Prominent Uptake Research Articles

Copper selenide sensitized low-cost porous coordination polymers towards efficient capture trace gaseous elemental mercury

Mercury, as a highly toxic atmospheric pollutant, poses serious hazards to global health and ecosystems. Developing low-cost sorbents with simultaneous fast capture rate and large uptake capacity to reduce elemental mercury (Hg0) emissions from industrial flue gas remains a formidable challenge. Herein, a rationally designed surfactant-assisted method was developed to construct copper selenide (CuSe) sensitized porous coordination polymers (CAU-10-H) as an efficient Hg remediator. The CuSe/CAU-10-H (0.8NC-CAU) exhibits superior near-100 % gaseous Hg0 removal efficiency over a wide temperature range (30–120 °C), implying its adaptability under different implementations. The equilibrium Hg0 adsorption capacity and initial Hg0 uptake rate of 0.8NC-CAU are 748.09 mg·g−1 and 63.21 μg·g−1·min−1, respectively, surpassing that of conventional sorbents and comparable to the benchmark materials. Furthermore, 0.8NC-CAU can adapt to harsh conditions with different flue gas impurities containing SO2, NO, and H2O to maintain high selectivity and stability, which is advantageous for real-world applications. Density functional theory (DFT) reveals that unsaturated selenium ligands as electron acceptors are critical affinity sites for facilitating Hg0 capture, resulting in stable HgSe species. More importantly, the facile preparation, prominent uptake capacity, and rapid capture rate of the 0.8NC-CAU material make it cost-effective. This work proposes a potential trap for Hg0 capture from industrial flue gas and facilitates the development of hybrid-functionalized materials for environmental remediation.

Automated production of [11C]butyrate for keto body PET imaging

The report describes an updated, fully automated method for the production of [11C]butyrate, validated for use in clinical studies. A commercially available GE Tracerlab FXM synthesis module was reconfigured to allow for air-free introduction of n-propyl magnesium chloride and to incorporate Sep-Pak cartridges to simplify and shorten the purification process, as compared to purifying the product using traditional HPLC. The method takes 20 min from end-of-bombardment and reliably produces injectable doses of [11C]butyrate (8029 ± 1628 MBq (217 ± 44 mCi), 14 % radiochemical yield based on [11C]CO2, non-decay corrected) in high radiochemical purity (>97 %), n = 3. With radiotracer in hand, PET scans of rats confirmed uptake of the radiopharmaceutical in the brain. Rat biodistribution data was obtained and used in conjunction with OLINDA software to determine an estimated human total body effective dose of 3.20 × 10−3 mSv/MBq (1.19 × 10−2 rem/mCi), along with preliminary rodent PET imaging that confirmed brain uptake. Lastly, our first human [11C]butyrate PET studies using a dynamic bolus injection technique (n = 5), with a graphical Logan analysis using a white matter reference region, confirmed good radiotracer uptake in the brain and with relatively more prominent uptake in the cerebellar hemispheres, vermis, cingulum cortex and the thalami.

18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients.

Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [18F]MFBG and [123I]MIBG. [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.

Effective boron removal from synthetic wastewater by multi-stage calcium-based chemical oxo-precipitation process

Chemical oxo-precipitation (COP) is a facile method to remove boron by the precipitation of perborate salts with the aid of hydrogen peroxide. Despite that the COP using barium precipitant (Ba–COP) has been advanced to provide excellent boron removal, the production of hazardous sludge limits the implementation. This study aims to improve the COP using calcium precipitant (Ca–COP) to provide boron removal comparable to COP without the production of hazardous waste. In addition to the precipitation of calcium perborate, the formation of calcium carbonate and calcium peroxide played decisive roles in the Ca–COP. The instant precipitation of calcium perborates (CaPBs) at pH 11 could eliminate boron from 1000 to 30 mg-B/L in 15 min. The prominent uptake of atmospheric CO2 induced the precipitation of calcium carbonate and consumed calcium ion, which resulted in the increment in boron level due to the incongruent dissolution of CaPBs. The formation of calcium carbonate and calcium perborate provided an additional route to remove boron through sorption. Accordingly, a multi-stage Ca–COP process was developed to remove precipitated CaPBs for preventing the incongruent dissolution and to dose calcium precipitant multiple times to induce the sorptive removal. The proposed process could eliminate boron from 1000 to 5 mg-B/L, which is comparable to the state-of-art Ba–COP process with 45% of its cost.

Metastatic pulmonary calcification in patients on long-term dialysis

A 72-year-old woman was on dialysis for 44 years. Chest radiography revealed hazy opacity in the upper lung field (Figure 1A). Chest computed tomography (CT) showed patchy ground-glass opacities and fusion with overt calcification (Figure 1B). She had mild hypoxemia and impaired diffusing capacity. 99mTc-HMDP scintigraphy showed a prominent uptake in the lung fields corresponding to the patchy opacities (Figure 1C), indicating the accumulation of calcium in the lung parenchyma.

The Synthesis and Initial Evaluation of MerTK Targeted PET Agents.

MerTK (Mer tyrosine kinase), a receptor tyrosine kinase, is ectopically or aberrantly expressed in numerous human hematologic and solid malignancies. Although a variety of MerTK targeting therapies are being developed to enhance outcomes for patients with various cancers, the sensitivity of tumors to MerTK suppression may not be uniform due to the heterogeneity of solid tumors and different tumor stages. In this report, we develop a series of radiolabeled agents as potential MerTK PET (positron emission tomography) agents. In our initial in vivo evaluation, [18F]-MerTK-6 showed prominent uptake rate (4.79 ± 0.24%ID/g) in B16F10 tumor-bearing mice. The tumor to muscle ratio reached 1.86 and 3.09 at 0.5 and 2 h post-injection, respectively. In summary, [18F]-MerTK-6 is a promising PET agent for MerTK imaging and is worth further evaluation in future studies.

Micellar paclitaxel boosts ICD and chemo-immunotherapy of metastatic triple negative breast cancer

Triple negative breast cancer (TNBC) with easy metastasis, “cold” tumor immune microenvironment, and lack of targeted therapy remains poorly prognosed. Chemo-immunotherapy deemed as a potential treatment for TNBC is however confronted by low TNBC selectivity, pronounced systemic toxicity, and limited immunogenic cell death (ICD) induction. Here, employing clinically validated ATN peptide as a ligand and reduction-sensitive biodegradable micelles as a vehicle we constructed α5β1 integrin-targeted micellar paclitaxel (ATN-MPTX) to elicit strong and selective ICD and chemo-immunotherapy of TNBC. ATN-MPTX exhibited evident targetability and prominent uptake in α5β1 integrin-positive 4 T1 cells and induced significantly stronger ICD than free PTX and non-targeted MPTX. The therapeutic studies in 4 T1 TNBC model demonstrated that ATN-MPTX caused superior tumor accumulation and treatment efficacy to all controls. Of note, ATN-MPTX plus nano-STING agonist further augmented the immunotherapeutic effects by increasing secretion of proinflammatory cytokines and CD4+ and CD8+ T cells in the tumor and spleen while reducing Treg, leading to significantly improved inhibition of 4 T1 primary tumor and more interestingly mitigated lung metastases. This strong and selective ICD induction of ATN-MPTX renders it an interesting tool to enhance chemo-immunotherapy of TNBC.

Arginine-Arginine-Leucine Peptide Targeting Heat Shock Protein 70 for Cancer Imaging.

Arg-Arg-Leu (RRL) is a potent tumor-homing tripeptide. However, the binding target is unclear. In this study, we intended to identify the binding target of RRL and evaluate the tumor targeting of 99mTc-MAG3-RRL in vivo. Biotin-RRL, 5-TAMRA-RRL, and 99mTc-MAG3-RRL were designed to trace the binding target and tumor lesion. Immunoprecipitation-mass spectrometry was conducted to identify the candidate proteins and determination of the subcellular localization was also performed. A pull-down assay was performed to demonstrate the immunoprecipitate. Fluorescence colocalization and cell uptake assays were performed to elucidate the correlation between the selected binding protein and RRL, and the internalization mechanism of RRL. Biodistribution and in vivo imaging were performed to evaluate the tumor accumulation and targeting of 99mTc-MAG3-RRL. The target for RRL was screened to be heat shock protein 70 (HSP70). The prominent uptake distribution of RRL was concentrated in the membrane and cytoplasm. A pull-down assay demonstrated the existence of HSP70 in the biotin-RRL captured complex. Regarding fluorescence colocalization and cell uptake assays, RRL may interact with HSP70 at the nucleotide-binding domain (NBD). Clathrin-dependent endocytosis and macropinocytosis could be a vital internalization mechanism of RRL. In vivo imaging and biodistribution both demonstrated that 99mTc-MAG3-RRL can trace tumors with satisfactory accumulation in hepatoma xenograft mice. The radioactive signals accumulated in tumor lesions can be blocked by VER-155008, which can bind to the NBD of HSP70. Our findings revealed that RRL may interact with HSP70 and that 99mTc-MAG3-RRL could be a prospective probe for visualizing overexpressed HSP70 tumor sections.

ImmunoPET/NIRF/Cerenkov multimodality imaging of ICAM-1 in pancreatic ductal adenocarcinoma.

We dual-labeled an intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb) and evaluated its effectiveness for lesion detection and surgical navigation in pancreatic ductal adenocarcinoma (PDAC) via multiple noninvasive imaging approaches, including positron emission tomography (PET), near-infrared fluorescence (NIRF), and Cerenkov luminescence imaging (CLI). ICAM-1 expression in PDAC cell lines (BxPC-3 and AsPC-1) was assessed via flow cytometry and immunofluorescent staining. An ICAM-1 mAb labeled by IRDye 800CW and radionuclide zirconium-89 (denoted as [89Zr]Zr-DFO-ICAM-1-IR800) was synthesized. Its performance was validated via in vivo comparative PET/NIRF/CLI and biodistribution (Bio-D) studies in nude mice bearing subcutaneous BxPC-3/AsPC-1 tumors or orthotopic BxPC-3 tumor models using nonspecific IgG as an isotype control tracer. ICAM-1 expression was strong in the BxPC-3 and minimal in the AsPC-1 cell line. Both multimodality imaging and Bio-D data exhibited more prominent uptake of [89Zr]Zr-DFO-ICAM-1-IR800 in BxPC-3 tumors than in AsPC-1 tumors. The uptake of [89Zr]Zr-DFO-IgG-IR800 in BxPC-3 tumors was similar to that of [89Zr]Zr-DFO-ICAM-1-IR800 in AsPC-1 tumors. These results demonstrate the desirable affinity and specificity of [89Zr]Zr-DFO-ICAM-1-IR800 compared to [89Zr]Zr-DFO-IgG-IR800. Orthotopic BxPC-3 tumor foci could also be clearly delineated by [89Zr]Zr-DFO-ICAM-1-IR800. An intermodal match was achieved in the ICAM-1-targeted immunoPET/NIRF/CLI. The positive expression levels of ICAM-1 in BxPC-3 tumor tissue were further confirmed by immunohistopathology. We successfully developed a dual-labeled ICAM-1-targeted tracer for PET/NIRF/CLI of PDAC that can facilitate better diagnosis and intervention of PDAC upon clinical translation.

18F-sodium fluoride coronary uptake in patients with coronary artery bypass grafts

Abstract 18F-Sodium fluoride (18F-NaF) positron emission tomography (PET) provides an assessment of active calcification (microcalcification) across a wide range of cardiovascular conditions including coronary artery disease, carotid and penile atherosclerosis, aortic and mitral valve disease, and abdominal aortic aneurysms. To date the significance of 18F-NaF uptake in patients with coronary artery bypass grafts (CABG) is unknown. We aimed to characterize 18F-NaF activity in CABG patients. We performed 18F-NaF PET (30-min long single bed position acquisition 1h after a 250mB injection of 18F-NaF) and coronary CT angiography in patients with multivessel coronary artery disease and followed them for fatal or non-fatal myocardial infarction over 42 [31,49] months. On motion-corrected datasets we quantified the whole-vessel coronary 18F-NaF PET uptake (the coronary microcalcification activity (CMA)) by measuring the activity of voxels above the background (right atrium activity) + 2 * standard deviations threshold. All study subjects underwent a comprehensive baseline clinical assessment including evaluation of their cardiovascular risk factor profile with the SMART [Secondary Manifestations of Arterial Disease] risk score calculated, and the coronary calcium burden assessed with calcium scoring (CCS). Among 293 study participants (65±9 years; 84% male), 48 (16%) had a history of CABG. Although the majority 124/128 (97%) of coronary bypass grafts showed no uptake, 4 saphenous vein grafts presented with a CMA>0 (range: 2.5–11.5, Figure). While a similar proportion of patients with and without prior CABG showed increased coronary 18F-NaF uptake (CMA>0) (58.3% versus 71.4%, p=0.11) overall prior-CABG subjects had higher CMA (2.0 [0.3, 6.6] versus 0.6 [0, 2.7], p=0.001) and CCS (1135 [631, 2120] versus 225 [59, 542], p<0.001), respectively. In line with the differences in the calcification activity and the coronary calcium burden, the SMART risk scores were higher in CABG patients (23 [17, 28] versus 17 [12, 24], p=0.01), and these patients were also older (68±8 versus 64±8, p=0.01). Despite the aforementioned differences the incidence of myocardial infarction 5/48 (9%) versus 15/245 (6%) and MACE 6/48 (12%) versus 34/245 (14%) during follow-up between subjects with and without prior CABG was similar (p=0.44 and p=0.80, respectively). CABG patients have a higher coronary microcalcification activity on 18F-NaF PET than multivessel coronary artery disease patients without prior CABG. Despite evidence of higher 18F-NaF uptake there is no difference in outcome between these two groups. Figure 1. 18F-NaF uptake in CABG patients. (A) 63-year old male with prominent uptake in stented saphenous vein bypass grafts and native coronary arteries who experienced a non-fatal non ST elevation myocardial infarction during follow-up. (B) 70-year old male with evident uptake in native coronary arteries and only little 18F-NaF activity within coronary bypasses. Funding Acknowledgement Type of funding source: Other. Main funding source(s): National Heart, Lung, and Blood Institute/National Institute of Health (NHLBI/NIH), British Heart Foundation

A regenerable ion-imprinted magnetic biocomposite for selective adsorption and detection of Pb2+ in aqueous solution

A regenerable ion-imprinted magnetic biocomposite (IIMB) was successfully synthesized for simultaneous removal of Pb2+ using Serratia marcescens and carboxymethyl chitosan (CMC) as functional carriers, Pb2+ was utilized as the imprinted ion, while Fe3O4 served as the magnetic component. The structure and properties of IIMB were characterized by various techniques. The adsorption kinetics, isotherms and thermodynamics were applied to interpret the Pb2+ adsorption process on IIMB. The results showed the IIMB possessed prominent uptake ability toward Pb2+. The pseudo-second-order kinetic (R2 = 0.9989) and Langmuir models (R2 = 0.9555) fitted the data well. Adsorption thermodynamics revealed that the adsorption was a spontaneous endothermic reaction. The possible adsorption mechanisms involved physical adsorption, electrostatic attraction and complexing. Moreover, because Pb2+ can be specifically and strongly adsorbed on IIMB, a simple method for detection of Pb2+ was established by coupling IIMB with flame atomic absorption spectrometry (IIMB-FAAS). The developed IIMB-FAAS assay can sensitively detect Pb2+ with a linear range from 5.0 to 500.0 μg/L. The detection limit (LOD) of 0.95 μg/L as well as a quantification limit (LOQ) of 3.20 μg/L were obtained. This work proved that the IIMB could selective and efficient adsorb Pb2+, which provided some insights into wastewater treatment, water quality inspection and environmental remediation.

Technetium-99m-PEGylated dendrimer-G2-(Dabcyle-Lys6,Phe7)-pHBSP: A novel Nano-Radiotracer for molecular and early detecting of cardiac ischemic region.

In cardiac ischemic disorder, pyroglutamate helix B surface peptide (pHBSP) which derived from erythropoietin causes to increase cell stability. To improve the serum stability of pHBSP, two lipophilic amino acids Arg6, Ala7 were replaced with Fmoc-(Dabcyle)-Lys-OH and Fmoc-Phe-OH during the peptide synthesis. This peptide was subsequently conjugated to PEGylated dendrimer-G2 and labeled with 99mTcO4- to detect cardiac ischemic region. Radiochemical purity (RCP) of 99mTc-PEGylated dendrimer-G2-(Dabcyle-Lys6,Phe7)-pHBSP was evaluated by ITLC method. In addition, the radiopeptide was investigated for stability in human serum and binding affinity to hypoxic cells in myocardium H9c2 cell lines. Biodistribution and SPECT/CT scintigraphy were assessed in cardiac ischemic rats. Radiochemical yield indicated that the anionic dendrimer has a very high potential to complex formation with 99mTcO-4 (RCP>94%) which was stable in human serum with RCP 89% up to 6h. The binding of 99mTc- nanoconjugate to hypoxic cells was significantly more than normoxic cells (3-fold higher compared to normoxic cells at 1h). In biodistribution studies, erythropoietin receptor-Beta common receptor (EPO-BcR)-positive uptake in the cardiac ischemic region was 3.62±0.44% ID/g 30min post injection. SPECT imaging showed a prominent uptake of 99mTc-nanoconjugate in EPO-BcR expressing ischemic heart.

Abstract P1-02-01: HER2/neu antibody-fluorophore conjugate for intraoperative detection of HER2-positive breast cancer

Abstract Background: Although advances in neoadjuvant and adjuvant treatments have led to enhanced survival in patients with HER2 positive breast cancer, intraoperative detection of residual disease and tumor margins (including HER2 positive DCIS) remain challenging. Real-time fluorescence imaging is being used during surgery to improve tumor visualization and identify margins. However, the lack of an approved intraoperative imaging agent that is specific for HER2 expressing cancers limits the utility of fluorescence-guided surgery (FGS) in this patient population. We examined the potential of using clinically approved anti-HER2 monoclonal antibodies (mAbs), trastuzumab and pertuzumab, for the development of fluorescent immunoconjugates dual-labeled with radioactivity to enable quantitative assessment. Methods: Trastuzumab, and pertuzumab were conjugated to the near-infrared (NIR) fluorophore, IR800CW, and radiometal chelator, deferoxamine (DFO), to permit dual labeling with 89Zr (positron emitting radionuclide). To confirm retention of HER2 specificity and functionality, flow cytometry analysis of the dual-labeled immunoconjugates was performed in HER2+ (BT474, SKBR3), HER2 moderate (MCF7), and HER2− (MDA231) cell lines. Using the same cell lines, radioactive uptake studies were employed to quantitatively measure cellular uptake study using 89Zr with and without blocking doses of unlabeled mAb. In vivo optical imaging of each immunoconjugate and IgG controls was performed in BT474 and MCF7 xenografts in BALB/c (nu/nu) mice 48 hours post injection using the BrukerXtreme system. Results: In vitro results confirmed retention of receptor mediated binding on both flow cytometry and radioactive analyses. As shown in Table 1, uptake of each immunoconjugate correlated with the degree of HER2 expression. Importantly, the addition of unlabeled mAb led to a 79-93% reduction in binding to cells with the highest HER2 expression (BT474 and SKBR3). In MDA231 cells binding of the immunoconjugates was similar to the IgG control and indicates low non-specific binding. In vivo and ex vivo analysis of HER2+ and HER2 moderate xenografts demonstrated prominent tumor uptake with minimal signal in non-clearance organs. As a result, tumor-to-muscle, tumor-to-fat pad, and tumor-to-lung ratios were >5, indicating excellent contrast in key regions where surgical excisions are performed clinically. Table 1: Uptake of 89Zr-mAb-IR800 in breast cancer cell linesCell Lines% Uptake of 89Zr-PertuzumabPertuzumab Block (Unlabeled)% Uptake of 89Zr-TrastuzumabTrastuzumab Block (Unlabeled)% Uptake of 89Zr-IgGBT47449.2±14.83.7±0.036.9±5.84.6±2.61.3±0SKBR337.9±1.77.9±0.942.8±3.52.9±1.73.5±0.4MCF721.7±2.63.2±0.44.0±0.12.5±0.11.3±0.7MDA2311.9±0.40.8±0.31.0±0.31.9±0.51.3±0.7 Conclusion: This study demonstrates the potential utility of HER2-targeted FGS to improve tumor visualization, increase the likelihood of obtaining clean surgical margins, and ultimately reduce morbidity in patients with HER2 breast cancer. Citation Format: Jo Simien, Julie Voss, A.M. Thompson, S.C. Ghosh, S. AghaAmiri, A. Azhdarinia, H.S. Tran-Cao. HER2/neu antibody-fluorophore conjugate for intraoperative detection of HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-02-01.

Sensing Living Bacteria in Vivo Using d-Alanine-Derived 11C Radiotracers.

Incorporation of d-amino acids into peptidoglycan is a unique metabolic feature of bacteria. Since d-amino acids are not metabolic substrates in most mammalian tissues, this difference can be exploited to detect living bacteria in vivo. Given the prevalence of d-alanine in peptidoglycan muropeptides, as well as its role in several antibiotic mechanisms, we targeted this amino acid for positron emission tomography (PET) radiotracer development. d-[3-11C]Alanine and the dipeptide d-[3-11C]alanyl-d-alanine were synthesized via asymmetric alkylation of glycine-derived Schiff-base precursors with [11C]methyl iodide in the presence of a cinchonidinium phase-transfer catalyst. In cell experiments, both tracers showed accumulation by a wide variety of both Gram-positive and Gram-negative pathogens including Staphylococcus aureus and Pseudomonas aeruginosa. In a mouse model of acute bacterial myositis, d-[3-11C]alanine was accumulated by living microorganisms but was not taken up in areas of sterile inflammation. When compared to existing clinical nuclear imaging tools, specifically 2-deoxy-2-[18F]fluoro-d-glucose and a gallium citrate radiotracer, d-alanine showed more bacteria-specific uptake. Decreased d-[3-11C]alanine uptake was also observed in antibiotic-sensitive microbes after antimicrobial therapy, when compared to that in resistant organisms. Finally, prominent uptake of d-[3-11C]alanine uptake was seen in rodent models of discitis-osteomyelitis and P. aeruginosa pneumonia. These data provide strong justification for clinical translation of d-[3-11C]alanine to address a number of important human infections.

99mTc-D(RGD): molecular imaging probe for diagnosis of αvβ3-positive tumors.

Arginine-glycine-aspartic acid (RGD) peptide with its specific binding affinity to integrin αvβ3, is widely investigated for the development of molecular imaging probes for diagnosis of αvβ3-positive tumors. The aim of this work was to evaluate the ability of Tc- HYNIC-D(RGD), a novel retro-inverso peptidomimetic derivative for U87MG tumor (αvβ3-positive) imaging. HYNIC-D(RGD) labeled with Tc using tricine/EDDA as an exchange coligands. Single-photon emission computed tomography imaging and biodistribution study were performed in nude mice bearing U87MG xenograft tumor. The labeling yield was >95%. The radiopeptide showed high uptake value in the U87MG tumor relative to muscle after 2 hours (1.43 ± 0.05 vs. 0.22 ± 0.11 %ID/g). The tumor/muscle ratio was 6.5. Blocking experiment showed specific binding towards tumor. Single-photon emission computed tomography imaging study revealed that radiopeptide had prominent uptake in U87MG tumor. The novel Tc HYNIC- D(RGD) was demonstrated to be a useful radiotracer for the assessment of αvβ3-positive tumor in animal model. Therefore, further clinical and preclinical studies are required.

Development of Bispecific NT-PSMA Heterodimer for Prostate Cancer Imaging: A Potential Approach to Address Tumor Heterogeneity

Prostate cancer is a heterogeneous disease with a poor survival rate at late stage. In this report, a dual targeting PET agent was developed to partially address the tumor heterogeneity issue. The heterodimer F-BCN-PSMA-NT was designed to target PSMA and neurotensin receptor1 (NTR1), both of which have demonstrated great potential in prostate cancer management. The heterodimer was synthesized through the conjugation of Glu-urea-lys(Ahx) (PSMA targeting motif) and NT20.3 (NTR1 targeting motif) to a symmetric trifunctional linker, bearing an azide group for further modification. Radio-labeling was performed using strain promoted azide-alkyne click reaction with high yield. Cell based assays suggested that F-BCN-PSMA-NT has comparable or only slightly reduced binding affinity with the corresponding monomers. Small animal PET clearly demonstrated that the heterodimer probe has prominent uptake not only in NTR1 positive/PSMA negative PC-3 tumors (1.4 ± 0.3%ID/g), but also in the PSMA positive/NTR1 negative LnCap tumors (1.3 ± 0.2%ID/g). The tracer showed comparable tumor to background ratio with each monomer. In summary, prostate cancer is a heterogeneous disease in need of improved diagnostics and treatments. The PSMA-NT heterodimer represents a new class of molecules that can be used to target two distinct antigens related to prostate cancer. In addition to the imaging applications demonstrated in this study, the agent also holds great potential on the treatment of heterogeneous prostate cancer.

Leukemic arthritis and severe hypercalcemia in a man with chronic myeloid leukemia: a case report and review of the literature

BackgroundPatients with chronic myeloid leukemia typically present with high white blood cell counts revealed during annual checkups. Leukemic arthritis and hypercalcemia are rare manifestations in patients with chronic myeloid leukemia.Case presentationA 35-year-old Thai man who had been diagnosed with chronic myeloid leukemia in the chronic phase developed blast crisis while he was receiving ongoing treatment with imatinib at 400 mg/day. Initially, he presented with oligoarthritis in both knees and ankles. A bone scintigraphy showed a prominent bony uptake, with a symmetrical, increased uptake in many bone areas. Induction therapy with a 7 + 3 induction regimen was prescribed in conjunction with 600 mg of imatinib once daily before switching to 140 mg of dasatinib. He subsequently developed severe hypercalcemia (total serum calcium of 17.8 mg/dL), with generalized osteolytic lesions detected on a bone survey. His serum vitamin D level was 50.64 ng/mL, while the serum parathyroid hormone level was 9.82 pg/mL. Despite the administration of an aggressive intravenously administered hydration, intravenously administered calcitonin, and 600 mg/day of imatinib, the severe hypercalcemia was refractory. We therefore decided to prescribe 20 mg/day of intravenously administered dexamethasone; fortunately, his serum calcium level decreased dramatically to normal range within a few days.ConclusionsAlthough leukemic arthritis and severe hypercalcemia are extraordinary presentations in patients with chronic myeloid leukemia, the advanced phase of the disease might bring on these symptoms. Apart from parathyroid hormone-related protein-related hypercalcemia, vitamin D is a mechanism of humoral-mediated hypercalcemia.

A magnetically recyclable chitosan composite adsorbent functionalized with EDTA for simultaneous capture of anionic dye and heavy metals in complex wastewater

Ascribing to their significant differences in physicochemical properties, it is extremely challenging to treat complex wastewater containing more than one class of pollutants via one-step treatment. Here, we focused on disposal of complex wastewater bearing organic dye and heavy metal by using adsorptive method. Thus, we successfully fabricated a novel and versatile EDTA functionalized magnetic chitosan composite adsorbent (Fe3O4-CS/EDTA) for simultaneous removal of methyl blue(MB) and heavy metal (Pb(II) and Cu(II)) from complex wastewater. In this setting, EDTA chelating groups are mainly responsible for the binding of heavy metals, while the protonated amino groups of CS adsorb anionic dyes through electrostatic interaction, thus enabling the simultaneous capture of these two classes of pollutants. In mono-pollutant system, the resulting material showed prominent uptake ability toward MB, Pb(II), and Cu(II) with uptake characteristics of pseudo-second-order model and Langmuir isotherm equation. The maximum monolayer uptake capacities were determined to be 225.0 mg g−1 of Cu(II), 220.0 mg g−1 of Pb(II), and 459.9 mg g−1 of MB at 303 K, respectively. More interestingly, in metal-MB binary system, uptake of MB was almost not affected by coexisting metal. While the uptake capacity of Cu(II) or Pb(II) was enhanced with increasing of MB concentration. These results demonstrated the synergetic removal performance of as-designed adsorbent toward cationic metal ions and anionic dye. Moreover, as-resulting adsorbent showed no significant adsorption capacity loss even after 8 runs of sorption-desorption cycle, manifesting that it is of great stability and could be regarded as a promising candidate adsorbent for treating complex wastewater. This study provides some insights into the design of highly efficient adsorbents with spatially separated sorption sites for disposing complex wastewater bearing organic and metallic contaminants.

Assessment of brain beta-amyloid deposition in transgenic mouse models of Alzheimer\u2019s disease with PET imaging agents 18F-flutemetamol and 18F-florbetaben

BackgroundAlthough amyloid beta (Aβ) imaging is widely used for diagnosing and monitoring Alzheimer’s disease in clinical fields, paralleling comparison between 18F-flutemetamol and 18F-florbetaben was rarely attempted in AD mouse model. We performed a comparison of Aβ PET images between 18F-flutemetamol and 18F-florbetaben in a recently developed APPswe mouse model, C57BL/6-Tg (NSE-hAPPsw) Korl.ResultsAfter an injection (0.23 mCi) of 18F-flutemetamol and 18F-florbetaben at a time interval of 2–3 days, we compared group difference of SUVR and kinetic parameters between the AD (n = 7) and control (n = 7) mice, as well as between 18F-flutemetamol and 18F-florbetaben image. In addition, bio-distribution and histopathology were conducted. With visual image and VOI-based SUVR analysis, the AD group presented more prominent uptake than did the control group in both the 18F-florbetaben and 18F-flutemetamol images. With kinetic analysis, the 18F-florbetaben images showed differences in K1 and k4 between the AD and control groups, although 18F-flutemetamol images did not show significant difference. 18F-florbetaben images showed more prominent cortical uptake and matched well to the thioflavin S staining images than did the 18F-flutemetamol image. In contrast, 18F-flutemetamol images presented higher K1, k4, K1/k2 values than those of 18F-florbetaben images. Also, 18F-flutemetamol images presented prominent uptake in the bowel and bladder, consistent with higher bio-distribution in kidney, lung, blood and heart.ConclusionsCompared with 18F-flutemetamol images, 18F-florbetaben images showed prominent visual uptake intensity, SUVR, and higher correlations with the pathology. In contrast, 18F-flutemetamol was more actively metabolized than was 18F-florbetaben (Son et al. in J Nucl Med 58(Suppl 1):S278, 2017].

Imaging c-Met expression using 18F-labeled binding peptide in human cancer xenografts.

Objectivesc-Met is a receptor tyrosine kinase shown inappropriate expression and actively involved in progression and metastasis in most types of human cancer. Development of c-Met-targeted imaging and therapeutic agents would be extremely useful. Previous studies reported that c-Met-binding peptide (Met-pep1, YLFSVHWPPLKA) specifically targets c-Met receptor. Here, we evaluated 18F-labeled Met-pep1 for PET imaging of c-Met positive tumor in human head and neck squamous cell carcinoma (HNSCC) xenografted mice.Methodsc-Met-binding peptide, Met-pep1, was synthesized and labeled with 4-nitrophenyl [18F]-2-fluoropropionate ([18F]-NPFP) ([18F]FP-Met-pep1). The cell uptake, internalization and efflux of [18F]FP-Met-pep1 were assessed in UM-SCC-22B cells. In vivo pharmacokinetics, blocking and biodistribution of the radiotracers were investigated in tumor-bearing nude mice by microPET imaging.ResultsThe radiolabeling yield for [18F]FP-Met-pep1 was over 55% with 97% purity. [18F]FP-Met-pep1 showed high tumor uptake in UM-SCC-22B tumor-bearing mice with clear visualization. The specificity of the imaging tracer was confirmed by significantly decreased tumor uptake after co-administration of unlabeled Met-pep1 peptides. Prominent uptake and rapid excretion of [18F]FP-Met-pep1 was also observed in the kidney, suggesting this tracer is mainly excreted through the renal-urinary routes. Ex vivo biodistribution showed similar results that were consistent with microPET imaging data.ConclusionsThese results suggest that 18F-labeled c-Met peptide may potentially be used for imaging c-Met positive HNSCC cancer in vivo and for c-Met-targeted cancer therapy.