Re and^99mTc complexes of BodP₃ – multi-modality imaging probes

A fluorescent tridentate phosphine, BodP(3) (2), forms rhenium complexes which effectively image cancer cells. Related technetium analogues are also readily prepared and have potential as dual SPECT/fluorescent biological probes

The ATLAS fast tracKer system

The ATLAS Fast TracKer (FTK) was designed to provide full tracking for the ATLAS high-level trigger by using pattern recognition based on Associative Memory (AM) chips and fitting in high-speed field programmable gate arrays. The tracks found by the FTK are based on inputs from all modules of the pixel and silicon microstrip trackers. The as-built FTK system and components are described, as is the online software used to control them while running in the ATLAS data acquisition system. Also described is the simulation of the FTK hardware and the optimization of the AM pattern banks. An optimization for long-lived particles with large impact parameter values is included. A test of the FTK system with the data playback facility that allowed the FTK to be commissioned during the shutdown between Run 2 and Run 3 of the LHC is reported. The resulting tracks from part of the FTK system covering a limited η-ϕ region of the detector are compared with the output from the FTK simulation. It is shown that FTK performance is in good agreement with the simulation. © The ATLAS collaboratio

Targeting prostate cancer cells with PSMA inhibitor-guided gold nanoparticles

Prostate-specific membrane antigen (PSMA) is a notable biomarker for diagnostic and therapeutic applications in prostate cancer. Gold nanoparticles (AuNPs) provide an attractive nanomaterial platform for combining a variety of targeting, imaging, and cytotoxic agents into a unified device for biomedical research. In this study, we present the generation and evaluation of the first AuNP system functionalized with a small molecule phosphoramidate peptidomimetic inhibitor for the targeted delivery to PSMA-expressing prostate cancer cells. The general approach involved the conjugation of streptavidin-coated AuNPs with a biotin-linked PSMA inhibitor (CTT54) to generate PSMA-targeted AuNPs. In vitro evaluations of these targeted AuNPs were conducted to determine PSMA-mediated and time-dependent binding to PSMA-positive LNCaP cells. The PSMA-targeted AuNPs exhibited significantly higher and selective binding to LNCaP cells compared to control non-targeted AuNPs, thus demonstrating the feasibility of this approach

The hydrazide/hydrazone click reaction as a biomolecule labeling strategy for M(CO)3 (M = Re, 99mTc) radiopharmaceuticals

Facile reactivity of hydrazides and aldehydes was explored as potential coupling partners for incorporation into M(CO) 3 (M = Re, 99m Tc) based radiopharmaceuticals. Both ‘click, then chelate’ and ‘prelabel, then click’ synthetic routes produced identical products in high yields and lacked metal-hydrazide/-hydrazone interactions, highlighting the potential of this click strategy

212Pb-Labeled Antibody 225.28 Targeted to Chondroitin Sulfate Proteoglycan 4 for Triple-Negative Breast Cancer Therapy in Mouse Models

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in the metastasis and recurrence of TNBC. Chondroitin sulfate proteoglycan 4 (CSPG4) is overexpressed on differentiated tumor cells and CICs obtained from TNBC patient specimens, suggesting that CSPG4 may be a clinically relevant target for the imaging and therapy of TNBC. The purpose of this study was to determine whether α-particle radioimmunotherapy (RIT) targeting TNBC cells using the CSPG4-specific monoclonal antibody (mAb) 225.28 as a carrier was effective at eliminating TNBC tumors in preclinical models. To this end, mAb 225.28 labeled with 212Pb (212Pb-225.28) as a source of α-particles for RIT was used for in vitro Scatchard assays and clonogenic survival assays with human TNBC cells (SUM159 and 2LMP) grown as adherent cells or non-adherent CIC-enriched mammospheres. Immune-deficient mice bearing orthotopic SUM159 or 2LMP xenografts were injected i.v. with the targeted (225.28) or irrelevant isotype-matched control (F3-C25) mAbs, labeled with 99mTc, 125I, or 212Pb for in vivo imaging, biodistribution, or tumor growth inhibition studies. 212Pb-225.28 bound to adherent SUM159 and 2LMP cells and to CICs from SUM159 and 2LMP mammospheres with a mean affinity of 0.5 nM. Nearly ten times more binding sites per cell were present on SUM159 cells and CICs compared with 2LMP cells. 212Pb-225.28 was six to seven times more effective than 212Pb-F3-C25 at inhibiting SUM159 cell and CIC clonogenic survival (p < 0.05). Radiolabeled mAb 225.28 showed significantly higher uptake than radiolabeled mAb F3-C25 in SUM159 and 2LMP xenografts (p < 0.05), and the uptake of 212Pb-225.28 in TNBC xenografts was correlated with target epitope expression. 212Pb-225.28 caused dose-dependent growth inhibition of SUM159 xenografts; 0.30 MBq 212Pb-225.28 was significantly more effective than 0.33 MBq 212Pb-F3-C25 at inhibiting tumor growth (p < 0.01). These results suggest that CSPG4-specific 212Pb-225.28 is a useful reagent for RIT of CSPG4-expressing tumors, including metastatic TNBC

Cu-Free 1,3-Dipolar Cycloaddition Click Reactions To Form Isoxazole Linkers in Chelating Ligands for <i>fac</i>-[M^I(CO)₃]⁺ Centers (M = Re, ^99mTc)

Isoxazole ring formation was examined as a potential Cu-free alternative click reaction to Cu^I-catalyzed alkyne/azide cycloaddition. The isoxazole reaction was explored at macroscopic and radiotracer concentrations with the <i>fac</i>-[M^I(CO)₃]⁺ (M = Re, ^99mTc) core for use as a noncoordinating linker strategy between covalently linked molecules. Two click assembly methods (<i>click, then chelate</i> and <i>chelate, then click</i>) were examined to determine the feasibility of isoxazole ring formation with either alkyne-functionalized tridentate chelates or their respective <i>fac</i>-[M^I(CO)₃]⁺ complexes with a model nitrile oxide generator. Macroscale experiments, alkyne-functionalized chelates, or Re complexes indicate facile formation of the isoxazole ring. ^99mTc experiments demonstrate efficient radiolabeling with <i>click, then chelate</i>; however, the <i>chelate, then click</i> approach led to faster product formation, but lower yields compared to the Re analogues

Determination of Flap Survival Isolated From Wound Bed Vasculature Using a Murine Axial Flap Model

Background: Axial pattern flaps are a common reconstructive option following resection of soft tissue malignancies. We determine the early dependence of an axial flap on wound bed vasculature by isolating the underlying wound bed and depriving contact with the overlying flap. Materials and Methods: Mice were divided into 5 groups: No silicone (n = 7), silicone in the proximal 50% of the wound bed (n = 8), silicone in the distal 50% of the wound bed (n = 5), silicone over the full length of the wound bed with pedicle preservation (n = 5), and silicone over the full length of the wound bed with pedicle sacrifice (n = 5). The pedicle was the lateral thoracic artery. Daily photographs were taken, and the percent of viable flap was determined using ImageJ© software (public domain JAVA image processing program, National Institute of Health, Bethesda, MA). Percent flap viability for each group was compared to the no silicone group, which acted as the reference. Results: Mean differences in percent flap necrotic area (with 95% confidence interval) compared to the no silicone group were −0.15% (−15.09 to 14.09), 2.07% (−5.26 to 9.39), 2.98% (−10.98 to 16.94), and 14.21% (0.48 to 27.94) for the full-length silicone with preserved pedicle, proximal silicone, distal silicone, and full-length silicone with sacrificed pedicle groups, respectively. The full-length silicone with sacrificed pedicle group had a significant difference in flap viability ( P = .045) compared to the no silicone group. Conclusion: We investigate the role of the wound bed vasculature in a murine axial flap model and demonstrate that the wound bed vasculature is not essential for early distal flap survival. </jats:p