Characterization, Bioactivity, and Biodistribution of 35 kDa Hyaluronan Fragment.

It has been reported that hyaluronic acid (HA) with a 35 kDa molecular weight (HA35) acts biologically to protect tissue from injury, but its biological properties are not yet fully characterized. This study aimed to evaluate the cellular effects and biodistribution of HA35 compared to HA with a 1600 kDa molecular weight (HA1600). We assessed the effects of HA35 and HA1600 on cell migration, NO and ROS generation, and gene expression in cultured macrophages, microglia, and lymphocytes.

An eNAMPT-neutralizing mAb reduces post-infarct myocardial fibrosis and left ventricular dysfunction.

Myocardial infarction (MI) triggers adverse ventricular remodeling (VR), cardiac fibrosis, and subsequent heart failure. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is postulated to play a significant role in VR processing via activation of the TLR4 inflammatory pathway. We hypothesized that an eNAMPT specific monoclonal antibody (mAb) could target and neutralize overexpressed eNAMPT post-MI and attenuate chronic cardiac inflammation and fibrosis.

Use of radiolabeled hyaluronic acid for preclinical assessment of inflammatory injury and acute respiratory distress syndrome.

Unlabelled: Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS.

PEGylated and Non-PEGylated TCP-1 Probes for Imaging of Colorectal Cancer.

Purpose: Previous studies indicate that Tc- and fluorescent-labeled c[Cys-Thr-Pro-Ser-Pro-Phe-Ser-His-Cys]OH (TCP-1) peptides were able to detect colorectal cancer (CRC) and tumor-associated vasculature. This study was designed to characterize the targeting properties of PEGylated and non-PEGylated TCP-1 peptides for CRC imaging.

Procedures: Cell uptake of cyanine 7 (Cy7)-labeled TCP-1 probes (Cy7-PEG-TCP-1 and Cy7-TCP-1) was investigated in three CRC cell lines (human, HCT116 and HT29; mouse, CT26).

Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization.

Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma.

Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody.

Rationale: The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target.

Methods: Wild-type C57BL/6J or endothelial cell (EC)-c knockout mice (targeted EC deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model.

Imaging assessment of cardioprotection mediated by a dodecafluoropentane oxygen-carrier administered during myocardial infarction.

Introduction: The objective of this study was to investigate the cardioprotective effects of a dodecafluoropentane (DDFP)-based perfluorocarbon emulsion (DDFPe) as an artificial carrier for oxygen delivery to ischemic myocardium, using Tc-duramycin SPECT imaging.

Methods: Rat hearts with Ischemia-reperfusion (I/R) was prepared by coronary ligation for 45-min followed by reperfusion. The feasibility of Tc-duramycin in detecting myocardial I/R injury and its kinetic profile were first verified in the ischemic hearts with 2-h reperfusion (n = 6).

Characterization of TCP-1 probes for molecular imaging of colon cancer.

Molecular probes capable of detecting colorectal cancer (CRC) are needed for early CRC diagnosis. The objective of this study was to characterize c[CTPSPFSHC]OH (TCP-1), a small peptide derived from phage display selection, for targeting human CRC xenografts using technetium-99m ((99m)Tc)-labeled TCP-1 and fluorescent cyanine-7 (Cy7)-labeled form of the peptide (Cy7-TCP-1). (99m)Tc-TCP-1 was generated by modifying TCP-1 with succinimidyl-6-hydrazino-nicotinamide (S-HYNIC) followed by radiolabeling.

Detection of atherosclerotic plaques in ApoE-deficient mice using (99m)Tc-duramycin.

Unlabelled: Apoptosis of macrophages and smooth muscle cells is linked to atherosclerotic plaque destabilization. The apoptotic cascade leads to exposure of phosphatidylethanolamine (PE) on the outer leaflet of the cell membrane, thereby making apoptosis detectable using probes targeting PE. The objective of this study was to exploit capabilities of a PE-specific imaging probe, (99m)Tc-duramycin, in localizing atherosclerotic plaque and assessing plaque evolution in apolipoprotein-E knockout (ApoE(-/-)) mice.

Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin.

The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression.

Inflammation imaging of atherosclerosis in Apo-E-deficient mice using a (99m)Tc-labeled dual-domain cytokine ligand.

Unlabelled: Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) play a critical role in initiating and accelerating atherosclerosis. This study evaluated the imaging properties of (99m)Tc-TNFR2-Fc-IL-1RA ((99m)Tc-TFI), a dual-domain cytokine radioligand that targets TNF-α and IL-1β pathways, in assessing atherosclerosis development in apolipoprotein-E-deficient (ApoE(-)(/)(-)) mice.

Methods: The feasibility and specificity of detecting atherosclerosis with (99m)Tc-TFI SPECT imaging were investigated in ApoE(-)(/)(-) and ApoE(+)(/)(+) mice.

Ultrasound current source density imaging of the cardiac activation wave using a clinical cardiac catheter.

Ultrasound current source density imaging (UCSDI), based on the acoustoelectric (AE) effect, is a noninvasive method for mapping electrical current in 4-D (space + time). This technique potentially overcomes limitations with conventional electrical mapping procedures typically used during treatment of sustained arrhythmias. However, the weak AE signal associated with the electrocardiogram is a major challenge for advancing this technology.

SPECT imaging of inflammatory response in ischemic-reperfused rat hearts using a 99mTc-labeled dual-domain cytokine ligand.

Unlabelled: Soluble tumor necrosis factor (TNF) receptor-2 (TNFR2) and interleukin-1 receptor antagonist (IL-1ra) were fused to the Fc portion of IgG1 using recombinant DNA technology. The resulting dual-domain cytokine ligand, TNFR2-Fc-IL-1ra, specifically binds to TNF and to the type I IL-1 receptor (IL-1RI). This study was designed to characterize the kinetic profile of (99m)Tc-labeled TNFR2-Fc-IL-1ra (TFI) for imaging inflammatory response in an ischemic-reperfused (IR) rat heart model.

Imaging of rat cerebral ischemia-reperfusion injury using(99m)Tc-labeled duramycin.

Objectives: Prompt identification of necrosis and apoptosis in the infarct core and penumbra region is critical in acute stroke for delineating the underlying ischemic/reperfusion molecular pathologic events and defining therapeutic alternatives. The objective of this study was to investigate the capability of (99m)Tc-labeled duramycin in detecting ischemia-reperfusion injury in rat brain after middle cerebral artery (MCA) occlusion.

Methods: Ischemic cerebral injury was induced in ten rats by vascular insertion of a nylon suture in the left MCA for 3 hr followed by 21-24hr reperfusion.

Characterization of 99mTc-labeled cytokine ligands for inflammation imaging via TNF and IL-1 pathways.

Introduction: TNFR2-Fc and IL-1ra-Fc are recombinant cytokine ligands that target TNF and IL-1. TNFR2-Fc-IL-1ra, a dual-domain agent that incorporates both ligands, allows bifunctional binding of IL-1 receptors and TNF. This study was designed to characterize (99m)Tc-labeled forms of these ligands, (99m)Tc-IL-1ra-Fc (IF), (99m)Tc-TNFR2-Fc (TF), and (99m)Tc-TNFR2-Fc-IL-1ra (TFI), for inflammation imaging.

Detection of myocardial ischemia-reperfusion injury using a fluorescent near-infrared zinc(II)-dipicolylamine probe and 99mTc glucarate.

A fluorescent zinc 2,2'-dipicolylamine coordination complex PSVue®794 (probe 1) is known to selectively bind to phosphatidylserine exposed on the surface of apoptotic and necrotic cells. In this study, we investigated the cell death targeting properties of probe 1 in myocardial ischemia-reperfusion injury. A rat heart model of ischemia-reperfusion was used.

A (99m)Tc-labeled dual-domain cytokine ligand for imaging of inflammation.

Introduction: Interleukin (IL)-1 and IL-18 are potent proinflammatory cytokines in inflammation-related diseases. Their actions are regulated by IL-1 receptor antagonist (IL-1ra) and IL-18 binding protein (IL-18bp). This study was designed to (99m)Tc-radiolabel an IL-1ra and IL-18bp dual-domain cytokine ligand, IL-18bp-Fc-IL-1ra, for specific inflammation targeting.

Synthesis and preliminary evaluation of radiolabeled bis(zinc(II)-dipicolylamine) coordination complexes as cell death imaging agents.

The aim of this study was the development of (⁹⁹m)Tc labeled bis(zinc(II)-dipicolylamine) (Zn²⁺-DPA) coordination complexes, and the in vivo evaluation of their usefulness as radiotracers for the detection of cell death. DPA ligand 1 was labeled with (⁹⁹m)Tc via the (⁹⁹m)Tc-tricarbonyl core ([(⁹⁹m)Tc(CO)₃-1]³⁺) or via HYNIC ((⁹⁹m)Tc-HYNIC-1) in good radiochemical yields. Highest in vitro stabilities were demonstrated for [(⁹⁹m)Tc(CO)₃-1]³⁺.

Kinetic characterization of a novel cationic (99m)Tc(I)-tricarbonyl complex, (99m)Tc-15C5-PNP, for myocardial perfusion imaging.

Background: Intense liver uptake of (99m)Tc-sestamibi (MIBI) often interferes with visualization of myocardial perfusion in the inferior wall of the left ventricle. To develop improved myocardial perfusion agents, crown ether-containing dithiocarbamates and bisphosphines have been introduced in recent years. This study was designed to investigate the myocardial imaging properties and in vivo kinetics of a cationic (99m)Tc(I)-tricarbonyl complex, (99m)Tc-15C5-PNP, in comparison with MIBI.