-15N3 and metronidazole-15N2 isotopologues are studied for rational design of 15N-enriched biomolecules for signal amplification by reversible exchange in microtesla fields. 15N relaxation dynamics mapping reveals the deleterious effects of interactions with the polarization transfer catalyst and a quadrupolar 14N nucleus within the spin-relayed 15N–15N network. [ABSTRACT FROM AUTHOR]

Optical coherence tomography (OCT), with a high‐spatial resolution (<10 microns), intermediate penetration depth (~1.5 mm) and volumetric imaging capability is a great candidate to be used as a diagnostic‐assistant modality in dermatology. At this time, the accuracy of OCT for melanoma detection is lower than anticipated. In this letter, we studied for the first time, the use of a novel contrast agent consist of ultra‐small nanoparticles conjugated to a melanoma biomarker to improve the accuracy of OCT for differentiation of melanoma cells from nonmelanoma cells, in vitro. We call this approach SMall nanoparticle Aggregation‐enhanced Radiomics of Tumor (SMART)‐OCT imaging. This initial proof of concept study is the first step toward the broad utilization of this method for high accuracy all types of tumor detection applications. [ABSTRACT FROM AUTHOR]

Objective: The current study was conducted to improve the understanding of relationships between regional cortical amyloid load, glucose metabolism, cortical morphology (volume), and severity of clinical symptoms in patients with AD, MCI, and age-matched controls.Methods: To objectivize the radiological evaluation of patients with suspected AD, head-to-head multi-modality imaging studies were conducted using MRI and PET/CT with [18F]FDG and [18F]AV45 for visualization and quantitation of brain morphology, glucose metabolism, and amyloid levels, respectively. A total of 84 subjects was studied, including 33 patients with AD, 31 patients with MCI, and 20 age-matched healthy controls (HC). A new quantitative index was calculated as a ratio of regional SUV of [18F]AV45 (normalized to cerebellar cortex) over the corresponding regional SUV of [18F]FDG, divided by the corresponding regional volume, measured from the co-registered MRI and normalized to the normal age-matched control group (AV45/FDG/NVol index). Relationships between clinical scores (TMSE, ADAS) and AV45/FDG/NVol indices for different structures of the brain in study groups were determined using linear regression analyses.Results: A significant direct linear correlation was observed between the AV45/FDG/NVol index and ADAS-Cog test score and an inverse correlation with TMSE score at baseline and with the degree of changes in ADAS and TMSE scores assessed one year later (disease progression). The observed correlations between AV45/FDG/NVol index and clinical scores were higher than those with MRI-based cortical volumes, FDG SUV, or cerebellum-normalized AV45 SUV alone.Conclusions: Current study demonstrated that AV45/FDG/NVol index mapping of the brain is a novel quantitative molecular imaging biomarker that correlates with clinical neurocognitive status and may facilitate more accurate diagnosis, staging, and prognosis of AD. Additional larger scale clinical studies are required to further evaluate the efficacy of this new quantitative index as a diagnostic and prognostic biomarker of AD as well as for the evaluation of safety and efficacy of novel agents undergoing clinical trials for therapy of AD. [ABSTRACT FROM AUTHOR]

We report the efficacy of dual positron emission tomography/computed tomography (PET/CT) imaging with [18F]-2'-fluoro-2'-deoxy-D-glucose ([18F]-FDG) and [18F]-fluorocholine ([18F]-FCH) in patients with gestational trophoblastic neoplasia (GTN) for primary diagnosis and staging of this rare pregnancy-related disorder. Whole-body PET/CT with [18F]-FDG and [18F]-FCH was performed in three patients with GTN in 2 consecutive days. Each detectable lesion was characterized by visual and quantitative analyses. As compared to CT alone, PET/CT with [18F]-FDG and [18F]-FCH PET/CT revealed more hypermetabolic metastatic lesions in the body, but not in the brain. The standard uptake value of [18F]-FDG was generally higher than [18F]-FCH in all detectable tumor lesions. In conclusion, both [18F]-FDG and [18F]-FCH PET/CT can be used for diagnosis and staging for GTN, based on their sensitivity for small extracerebral metastatic lesions. Additional studies are warranted to determine whether the PET/CT imaging with [18F]-FDG and [18F]-FCH can serve as a biomarker of GTN aggressiveness, for prediction of treatment response. [ABSTRACT FROM AUTHOR]

Bacteriophage (phage) have attractive advantages as delivery systems compared with mammalian viruses, but have been considered poor vectors because they lack evolved strategies to confront and overcome mammalian cell barriers to infective agents. We reasoned that improved efficacy of delivery might be achieved through structural modification of the viral capsid to avoid pre- and postinternalization barriers to mammalian cell transduction. We generated multifunctional hybrid adeno-associated virus/phage (AAVP) particles to enable simultaneous display of targeting ligands on the phage's minor pIII proteins and also degradation-resistance motifs on the very numerous pVIII coat proteins. This genetic strategy of directed evolution bestows a next-generation of AAVP particles that feature resistance to fibrinogen adsorption or neutralizing antibodies and ability to escape endolysosomal degradation. This results in superior gene transfer efficacy in vitro and also in preclinical mouse models of rodent and human solid tumors. Thus, the unique functions of our next-generation AAVP particles enable improved targeted gene delivery to tumor cells. [ABSTRACT FROM AUTHOR]

The NMR hyperpolarization of uniformly 15N‐labeled [15N3]metronidazole is demonstrated by using SABRE‐SHEATH. In this antibiotic, the 15NO2 group is hyperpolarized through spin relays created by 15N spins in [15N3]metronidazole, and the polarization is transferred from parahydrogen‐derived hydrides over six chemical bonds. In less than a minute of parahydrogen bubbling at approximately 0.4 μT, a high level of nuclear spin polarization (P15N) of around 16 % is achieved on all three 15N sites. This product of 15N polarization and concentration of 15N spins is around six‐fold better than any previous value determined for 15N SABRE‐derived hyperpolarization. At 1.4 T, the hyperpolarized state persists for tens of minutes (relaxation time, T1≈10 min). A novel synthesis of uniformly 15N‐enriched metronidazole is reported with a yield of 15 %. This approach can potentially be used for synthesis of a wide variety of in vivo metabolic probes with potential uses ranging from hypoxia sensing to theranostic imaging. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues.Procedures: A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (Kcat/Km 716.5 ± 72.8, 615.4 ± 50.5, 269.5 ± 52.1/s mol, respectively). Radiosynthesis of 12- [18F]fluorododecanoic aminohexanoicanilide (12-[18F]DDAHA) was achieved by nucleophilic radiofluorination of 12-iododecanoic-AHA precursor.Results: A significantly higher accumulation of 12-[18F]DDAHA was observed in MCF-7 and MDA-MB-435 cells in vitro as compared to U87, MiaPaCa, and MCF10A, which was consistent with levels of SIRT2 expression. Initial in vivo studies using 12-[18F]DDAHA conducted in a 9L glioma-bearing rats were discouraging, due to rapid defluorination of this radiotracer upon intravenous administration, as evidenced by significant accumulation of F-18 radioactivity in the skull and other bones, which confounded the interpretation of images of radiotracer accumulation within the tumor and other regions of the brain.Conclusions: The next generation of SIRT2-specific radiotracers resistant to systemic defluorination should be developed using alternative sites of radiofluorination on the aliphatic chain of DDAHA. A SIRT2-selective radiotracer may provide information about SIRT2 expression and activity in tumors and normal organs and tissues, which may help to better understand the roles of SIRT2 in different diseases. [ABSTRACT FROM AUTHOR]

Introduction: Epidermal growth factor receptor (EGFR)-targeted therapies with antibodies and small molecular EGFR kinase inhibitors have shown poor efficacy in unselected populations of patients with advanced non-small cell lung carcinomas (NSCLC). In contrast, patients with overexpression of EGFR and activating mutations in EGFR kinase domain demonstrated improved responses to EGFR kinase inhibitors. Therefore, we have developed a novel radiotracer, [(18)F]F-PEG(6)-IPQA for PET imaging of EGFR expression-activity in NSCLC, and have described its radiosynthesis and in vitro evaluation in two NSCLC cell lines with wild-type and L858R active mutant EGFR.Methods: A mesylate precursor was synthesized in multiple steps and radiofluorinated using K(18)F/Kryptofix. The fluorinated intermediate compound was reduced to an amino derivative then treated with acryloyl isobutyl carbonate, followed by purification by HPLC to obtain the desired product.Results: Decay-corrected radiochemical yields of [(18)F]F-PEG(6)-IPQA were 3.9-17.6%, with an average of 9.0% (n = 11). Radiochemical purity was >97% with specific activity of 34 GBq/μmol (mean value, n = 10) at the end of synthesis. The accumulation of [(18)F]F-PEG(6)-IPQA in H3255 cells was ten-fold higher than in H441 cells, despite a two-fold lower level of activated phospho-EGFR expression in H3255 cells compared with H441 cells. The accumulation of [(18)F]F-PEG(6)-IPQA in both cell lines was significantly decreased in the presence of a small molecular EGFR kinase inhibitor, Iressa, at 100 μM concentration in culture medium.Conclusion: We have synthesized [(18)F]F-PEG(6)-IPQA and demonstrated its highly selective accumulation in active mutant L858R EGFR-expressing NSCLC cells in vitro. Further in vivo studies are warranted to assess the ability of PET imaging with [(18)F]F-PEG(6)-IPQA to discriminate the active mutant L858R EGFR-expressing NSCLC that are sensitive to therapy with EGFR kinase inhibitors vs NSCLC that express wild-type EGFR. [ABSTRACT FROM AUTHOR]

Purpose: We have incorporated a positron emission tomography (PET) functionality in T cells expressing a CD19-specific chimeric antigen receptor (CAR) to non-invasively monitor the adoptively transferred cells.Procedures: We engineered T cells to express CD19-specific CAR, firefly luciferase (ffLuc), and herpes simplex virus type-1 thymidine kinase (TK) using the non-viral-based Sleeping Beauty (SB) transposon/transposase system adapted for human application. Electroporated primary T cells were propagated on CD19+ artificial antigen-presenting cells.Results: After 4 weeks, 90 % of cultured cells exhibited specific killing of CD19+ targets in vitro, could be ablated by ganciclovir, and were detected in vivo by bioluminescent imaging and PET following injection of 2'-deoxy-2'-[18F]fluoro-5-ethyl-1-β-D-arabinofuranosyl-uracil ([18F]FEAU).Conclusion: This is the first report demonstrating the use of SB transposition to generate T cells which may be detected using PET laying the foundation for imaging the distribution and trafficking of T cells in patients treated for B cell malignancies. [ABSTRACT FROM AUTHOR]

Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVPTNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptormediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well. [ABSTRACT FROM AUTHOR]

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogelbased nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we showa broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical application.s [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDAC’s) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors. Class IIa deacetylases possess only minimal deacetylase activity against acetylated histones, but have several other client proteins as substrates through which they participate in epigenetic regulation. Herein, we report the radiosyntheses of the second generation of HDAC class IIa–specific radiotracers: 6-(di-fluoroacetamido)-1-hexanoicanilide (DFAHA) and 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]-TFAHA). The selectivity of these radiotracer substrates to HDAC class IIa enzymes was assessed in vitro, in a panel of recombinant HDACs, and in vivo using PET/CT imaging in rats. [18F]TFAHA showed significantly higher selectivity for HDAC class IIa enzymes, as compared to [18F]DFAHA and previously reported [18F]FAHA. PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo. Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases. [ABSTRACT FROM AUTHOR]

Bacterial nitroreductases (NTRs) have been widely utilized in the development of novel antibiotics, degradation of pollutants, and gene-directed enzyme prodrug therapy (GDEPT) of cancer that reached clinical trials. In case of GDEPT, since NTR is not naturally present in mammalian cells, the prodrug is activated selectively in NTR-transformed cancer cells, allowing high efficiency treatment of tumors. Currently, no bioluminescent probes exist for sensitive, non-invasive imaging of NTR expression. We therefore developed a "NTR caged luciferin" (NCL) probe that is selectively reduced by NTR, producing light proportional to the NTR activity. Here we report successful application of this probe for imaging of NTR in vitro, in bacteria and cancer cells, as well as in vivo in mouse models of bacterial infection and NTR-expressing tumor xenografts. This novel tool should significantly accelerate the development of cancer therapy approaches based on GDEPT and other fields where NTR expression is important. [ABSTRACT FROM AUTHOR]

Introduction Earlier, we reported syntheses of ethyl- β- d-galactopyranosyl-(1,4′)-2′-deoxy-2′-[18F]fluoro- β- d-glucopyranoside (Et-[18F]FDL) and 1′-[18F]fluoroethyl- β- d-lactose ([18F]-FEL) for positron emission tomography (PET) of pancreatic carcinoma. Et-[18F]FDL requires a precursor, which involves 11 steps to synthesize and produces overall low yields. Synthesis of precursors for [18F]-FEL requires four steps, but those precursors produced low radiochemical yields. Here, we report new precursors and an improved synthesis of [18F]-FEL. Method Two precursors, 1′-(methanesulfonyl)ethyl-2′,3′,6′,2,3,4,6-hepta- O-acetyl- β- d-lactose 2a and 1′-( p-nitrophenyl-sulfonyl)ethyl-2′,3′,6′,2,3,4,6-hepta- O-acetyl- β- d-lactose 2b, were synthesized from lactose in four steps. Radiofluorination reactions were performed using K18F/kryptofix and the crude product [18F]-3 was purified by HPLC. Basic hydrolysis of [18F]-3 produced 1′-[18F]fluoroethyl- β- d-lactose [18F]-4, which was neutralized, diluted with saline, filtered on a 0.22-µm filter, and analyzed by radio-TLC. Results The average radiochemical yields of [18F]-4 (d. c.) from 2a and 2b were 21% ( n = 6) and 65% ( n = 6), respectively, with >99% radiochemical purity and specific activity of 55.5 GBq/µmol. Synthesis time was 90-95 min from the end of bombardment. Conclusion An improved synthesis of [18F]FEL has been achieved in high yields, with high purity and specific activity. Precursor 2b with this method should be applicable for high yield automated production in a commercial synthesis module for clinical application. [ABSTRACT FROM AUTHOR]

Purpose: Abnormal fatty acid (FA) synthesis is one of the common features of cancer. Fatty acid synthase (FASN), a multifunctional enzyme playing a key role in biosynthesis of FA, is up-regulated in prostate, breast, and lung carcinomas. Orlistat is a FDA-approved anti-obesity drug that inhibits the thioesterase domain of FASN, interferes with cellular FA synthesis, can arrest tumor cell proliferation, and induces tumor cell apoptosis. The current study was aimed to investigate the metabolic changes associated with FASN inhibition by orlistat and to understand the molecular mechanisms behind the observed metabolic changes in non-small cell lung carcinoma (NSCLC) cell lines. Procedures: Changes in metabolite pools in four NSCLC cell lines (H441, H1975, H3255, and PC14) with different mutational profiles were studied using NMR spectroscopy before and after in vitro incubation with sub-toxic concentration of orlistat and [1-C] d-glucose or [1,2-C]choline. In vitro radiotracer accumulation assays in cells were performed with [H]acetate, [C]fluoroacetate, and 2-deoxy-2-[F]fluoro- d-glucose. In parallel, microarray profiling of genes involved in the regulation of carbohydrate and lipid metabolism was performed. Results: In orlistat-treated NSCLC cells, FASN inhibition results in characteristic changes in intermediary metabolites (FAs, choline, phospholipids, and TCA cycle metabolites) as observed by magnetic resonance spectroscopy. Further, FASN inhibition by orlistat induces multiple adaptive changes in FA synthetic pathway and associated metabolic pathways, including induction of ketone metabolism and glutaminolysis, as well as the up-regulation of 5' adenosine monophosphate-activated protein kinase. Conclusions: These observed changes in metabolic pools in orlistat-treated cells demonstrate the critical role of fatty acid de novo synthesis and metabolism for cellular energy production, especially in tumor cells with low glycolytic activity, which goes beyond the widely accepted concept that FA synthesis is important for cell membrane biosynthesis in rapidly proliferating tumor cells. [ABSTRACT FROM AUTHOR]

Purpose: The understanding of the role of genetic alterations in Wilms tumor development could be greatly advanced using a genetically engineered mouse models that can replicate the development and progression of this disease in human patients and can be monitored using non-invasive structural and molecular imaging optimized for renal tumors. Procedures: Repetitive dual-contrast computed tomography (CT; intravenous and intraperitoneal contrast), T2-weighted magnetic resonance imaging (MRI), and delayed 2-deoxy-2-[F]fluoro- d-glucose (F-FDG) positron emission tomography (PET) were utilized for characterization of Igf2 biallelic expression/ Wt1 knockout mouse model of Wilms tumor. For CT imaging, Ioversol 678 mg/ml in 200 μl was administered i.p. followed by 100 μl injected intravenously at 20 and 15 min prior to imaging, respectively. Static PET imaging studies were acquired at 1, 2, and 3 h after i.v. administration of F-FDG (400 μCi). Coronal and sagittal T1-weighted images (T/T 8.5/620 ms) were acquired before and immediately after i.v. injection of 0.4 ml/kg gadopentetate dimeglumine followed by T2-weighted images (T/T 60/300 ms). Tumor tissue samples were characterized by histopathology and immunohistochemistry for Glut1, FASN, Ki67, and CD34. In addition, six Wt1-Igf2 mice were treated with a mitogen-activated protein kinase (MEK) inhibitor U0126 (50 μmol/kg i.p.) every 4 days for 6 weeks. F-FDG PET/CT imaging was repeated at different days after initiation of therapy with U0126. The percent change of initial tumor volume and SUV was compared to non-treated historic control animals. Results: Overall, the best tumor-to-adjacent kidney contrast as well as soft tissue contrast for other abdominal organs was achieved using T2-weighted MRI. Delayed F-FDG PET (3-h post F-FDG administration) and dual-contrast CT (intravenous and intraperitoneal contrast) provided a more accurate anatomic and metabolic characterization of Wilms tumors in Wt1-Igf2 mice during early development and progression of renal tumors. Over the 8-month period, 46 Wt1-Igf2 mice and 8 littermate control mice were studied. Renal tumors were identified in 54.3 % of Wt1-Igf2 mice between post-natal 50-100 days. In 35.6 % of Wt1-Igf2 mice, tumors were localized in the right kidney; in 24 %, in the left kidney, while 40.4 % of Wt1-Igf2 mice had bilateral kidney tumors. Metastatic lesions were identified in 15.4 % of Wt1-Igf2 mice. Increased levels of Glut1 and IGF1R expression, high Ki67 labeling index, and a dense network of CD34+ microvessels in renal tumors was consistent with increased F-FDG accumulation. Treatment with a MEK 1/2 inhibitor U0126 did not cause the inhibition of tumor growth as compared to untreated animals. However, after the first three to four doses (~2 weeks of treatment), a decrease in F-FDG SUV was observed, as compared to pre-treatment levels ( p < 0.05, paired Student t test), which constitutes a metabolic response. Six weeks later, despite continuing therapy, the F-FDG SUV increased again to previous levels. Conclusions: The optimized dual contrast PET/CT imaging with early post i.v. and i.p. contrast CT and 3 h delayed PET imaging after F-FDG administration provides a sensitive and reliable method for detecting early tumor lesions in this endogenous mouse model of Wilms tumor and for monitoring their growth in response to targeted therapies. Therapy with MEK inhibitor U0126 produces only a transient inhibition of tumor glycolytic activity but does not inhibit tumor growth, which is due to continuing IGF2-induced signaling from IGF1R through the PI3K-AKT-mTOR pathway. [ABSTRACT FROM AUTHOR]

Mutations in the kinase domain of epidermal growth factor receptor (EGFR) have high levels of basal receptor phosphorylation and are associated with clinical responsiveness to Iressa in patients with nonsmall cell lung cancer (NSCLC). This study aimed to assess the feasibility of morpholino-[124I]IPQA derivative as an in vivo PET imaging tool for the expression of different EGFR mutants in NSCLC. In vitro radiotracer accumulation and washout studies demonstrated a rapid accumulation and progressive retention after washout of morpholino-[131I]IPQA derivative in high EGFR-expressing H1299 NSCLC derivative cell lines (L858R and E746-A750 del cell lines), but not in EGFR-transfected H1299 cell line and vector-transfected H1299 cell line. Using the morpholino- [124I]IPQA derivative, we obtained noninvasive microPET images of EGFR activity in L858R and E746-A750 del subcutaneous tumor xenografts, but not in subcutaneous tumor xenografts grown form control cell line. Different EGFR mutant (activity) tumors have a different morpholino-[*I]IPQA derivative uptake. However, it still needs to modify the structure of IPQA to increase its water solubility and reduce hepatobiliary clearance. Morpholino-[124I]IPQA derivative may be a potential probe for selection of the candidate patients suffering from NSCLC for the small molecule tyrosine kinase inhibitor therapy (e.g., Iressa) in the future. [ABSTRACT FROM AUTHOR]

Purpose: The translocator protein (18 kDa) (TSPO) is highly expressed on the bronchial and bronchiole epithelium, submucosal glands in intrapulmonary bronchi, pneumocytes and alveolar macrophages in human lung. This study aimed to perform positron emission tomography (PET) imaging of lung inflammation with [18F]FEDAC, a specific TSPO radioligand, and to determine cellular sources enriching TSPO expression in the lung. Methods: An acute lung injury model was prepared by intratracheal administration of lipopolysaccharide (LPS) to rat. Uptake of radioactivity in the rat lungs was measured with small-animal PET after injection of [18F]FEDAC. Presence of TSPO was examined in the lung tissue using Western blot and immunohistochemical assays. Results: The uptake of [18F]FEDAC increased in the lung with the progress of inflammation by treatment with LPS. Pretreatment with a TSPO-selective ligand PK11195 showed a significant decrease in the lung uptake of [18F]FEDAC due to competitive binding to TSPO. TSPO expression was elevated in the inflamed lung section and its level responded to the [18F]FEDAC uptake and severity of inflammation. Increase of TSPO expression was mainly found in the neutrophils and macrophages of inflamed lungs. Conclusion: From this study we conclude that PET with [18F]FEDAC may be a useful tool for imaging TSPO expression and evaluating progress of lung inflammation. Study on human lung using [18F]FEDAC-PET is promising. [ABSTRACT FROM AUTHOR]

Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement is Zyflamend, a polyherbal preparation with potent anti-inflammatory activities and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1 and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis. [ABSTRACT FROM AUTHOR]

Purpose: For targeted imaging and therapy of hepatocellular carcinoma (HCC), we established a chimeric promoter (EIIAPA) containing alpha-fetoprotein (AFP) promoter and hepatitis B virus enhancer II (EIIA) to control downstream expression of reporter and therapeutic genes. Procedures: We combined AFP promoter and EIIA to establish a chimeric EIIAPA promoter, then developed a bi-cistronic plasmid vector containing HSV1-tk and luciferase genes controlled by EIIAPA to stably transfect HCC cells. The selective transcriptional activity of EIIAPA was assayed by bioluminescence imaging (BLI) and the function of EIIAPA was determined by in vivo microPET and BLI. Results: The luciferase expression driven by EIIAPA was higher than that driven by AFP promoter in HCC cell lines. EIIAPA-tk induced cytotoxicity was observed only in HepG2 cells. Accumulation of I-FIAU and bioluminescent signal were detected on HepG2 tumors but not in parental tumors. The HepG2 tumors derived from lentiviral-transduced EIIAPA-tk expressing cells accumulated I-FIAU whereas the ARO tumors did not. The transfected HepG2 tumors expressed adequate EIIAPA-controlled HSV1-TK and the tumor regressed after ganciclovir treatment. Conclusion: The chimeric EIIAPA is a potential candidate promoter for targeted imaging and gene therapy of HCC. [ABSTRACT FROM AUTHOR]

Introduction: Oncolytic viruses show promise for treating cancer. However, to assess therapy and potential toxicity, a noninvasive imaging modality is needed. This study aims to determine the in vivo biodistribution, and imaging and timing characteristics of a vaccinia virus, GLV-1h153, encoding the human sodium iodide symporter (hNIS. Methods:GLV-1h1 53 was modified from GLV-1h68 to encode the hNIS gene. Timing of cellular uptake of radioiodide 131I in human pancreatic carcinoma cells PANC-1 was assessed using radiouptake assays. Viral biodistribution was determined in nude mice bearing PANC-1 xenografts, and infection in tumors confirmed histologically and optically via Green Fluorescent Protein (GFP) and bioluminescence. Timing characteristics of enhanced radiouptake in xenografts were assessed via 124I-positron emission tomography (PET). Detection of systemic administration of virus was investigated with both 124I-PET and 99m-technecium gamma- scintigraphy. Results: GLV-1 h1 53 successfully facilitated time-dependent intracellular uptake of 131I in PANC-1 cells with a maximum uptake at 24 hours postinfection (P,0.05). In vivo, biodistribution profiles revealed persistence of virus in tumors 5 weeks postinjection at 109 plaque-forming unit (PFU)/gm tissue, with the virus mainly cleared from all other major organs. Tumor infection by GLV-1 h1 53 was confirmed via optical imaging and histology. GLV-1 h1 53 facilitated imaging virus replication in tumors via PET even at 8 hours post radiotracer injection, with a mean %ID/gm of 3.82±0.46 (P<0.05) 2 days after intratumoral administration of virus, confirmed via tissue radiouptake assays. One week post systemic administration, GLV-1h153-infected tumors were detected via 124I-PET and 99m-technecium-scintigraphy. Conclusion: GLV-1 h1 53 is a promising oncolytic agent against pancreatic cancer with a promising biosafety profile. GLV-1 h1 53 facilitated time-dependent hNIS- specific radiouptake in pancreatic cancer cells, facilitating detection by PET with both intratumoral and systemic administration. Therefore, GLV-1 h1 53 is a promising candidate for the noninvasive imaging of virotherapy and warrants further study into longterm monitoring of virotherapy and potential radiocombination therapies with this treatment and imaging modality. [ABSTRACT FROM AUTHOR]

Numerous cancer therapeutics were originally identified from natural products used in traditional medicine. One such agent is acetyl-11-keto-beta-boswellic acid (AKBA), derived from the gum resin of the Boswellia serrata known as Salai guggal or Indian frankincense. Traditionally, it has been used in Ayurvedic medicine to treat proinflammatory conditions. In this report, we hypothesized that AKBA can affect the growth and metastasis of colorectal cancer (CRC) in orthotopically implanted tumors in nude mice. We found that the oral administration of AKBA (50-200 mg/kg) dose-dependently inhibited the growth of CRC tumors in mice, resulting in decrease in tumor volumes than those seen in vehicle-treated mice without significant decreases in body weight. In addition, we observed that AKBA was highly effective in suppressing ascites and distant metastasis to the liver, lungs and spleen in orthotopically implanted tumors in nude mice. When examined for the mechanism, we found that markers of tumor proliferation index Ki-67 and the microvessel density cluster of differentiation (CD31) were significantly downregulated by AKBA treatment. We also found that AKBA significantly suppressed nuclear factor-κB (NF-κB) activation in the tumor tissue and expression of proinflammatory (cyclooxygenase-2), tumor survival (bcl-2, bcl-xL, inhibitor of apoptosis (IAP-1) and survivin), proliferative (cyclin D1), invasive (intercellular adhesion molecule 1 and matrix metalloproteinase-9) and angiogenic C-X-C (CXC) receptor 4 and vascular endothelial growth factor) biomarkers. When examined for serum and tissue levels of AKBA, a dose-dependent increase in the levels of the drug was detected, indicating its bioavailability. Thus, our findings suggest that this boswellic acid analog can inhibit the growth and metastasis of human CRC in vivo through downregulation of cancer-associated biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: To facilitate the clinical translation of F-fluoroacetate (F-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of F-FACE were determined in non-human primates. Methods: F-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with F-FACE (165.4 ± 28.5 MBq), followed by dynamic positron emission tomography (PET) imaging of the thoracoabdominal area during 0-30 min post-injection and static whole-body PET imaging at 40, 100, and 170 min. Serial blood samples and a urine sample were obtained from each animal to determine the time course of F-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of F-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of F-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans. Results: The blood clearance of F-FACE exhibited bi-exponential kinetics with half-times of 4 and 250 min for the fast and slow phases, respectively. A rapid accumulation of F-FACE-derived radioactivity was observed in the liver and kidneys, followed by clearance of the radioactivity into the intestine and the urinary bladder. Radio-HPLC analyses of blood and urine samples demonstrated that F-fluoride was the only detectable radiolabeled metabolite at the level of less than 9% of total radioactivity in blood at 180 min after the F-FACE injection. The uptake of free F-fluoride in the bones was insignificant during the course of the imaging studies. No significant changes in ECG, CBC, liver enzymes, or renal function were observed. The estimated effective dose for an adult human is 3.90-7.81 mSv from the administration of 185-370 MBq of F-FACE. Conclusions: The effective dose and individual organ radiation absorbed doses from administration of a diagnostic dosage of F-FACE are acceptable. From a pharmacologic perspective, diagnostic dosages of F-FACE are non-toxic in primates and, therefore, could be safely administered to human patients for PET imaging. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies demonstrated that the lactose-binding protein (hepatocellular carcinoma-intestine-pancreas and pancreatitis-associated proteins (HIP/PAP)) is upregulated >130 times in peritumoral pancreatic tissue as compared to normal pancreatic tissue. Therefore, we developed a new radiolabeled ligand of HIP/PAP, the ethyl-β-D-galactopyranosyl-(1,4')-2'-deoxy-2'-[¹⁸F]fluoro-β-D-glucopyranoside (Et-[¹⁸F]FDL) for noninvasive imaging of pancreatic carcinoma using positron emission tomography and computerized tomography (PET/CT).Methods: The novel precursor and radiolabeling methods for synthesis of Et-[¹⁸F]FDL produced no isomers; the average decay-corrected radiochemical yield was 68%, radiochemical purity >99%, and specific activity >74 GBq/µmol. The radioligand properties of Et-[¹⁸F]FDL were evaluated using an ex vivo autoradiography and immunohistochemistry in pancreatic tissue sections obtained from mice-bearing orthotopic pancreatic tumor xenografts.Results and Discussion: Et-[¹⁸F]FDL binding to peritumoral pancreatic tissue sections strongly correlated with HIP/PAP expression (r = 0.81) and could be completely blocked by treatment with 1 mM lactose.Conclusion: These results suggest that Et-[¹⁸F]FDL is a promising agent which should be evaluated for detection of early pancreatic carcinomas by PET/CT imaging. [ABSTRACT FROM AUTHOR]