In vivo Biodistribution of Radiolabeled Acoustic Protein Nanostructures

Purpose: Contrast-enhanced ultrasound plays an expanding role in oncology, but its applicability to molecular imaging is hindered by a lack of nanoscale contrast agents that can reach targets outside the vasculature. Gas vesicles (GVs)—a unique class of gas-filled protein nanostructures—have recently been introduced as a promising new class of ultrasound contrast agents that can potentially access the extravascular space and be modified for molecular targeting. The purpose of the present study is to determine the quantitative biodistribution of GVs, which is critical for their development as imaging agents. Procedures: We use a novel bioorthogonal radiolabeling strategy to prepare technetium-99m-radiolabeled ([99mTc])GVs in high radiochemical purity. We use single photon emission computed tomography (SPECT) and tissue counting to quantitatively assess GV biodistribution in mice. Results: Twenty minutes following administration to mice, the SPECT biodistribution shows that 84 % of [99mTc]GVs are taken up by the reticuloendothelial system (RES) and 13 % are found in the gall bladder and duodenum. Quantitative tissue counting shows that the uptake (mean ± SEM % of injected dose/organ) is 0.6 ± 0.2 for the gall bladder, 46.2 ± 3.1 for the liver, 1.91 ± 0.16 for the lungs, and 1.3 ± 0.3 for the spleen. Fluorescence imaging confirmed the presence of GVs in RES. Conclusions: These results provide essential information for the development of GVs as targeted nanoscale imaging agents for ultrasound

In vivo Biodistribution of Radiolabeled Acoustic Protein Nanostructures

Purpose: Contrast-enhanced ultrasound plays an expanding role in oncology, but its applicability to molecular imaging is hindered by a lack of nanoscale contrast agents that can reach targets outside the vasculature. Gas vesicles (GVs)—a unique class of gas-filled protein nanostructures—have recently been introduced as a promising new class of ultrasound contrast agents that can potentially access the extravascular space and be modified for molecular targeting. The purpose of the present study is to determine the quantitative biodistribution of GVs, which is critical for their development as imaging agents. Procedures: We use a novel bioorthogonal radiolabeling strategy to prepare technetium-99m-radiolabeled ([99mTc])GVs in high radiochemical purity. We use single photon emission computed tomography (SPECT) and tissue counting to quantitatively assess GV biodistribution in mice. Results: Twenty minutes following administration to mice, the SPECT biodistribution shows that 84 % of [99mTc]GVs are taken up by the reticuloendothelial system (RES) and 13 % are found in the gall bladder and duodenum. Quantitative tissue counting shows that the uptake (mean ± SEM % of injected dose/organ) is 0.6 ± 0.2 for the gall bladder, 46.2 ± 3.1 for the liver, 1.91 ± 0.16 for the lungs, and 1.3 ± 0.3 for the spleen. Fluorescence imaging confirmed the presence of GVs in RES. Conclusions: These results provide essential information for the development of GVs as targeted nanoscale imaging agents for ultrasound

Filtration Improves the Performance of a High-Throughput Screen for Anti-Mycobacterial Compounds

The tendency for mycobacteria to aggregate poses a challenge for their use in microplate based assays. Good dispersions have been difficult to achieve in high-throughput screening (HTS) assays used in the search for novel antibacterial drugs to treat tuberculosis and other related diseases. Here we describe a method using filtration to overcome the problem of variability resulting from aggregation of mycobacteria. This method consistently yielded higher reproducibility and lower variability than conventional methods, such as settling under gravity and vortexing

UNC1062, a new and potent Mer inhibitor

Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development

SN 2022crv: IIb, Or Not IIb: That is the Question

We present optical and near-infrared observations of SN~2022crv, a stripped envelope supernova in NGC~3054, discovered within 12 hrs of explosion by the Distance Less Than 40 Mpc Survey. We suggest SN~2022crv is a transitional object on the continuum between SNe Ib and SNe IIb. A high-velocity hydrogen feature ($\sim$$-$20,000 -- $-$16,000 $\rm km\,s^{-1}$) was conspicuous in SN~2022crv at early phases, and then quickly disappeared around maximum light. By comparing with hydrodynamic modeling, we find that a hydrogen envelope of $\sim 10^{-3}$ \msun{} can reproduce the behaviour of the hydrogen feature observed in SN~2022crv. The early light curve of SN~2022crv did not show envelope cooling emission, implying that SN~2022crv had a compact progenitor with extremely low amount of hydrogen. The analysis of the nebular spectra shows that SN~2022crv is consistent with the explosion of a He star with a final mass of $\sim$4.5 -- 5.6 \msun{} that has evolved from a $\sim$16 -- 22 \msun{} zero-age main sequence star in a binary system with about 1.0 -- 1.7 \msun{} of oxygen finally synthesized in the core. The high metallicity at the supernova site indicates that the progenitor experienced a strong stellar wind mass loss. In order to retain a small amount of residual hydrogen at such a high metallicity, the initial orbital separation of the binary system is likely larger than $\sim$1000~$\rm R_{\odot}$. The near-infrared spectra of SN~2022crv show a unique absorption feature on the blue side of He I line at $\sim$1.005~$\mu$m. This is the first time that such a feature has been observed in a Type Ib/IIb, and could be due to \ion{Sr}{2}. Further detailed modelling on SN~2022crv can shed light on the progenitor and the origin of the mysterious absorption feature in the near infrared.Comment: 33 pages, 23 figures, submitted to Ap

Synthesis, radiolabelling and biodistribution studies of triazole derivatives for targeting melanoma

Abstract: Molecular probes that target specific markers expressed in solid tumours are in demand for cancer imaging and radionuclide therapy applications. The synthesis, characterization, and in vivo evaluation of radioiodinated triazoles designed as probes to target melanoma is described here. Compounds were prepared using a thermal click reaction between ethynylstannane and methyl 2-azidoacetate resulting in preferential formation of the corresponding 1,4-tin triazole. The primary amine of various targeting vectors was then coupled to the resulting tin triazole methyl ester. These precursors were labelled with no carrier added 123I or 125I and purified by high performance liquid chromatography to give isolated radiochemical yields between 6% and 51%, and radiochemical purities of >95% in all cases. Among the evaluated compounds, N-(2-diethylamino-ethyl)-2-(4-iodo-[1,2,3]triazol-1-yl)acetamide (7a) and N-(1-benzylpiperidin-4-yl)-2-(4-iodo-1H-1,2,3-triazol-1-yl)acetamide (7d) showed the most promising in vivo data and their 123I-labelled forms were used in single photon emission computed tomography-computed tomography (SPECT-CT) imaging studies. The imaging data showed excellent tumour visualization with a very high signal to noise ratio.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Room-Temperature Synthesis of Re(I) and Tc(I) Metallocarboranes

A series of carborane derivatives bearing guanidine substituents were prepared and characterized, and their reactivity toward Re­(I) and Tc­(I) in aqueous media was evaluated. Guanidinylation was achieved by treating 1-aminomethyl-1,2-<i>closo</i>-dodecaborane with <i>N</i>¹,<i>N</i>²-di-Boc-1<i>H</i>-pyrazole-1-carboxamidine, and the associated <i>N</i>-ethyl derivative, which produced the desired products in good (circa 50%) yield. These were deprotected and converted to the corresponding <i>nido</i>-carboranes, which, when combined with [M­(CO)₃(H₂O)₃]⁺ (M = Re and ^99mTc) at room temperature for 3 h or 35 °C for 1 h, afforded the corresponding η⁵-metallocarborane complexes. Corresponding reactions involving carboranes without basic substituents generally require microwave heating at temperatures greater than 150 °C. The rate, yields, and the temperature of the reaction appear to be dependent on the basicity of the guanidines tested. The biodistribution of two of the ^99mTc complexes, which are stable indefinitely in solution, were evaluated in vivo in CD1 mice and showed that the ^99mTc–carboranyl guanidine complexes clear key nontarget organs and tissues within one half-life (6 h) and have properties that are desirable for developing targeted molecular imaging probes