Odd–Even Effects in Charge Transport through Self-Assembled Monolayer of Alkanethiolates

It has been demonstrated in experiments that charge transport through self-assembled monolayers (SAMs) of alkanethiolates shows intriguing odd–even effects when the number of methylene groups changes. Most previously reported theoretical investigations were based on semiempirical methods or largely simplified models and the quantum origin of the observed odd–even effects is still unclear. In the current study, we performed ab initio calculations for electronic and transport properties of SAM of alkanethiolates on Ag [111] surface. Extensive density functional theory (DFT) based energy minimizations of the system geometries were conducted to pinpoint the most accurate geometries amenable to experimental observations. The recently proposed dual mean field (DMF) approach that includes bias-induced nonequilibrium effects in density functionals is used to determine current–voltage characteristics. Odd–even effects are observed in both electric currents and binding energies between the SAM and the probing electrode. The significant difference between the tunneling barriers across the “top” contact of odd and even molecular junctions is revealed to be the origin of the odd–even effects in electron transport. Our calculations suggest that the odd–even effects in charge transport in the system under study occur for alkanethiolate molecules with a certain length (10 < <i>n</i> < 19, where <i>n</i> is the number of methylene groups)

High Catalytic Activity of Au Clusters Supported on ZnO Nanosheets

Catalytic activity of metal clusters supported on a two-dimensional (2d) nanosheet has attracted great interest recently. In this paper, via first-principles calculations, we investigate for the first time Au catalysis on recently proposed 2d one-atom-thick ZnO nanosheets. An Au₈ cluster adsorbed on a 2d ZnO sheet (Au₈/ZnO) is chosen as a model catalyst, and the CO oxidation is used as the probe reaction for the catalytic activity. When adsorbed on 2d one-atom-thick ZnO, the Au₈ cluster is found to adopt a planar structure and exhibit high catalytic activities for the CO oxidation with a low reaction barrier around 0.3 eV. The catalyzed CO oxidation highly prefers the Eley–Rideal (ER) mechanism, and the coadsorption of CO and O₂ on the Au₈ cluster plays an essential role in the ER type of reaction in which an additional CO approaches O₂ in a vacuum. The high catalytic activity (low reaction barrier) is due to the charge transfer from Au₈/ZnO to the antibonding 2π* orbital of the O₂ molecule that is facilitated by the coadsorption of a CO molecule. These findings provide new opportunities for the future development of ZnO-based catalysts

A Novel Aliphatic ¹⁸F‑Labeled Probe for PET Imaging of Melanoma

Radiofluorinated benzamide and nicotinamide analogues are promising molecular probes for the positron emission tomography (PET) imaging of melanoma. Compounds containing aromatic (benzene or pyridine) and <i>N,N-</i>diethylethylenediamine groups have been successfully used for development of melanin targeted PET and single-photon emission computed tomography (SPECT) imaging agents for melanoma. The objective of this study was to determine the feasibility of using aliphatic compounds as a molecular platform for the development of a new generation of PET probes for melanoma detection. An aliphatic <i>N,N-</i>diethylethylenediamine precursor was directly coupled to a radiofluorination synthon, <i>p</i>-nitrophenyl 2-¹⁸F-fluoropropionate (¹⁸F-NFP), to produce the probe <i>N</i>-(2-(diethylamino)­ethyl)-2-¹⁸F-fluoropropanamide (¹⁸F-FPDA). The melanoma-targeting ability of ¹⁸F-FPDA was further evaluated both <i>in vitro</i> and <i>in vivo</i> through cell uptake assays, biodistribution studies, and small animal PET imaging in C57BL/6 mice bearing B16F10 murine melanoma tumors. Beginning with the precursor ¹⁸F-NFP, the total preparation time for ¹⁸F-FPDA, including the final high-performance liquid chromatography purification step, was approximately 30 min, with a decay-corrected radiochemical yield of 79.8%. The melanin-targeting specificity of ¹⁸F-FPDA was demonstrated by significantly different uptake rates in tyrosine-treated and untreated B16F10 cells <i>in vitro</i>. The tumor uptake of ¹⁸F-FPDA <i>in vivo</i> reached 2.65 ± 0.48 %ID/g at 2 h postinjection (p.i.) in pigment-enriched B16F10 xenografts, whereas the tumor uptake of ¹⁸F-FPDA was close to the background levels, with rates of only 0.37 ± 0.07 %ID/g at 2 h p.i. in the nonpigmented U87MG tumor mouse model. Furthermore, small animal PET imaging studies revealed that ¹⁸F-FPDA specifically targeted the melanotic B16F10 tumor, yielding a tumor-to-muscle ratio of approximately 4:1 at 1 h p.i. and 7:1 at 2 h p.i. In summary, we report the development of a novel ¹⁸F-labeled aliphatic compound for melanoma imaging that can be easily synthesized in high yields using the radiosynthon ¹⁸F-NFP. The PET probe ¹⁸F-FPDA exhibits high B16F10 tumor-targeting efficacy and favorable <i>in vivo</i> pharmacokinetics. Our study demonstrates that aliphatic compounds can be used as a new generation molecular platform for the development of novel melanoma targeting agents. Further evaluation and optimization of ¹⁸F-FPDA for melanin targeted molecular imaging are therefore warranted

Development of ¹⁸F‑Labeled Picolinamide Probes for PET Imaging of Malignant Melanoma

Melanoma is an aggressive skin cancer with worldwide increasing incidence. Development of positron emission tomography (PET) probes for early detection of melanoma is critical for improving the survival rate of melanoma patients. In this research, ¹⁸F-picolinamide-based PET probes were prepared by direct radiofluorination of the bromopicolinamide precursors using no-carrier-added ¹⁸F-fluoride. The resulting probes, ¹⁸F-<b>1</b>, ¹⁸F-<b>2</b> and ¹⁸F-<b>3</b>, were then evaluated <i>in vivo</i> by small animal PET imaging and biodistribution studies in C57BL/6 mice bearing B16F10 murine melanoma tumors. Noninvasive small animal PET studies demonstrated excellent tumor imaging contrasts for all probes, while ¹⁸F-<b>2</b> showed higher tumor to muscle ratios than ¹⁸F-<b>1</b> and ¹⁸F-<b>3</b>. Furthermore, ¹⁸F-<b>2</b> demonstrated good <i>in vivo</i> stability as evidenced by the low bone uptake in biodistribution studies. Collectively, these findings suggest ¹⁸F-<b>2</b> as a highly promising PET probe for translation into clinical detection of melanoma

Orientation and Electronic Structures of Multilayered Graphene Nanoribbons Produced by Two-Zone Chemical Vapor Deposition

The orientation and electronic structure of multilayered graphene nanoribbons with an armchair-edge (AGNRs) were determined by low-temperature scanning tunneling microscopy in this study. The orientation of AGNRs was found to be an edge-on structure when positioned as a top layer, while previous reports showed a face-on structure for monolayered AGNRs on Au(111). According to density functional theory calculations, AGNRs in a top layer preferentially form as edge-on structures rather than face-on structures due to the balance of CH−π and π–π interactions between AGNRs. Scanning tunneling spectroscopy and density functional theory calculations revealed that the electronic structures of multilayered AGNRs are similar to those in a gas-phase due to the lack of interaction between AGNRs and the Au(111) substrate. The observation of AGNRs in mutilayers might suggest the conformation-assisted mechanism of dehydrogenation when there is no contact with the Au(111) substrate

EphB4-Targeted Imaging with Antibody h131, h131-F(ab′)₂ and h131-Fab

Accumulating evidence suggests that overexpression of the tyrosine kinase receptor EphB4, a mediator of vascular development, is a novel target for tumor diagnosis, prognosis and therapy. Noninvasive imaging of EphB4 expression could therefore be valuable for evaluating disease course and therapeutic efficacy at the earliest stages of anti-EphB4 treatment. In this study, we systematically investigated the use of anti-EphB4 antibody h131 (150 kDa) and its fragments (h131-F­(ab′)₂, 110 kDa; h131-Fab, 50 kDa) for near-infrared fluorescence (NIRF) imaging of EphB4 expression <i>in vivo</i>. h131-F­(ab′)₂ and h131-Fab were produced through pepsin and papain digestion of h131 respectively, whose purity was confirmed by FPLC and SDS–PAGE. After conjugation with Cy5.5, <i>in vivo</i> characteristics of h131, h131-F­(ab′)₂ and h131-Fab were evaluated in EphB4-positive HT29 tumor model. Although h131-Cy5.5 demonstrated highest tumor uptake among these probes, its optimal tumor uptake level was obtained at 2 days post injection (p.i.). For h131-Fab-Cy5.5, maximum tumor uptake was achieved at 4 h p.i. However, no significant difference was observed between h131-Fab-Cy5.5 and hIgG-Fab-Cy5.5, indicating the tumor accumulation was mainly caused by passive targeting. In contrast, h131-F­(ab′)₂-Cy5.5 demonstrated prominent tumor uptake at 6 h p.i. The target specificity was confirmed by hIgG-F­(ab′)₂-Cy5.5 control and immunofluorescent staining. Collectively, h131-F­(ab′)₂ exhibited prominent and specific tumor uptake at early time points, which suggests it is a promising agent for EphB4-targeted imaging

Improved Metabolic Stability for ¹⁸F PET Probes Rapidly Constructed via Tetrazine <i>trans</i>-Cyclooctene Ligation

The fast kinetics and bioorthogonal nature of the tetrazine <i>trans</i>-cyclooctene (TCO) ligation makes it a unique tool for PET probe construction. In this study, we report the development of an ¹⁸F-labeling system based on a CF₃-substituted diphenyl-<i>s</i>-tetrazine derivative with the aim of maintaining high reactivity while increasing in vivo stability. c­(RGDyK) was tagged by a CF₃-substituted diphenyl-<i>s</i>-tetrazine derivative via EDC-mediated coupling. The resulting tetrazine-RGD conjugate was combined with a ¹⁹F-labeled TCO derivative to give HPLC standards. The analogous ¹⁸F-labeled TCO derivative was combined with the diphenyl-<i>s</i>-tetrazine-RGD at μM concentration. The resulting tracer was subjected to in vivo metabolic stability assessment, and microPET studies in murine U87MG xenograft models. The diphenyl-<i>s</i>-tetrazine-RGD combines with an ¹⁸F-labeled TCO in high yields (>97% decay-corrected on the basis of TCO) using only 4 equiv of tetrazine-RGD relative to the ¹⁸F-labeled TCO (concentration calculated based on product’s specific activity). The radiochemical purity of the ¹⁸F-RGD peptides was >95% and the specific activity was 111 GBq/μmol. Noninvasive microPET experiments demonstrated that ¹⁸F-RGD had integrin-specific tumor uptake in subcutaneous U87MG glioma. In vivo metabolic stability of ¹⁸F-RGD in blood, urine, and major organs showed two major peaks: one corresponded to the Diels–Alder conjugate and the other was identified as the aromatized analog. A CF₃-substituted diphenyl-<i>s</i>-tetrazine displays excellent speed and efficiency in ¹⁸F-PET probe construction, providing nearly quantitative ¹⁸F labeling within minutes at low micromolar concentrations. The resulting conjugates display improved in vivo metabolic stability relative to our previously described system

Bifunctional Elastin-like Polypeptide Nanoparticles Bind Rapamycin and Integrins and Suppress Tumor Growth in Vivo

Recombinant protein–polymer scaffolds such as elastin-like polypeptides (ELPs) offer drug-delivery opportunities including biocompatibility, monodispersity, and multifunctionality. We recently reported that the fusion of FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) increases rapamycin (Rapa) solubility, suppresses tumor growth in breast cancer xenografts, and reduces side effects observed with free-drug controls. This new report significantly advances this carrier strategy by demonstrating the coassembly of two different ELP diblock copolymers containing drug-loading and tumor-targeting domains. A new ELP nanoparticle (ISR) was synthesized that includes the canonical integrin-targeting ligand (Arg-Gly-Asp, RGD). FSI and ISR mixed in a 1:1 molar ratio coassemble into bifunctional nanoparticles containing both the FKBP domain for Rapa loading and the RGD ligand for integrin binding. Coassembled nanoparticles were evaluated for bifunctionality by performing in vitro cell-binding and drug-retention assays and in vivo MDA-MB-468 breast tumor regression and tumor-accumulation studies. The bifunctional nanoparticle demonstrated superior cell target binding and similar drug retention to FSI; however, it enhanced the formulation potency, such that tumor growth was suppressed at a 3-fold lower dose compared to an untargeted FSI–Rapa control. This data suggests that ELP-mediated scaffolds are useful tools for generating multifunctional nanomedicines with potential activity in cancer

A Hybrid Protein–Polymer Nanoworm Potentiates Apoptosis Better than a Monoclonal Antibody

B-cell lymphomas continue to occur with a high incidence. The chimeric antibody known as Rituximab (Rituxan) has become a vital therapy for these patients. Rituximab induces cell death <i>via</i> binding and clustering of the CD20 receptor by Fcγ expressing effector cells. Because of the limited mobility of effector cells, it may be advantageous to cluster CD20 directly using multivalent nanostructures. To explore this strategy, this manuscript introduces a nanoparticle that assembles from a fusion between a single chain antibody and a soluble protein polymer. These hybrid proteins express in <i>Escherichia coli</i> and do not require bioconjugation between the antibody and a substrate. Surprisingly a fusion between an anti-CD20 single chain antibody and a soluble protein polymer assemble worm-like nanostructures, which were characterized using light scattering and cryogenic transmission electron microscopy. These nanoworms competitively bind CD20 on two B-cell lymphoma cell lines, exhibit concentration-dependent induction of apoptosis, and induce apoptosis better than Rituximab alone. Similar activity was observed <i>in vivo</i> using a non-Hodgkin lymphoma xenograft model. In comparison to Rituximab, systemic nanoworms significantly slowed tumor growth. These findings suggest that hybrid nanoworms targeted at CD20 may be useful treatments for B-cell related malignancies. Because of the ubiquity of antibody therapeutics, related nanoworms may have uses against other molecular targets

Multimeric Disintegrin Protein Polymer Fusions That Target Tumor Vasculature

Recombinant protein therapeutics have increased in number and frequency since the introduction of human insulin, 25 years ago. Presently, proteins and peptides are commonly used in the clinic. However, the incorporation of peptides into clinically approved nanomedicines has been limited. Reasons for this include the challenges of decorating pharmaceutical-grade nanoparticles with proteins by a process that is robust, scalable, and cost-effective. As an alternative to covalent bioconjugation between a protein and nanoparticle, we report that biologically active proteins may themselves mediate the formation of small multimers through steric stabilization by large protein polymers. Unlike multistep purification and bioconjugation, this approach is completed during biosynthesis. As proof-of-principle, the disintegrin protein called vicrostatin (VCN) was fused to an elastin-like polypeptide (A192). A significant fraction of fusion proteins self-assembled into multimers with a hydrodynamic radius of 15.9 nm. The A192-VCN fusion proteins compete specifically for cell-surface integrins on human umbilical vein endothelial cells (HUVECs) and two breast cancer cell lines, MDA-MB-231 and MDA-MB-435. Confocal microscopy revealed that, unlike linear RGD-containing protein polymers, the disintegrin fusion protein undergoes rapid cellular internalization. To explore their potential clinical applications, fusion proteins were characterized using small animal positron emission tomography (microPET). Passive tumor accumulation was observed for control protein polymers; however, the tumor accumulation of A192-VCN was saturable, which is consistent with integrin-mediated binding. The fusion of a protein polymer and disintegrin results in a higher intratumoral contrast compared to free VCN or A192 alone. Given the diversity of disintegrin proteins with specificity for various cell-surface integrins, disintegrin fusions are a new source of biomaterials with potential diagnostic and therapeutic applications