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The Mesenchymal Epithelial Transition (MET) receptor tyrosine kinase is upregulated or mutated in 5% of non-small-cell lung cancer (NSCLC) patients and overexpressed in multiple other cancers. We sought to develop a novel single-domain camelid antibody with high affinity for MET that could be used to deliver conjugated payloads to MET expressing cancers. From a naïve camelid variable-heavy-heavy (VHH) domain phage display library, we identified a VHH clone termed 1E7 that displayed high affinity for human MET and was cross-reactive with MET across multiple species. When expressed as a bivalent human Fc fusion protein, 1E7-Fc was found to selectively bind to EBC-1 (MET amplified) and UW-Lung 21 (MET exon 14 mutated) cell lines by flow cytometry and immunofluorescence imaging. Next, we investigated the ability of [ 89 Zr]Zr-1E7-Fc to detect MET expression in vivo by PET/CT imaging. [ 89 Zr]Zr-1E7-Fc demonstrated rapid localization and high tumor uptake in both xenografts with a %ID/g of 6.4 and 5.8 for EBC-1 and UW-Lung 21 at 24 h, respectively. At the 24 h time point, clearance from secondary and nontarget tissues was also observed. Altogether, our data suggest that 1E7-Fc represents a platform technology that can be employed to potentially both image and treat MET-altered NSCLC.

Cobalt-sarcophagine complexes exhibit high kinetic inertness under various stringent conditions, but there is limited literature on radiolabeling and in vivo positron emission tomography (PET) imaging using no carrier added 55 Co. To fill this gap, this study first investigates the radiolabeling of DiAmSar (DSar) with 55 Co, followed by stability evaluation in human serum and EDTA, pharmacokinetics in mice, and a direct comparison with [ 55 Co]CoCl 2 to assess differences in pharmacokinetics. Furthermore, the radiolabeling process was successfully used to generate the NTSR1-targeted PET agent [ 55 Co]Co-NT-Sarcage (a DSar-functionalized SR142948 derivative) and administered to HT29 tumor xenografted mice. The [ 55 Co]Co-DSar complex can be formed at 37 °C with purity and stability suitable for preclinical in vivo radiopharmaceutical applications, and [ 55 Co]Co-NT-Sarcage demonstrated prominent tumor uptake with a low background signal. In a direct comparison with [ 64 Cu]Cu-NT-Sarcage, [ 55 Co]Co-NT-Sarcage achieved a higher tumor-to-liver ratio but with overall similar biodistribution profile. These results demonstrate that Sar would be a promising chelator for constructing Co-based radiopharmaceuticals including 55 Co for PET and 58m Co for therapeutic applications.

The therapeutic potential of the Meitner-Auger- and conversion-electron emitting radionuclide 119 Sb remains unexplored because of the difficulty of incorporating it into biologically targeted compounds. To address this challenge, we report the development of 119 Sb production from electroplated tin cyclotron targets and its complexation by a novel trithiol chelate. The chelation reaction occurs in harsh solvent conditions even in the presence of large quantities of tin, which are necessary for production on small, low energy (16 MeV) cyclotrons. The 119 Sb-trithiol complex has high stability and can be purified by HPLC. The third generation trithiol chelate and the analogous stable nat Sb-trithiol compound were synthesized and characterized, including by single-crystal X-ray diffraction analyses.

Nuclear medicine leverages different types of radiometals for disease diagnosis and treatment, but these applications usually require them to be stably chelated. Given the often-disparate chemical properties of these radionuclides, it is challenging to find a single chelator that binds all of them effectively. Toward addressing this problem, we recently reported a macrocyclic chelator macrodipa with an unprecedented "dual-size-selectivity" pattern for lanthanide (Ln 3+ ) ions, characterized by its high affinity for both the large and the small Ln 3+ ( J. Am. Chem. Soc , 2020, 142, 13500). Here, we describe a second-generation "macrodipa-type" ligand, py-macrodipa. Its coordination chemistry with Ln 3+ was thoroughly investigated experimentally and computationally. These studies reveal that the Ln 3+ -py-macrodipa complexes exhibit enhanced thermodynamic and kinetic stabilities compared to Ln 3+ -macrodipa, while retaining the unusual dual-size selectivity. Nuclear medicine applications of py-macrodipa for chelating radiometals with disparate chemical properties were assessed using the therapeutic 135 La 3+ and diagnostic 44 Sc 3+ radiometals representing the two size extremes within the rare-earth series. Radiolabeling and stability studies demonstrate that the rapidly formed complexes of these radionuclides with py-macrodipa are highly stable in human serum. Thus, in contrast to gold standard chelators like DOTA and macropa, py-macrodipa can be harnessed for the simultaneous, efficient binding of radiometals with disparate ionic radii like La 3+ and Sc 3+ , signifying a substantial achievement in nuclear medicine. This concept could enable the facile incorporation of a breadth of medicinally relevant radiometals into chemically identical radiopharmaceutical agents. The fundamental coordination chemistry learned from py-macrodipa provides valuable insight for future chelator development.

Pancreatic cancer is highly aggressive, with a median survival time of less than 6 months and a 5-year overall survival rate of around 7%. The poor prognosis of PaCa is largely due to its advanced stage at diagnosis and the lack of efficient therapeutic options. Thus, the development of an efficient, multifunctional PaCa theranostic system is urgently needed. Overexpression of tissue factor (TF) has been associated with increased tumor growth, angiogenesis, and metastasis in many malignancies, including pancreatic cancer. Herein, we propose the use of a TF-targeted monoclonal antibody (ALT836) conjugated with the pair 86/90 Y as a theranostic agent against pancreatic cancer. For methods, serial PET imaging with 86 Y-DTPA-ALT836 was conducted to map the biodistribution the tracer in BXPC-3 tumor-bearing mice. 90 Y-DTPA-ALT836 was employed as a therapeutic agent that also allowed tumor burden monitoring through Cherenkov luminescence imaging. The results were that the uptake of 86 Y-DTPA-ALT836 in BXPC-3 xenograft tumors was high and increased over time up to 48 h postinjection (p.i.), corroborated through ex vivo biodistribution studies and further confirmed by Cherenkov luminescence Imaging. In therapeutic studies, 90 Y-DTPA-ALT836 was found to slow tumor growth relative to the control groups and had significantly smaller ( p < 0.05) tumor volumes 1 day p.i. Histological analysis of ex vivo tissues revealed significant damage to the treated tumors. The conclusion is that the use of the 86/90 Y theranostic pair allows PET imaging with excellent tumor-to-background contrast and treatment of TF-expressing pancreatic tumors with promising therapeutic outcomes.

44 Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc 3+ ion with nonmacrocyclic chelator H 4 pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques ( 1 H, 13 C, 1 H- 13 C HSQC, 1 H- 13 C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)] - presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)] - was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)] - (24.7) and [Sc(DOTA)] - (23.9). In radiolabeling, [ 44 Sc][Sc(pypa)] - formed efficiently at RT in 15 min over a range of pH (2-5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H 4 pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.

Angiogenesis is widely recognized as one of the hallmarks of cancer. Therefore, imaging and therapeutic agents targeted to angiogenic vessels may be widely applicable in many types of cancer. To this end, the theranostic isotope pair, 86 Y and 90 Y, were used to create a pair of agents for targeted imaging and therapy of neovasculature in murine breast cancer models using a chimeric anti-CD105 antibody, TRC105. Serial positron emission tomography imaging with 86 Y-DTPA-TRC105 demonstrated high uptake in 4T1 tumors, peaking at 9.6 ± 0.3%ID/g, verified through ex vivo studies. Additionally, promising results were obtained in therapeutic studies with 90 Y-DTPA-TRC105, wherein significantly ( p < 0.05) decreased tumor volumes were observed for the targeted treatment group over all control groups near the end of the study. Dosimetric extrapolation and tissue histological analysis corroborated trends found in vivo. Overall, this study demonstrated the potential of the pair 86/90 Y for theranostics, enabling personalized treatments for cancer.

Nowadays, SWCNTs are envisaged to enhance the charge separation or transport of conjugated polymer-fullerene derivatives blends. In this work we studied, by means of ultrafast transient absorption spectroscopy, three components blends in which commercially available SWCNTs are added to the standard bulk heterojunction. We explored three different configurations that give rise to diverse interfacing scenarios. We found strong evidence of a direct hole transfer from photoexcited SWCNTs to the P3HT polymer. The transfer efficiency depends on the interface configuration. It is the highest for the blend where we achieve closer contact between the (6,5) SWCNTs and the polymer. When the polymer blend is deposited on top of the nanotube film or the nanotube film is deposited onto the polymer blend, the process is slowed down due to less or missing interfacing of the carbon nanotubes with the polymer chains. Additionally we demonstrate a cascading effect in the electron path, which stabilizes charge separation by further transferring the electron left behind by hole transfer to the polymer to the adjacent (7,5) SWCNTs. Our results highlight the potential of semiconducting SWCNTs to improving the performance of organic solar cells.

The performance of organic photovoltaic devices (OPV) with nanostructured polymer:perylene diimide (PDI) photoactive layers approaches the levels of the corresponding polymer:fullerene systems. Nevertheless, a coherent understanding of the difficulty for PDI-based OPV devices to deliver high power conversion efficiencies remains elusive. Here we perform a comparative study of a set of four different polymer:PDI OPV model systems. The different device performances observed are attributed to differences in the nanostructural motif of these composites, as determined by wide-angle X-ray scattering (WAXS) measurements. Long-range structural order in the PDI domain dictates (i) the stabilization energy and (ii) the concentration of the PDI excimers in the composites. The quenching of the PDI excimer photoluminescence (PL) is found to be insensitive to the former, but it depends on the latter. High PL quenching occurs for the low concentration of PDI excimers that are formed in PDI columns with a length comparable to the PDI excimer diffusion length. The stabilization of the PDI excimer state increases as the long-range order in the PDI domains improves. The structural order of the PDI domains primarily affects charge transport. Electron mobility reduces as the size of the PDI domain increases, suggesting that well-ordered PDI domains suffer from poor electronic connectivity. WAXS further reveals the presence of additional intermolecular PDI interactions, other than the direct face-to-face intermolecular coupling, that introduce a substantial energetic disorder in the polymer:PDI composites. Conventional device architectures with hole-collecting ITO/PEDOT:PSS bottom electrodes are compared with inverted device architectures bearing bottom electron-collecting electrodes of ITO/ZnO. In all cases the ZnO-functionalized devices surpass the performance of the conventional device analogues. X-ray photoelectron spectroscopy explains that in, Pedot: PSS-functionalized devices, the PDI component preferentially segregates closer to the hydrophilic, Pedot: PSS electrode, thus impeding the efficient charge extraction and limiting device photocurrent.