10 research outputs found
OddâEven 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
oddâeven 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 oddâeven 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 currentâvoltage
characteristics. Oddâeven 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
âtopâ contact of odd and even molecular junctions is
revealed to be the origin of the oddâeven effects in electron
transport. Our calculations suggest that the oddâeven 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 Au<sub>8</sub> cluster adsorbed on a 2d ZnO sheet (Au<sub>8</sub>/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 Au<sub>8</sub> 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 EleyâRideal (ER) mechanism,
and the coadsorption of CO and O<sub>2</sub> on the Au<sub>8</sub> cluster plays an essential role in the ER type of reaction in which
an additional CO approaches O<sub>2</sub> in a vacuum. The high catalytic
activity (low reaction barrier) is due to the charge transfer from
Au<sub>8</sub>/ZnO to the antibonding 2Ď* orbital of the O<sub>2</sub> 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 <sup>18</sup>FâLabeled 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-<sup>18</sup>F-fluoropropionate
(<sup>18</sup>F-NFP), to produce the probe <i>N</i>-(2-(diethylamino)Âethyl)-2-<sup>18</sup>F-fluoropropanamide (<sup>18</sup>F-FPDA). The melanoma-targeting
ability of <sup>18</sup>F-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 <sup>18</sup>F-NFP, the total preparation time for <sup>18</sup>F-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 <sup>18</sup>F-FPDA was demonstrated by significantly different uptake rates in
tyrosine-treated and untreated B16F10 cells <i>in vitro</i>. The tumor uptake of <sup>18</sup>F-FPDA <i>in vivo</i> reached 2.65 Âą 0.48 %ID/g at 2 h postinjection (p.i.) in pigment-enriched
B16F10 xenografts, whereas the tumor uptake of <sup>18</sup>F-FPDA
was close to the background levels, with rates of only 0.37 Âą
0.07 %ID/g at 2 h p.i. in the nonpigmented U87MG tumor mouse model.
Furthermore, small animal PET imaging studies revealed that <sup>18</sup>F-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 <sup>18</sup>F-labeled aliphatic compound for melanoma imaging that can be easily
synthesized in high yields using the radiosynthon <sup>18</sup>F-NFP.
The PET probe <sup>18</sup>F-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 <sup>18</sup>F-FPDA for melanin targeted molecular imaging are therefore warranted
Development of <sup>18</sup>FâLabeled 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, <sup>18</sup>F-picolinamide-based
PET probes were prepared by direct radiofluorination of the bromopicolinamide
precursors using no-carrier-added <sup>18</sup>F-fluoride. The resulting
probes, <sup>18</sup>F-<b>1</b>, <sup>18</sup>F-<b>2</b> and <sup>18</sup>F-<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 <sup>18</sup>F-<b>2</b> showed higher
tumor to muscle ratios than <sup>18</sup>F-<b>1</b> and <sup>18</sup>F-<b>3</b>. Furthermore, <sup>18</sup>F-<b>2</b> demonstrated good <i>in vivo</i> stability as evidenced
by the low bone uptake in biodistribution studies. Collectively, these
findings suggest <sup>18</sup>F-<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 CHâĎ and
ĎâĎ 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(abâ˛)<sub>2</sub> 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-FÂ(abâ˛)<sub>2</sub>, 110 kDa; h131-Fab, 50 kDa) for near-infrared fluorescence
(NIRF) imaging of EphB4 expression <i>in vivo</i>. h131-FÂ(abâ˛)<sub>2</sub> and h131-Fab were produced through pepsin and papain digestion
of h131 respectively, whose purity was confirmed by FPLC and SDSâPAGE.
After conjugation with Cy5.5, <i>in vivo</i> characteristics
of h131, h131-FÂ(abâ˛)<sub>2</sub> 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-FÂ(abâ˛)<sub>2</sub>-Cy5.5 demonstrated prominent
tumor uptake at 6 h p.i. The target specificity was confirmed by hIgG-FÂ(abâ˛)<sub>2</sub>-Cy5.5 control and immunofluorescent staining. Collectively,
h131-FÂ(abâ˛)<sub>2</sub> 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 <sup>18</sup>F 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 <sup>18</sup>F-labeling system based on a CF<sub>3</sub>-substituted
diphenyl-<i>s</i>-tetrazine derivative with the aim of maintaining
high reactivity while increasing in vivo stability. cÂ(RGDyK) was tagged
by a CF<sub>3</sub>-substituted diphenyl-<i>s</i>-tetrazine
derivative via EDC-mediated coupling. The resulting tetrazine-RGD
conjugate was combined with a <sup>19</sup>F-labeled TCO derivative
to give HPLC standards. The analogous <sup>18</sup>F-labeled TCO derivative
was combined with the diphenyl-<i>s</i>-tetrazine-RGD at
ÎźM 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 <sup>18</sup>F-labeled TCO in high yields (>97% decay-corrected
on the basis of TCO) using only 4 equiv of tetrazine-RGD relative
to the <sup>18</sup>F-labeled TCO (concentration calculated based
on productâs specific activity). The radiochemical purity of
the <sup>18</sup>F-RGD peptides was >95% and the specific activity
was 111 GBq/Îźmol. Noninvasive microPET experiments demonstrated
that <sup>18</sup>F-RGD had integrin-specific tumor uptake in subcutaneous
U87MG glioma. In vivo metabolic stability of <sup>18</sup>F-RGD in
blood, urine, and major organs showed two major peaks: one corresponded
to the DielsâAlder conjugate and the other was identified as
the aromatized analog. A CF<sub>3</sub>-substituted diphenyl-<i>s</i>-tetrazine displays excellent speed and efficiency in <sup>18</sup>F-PET probe construction, providing nearly quantitative <sup>18</sup>F 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
proteinâpolymer 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 FSIâRapa control.
This data suggests that ELP-mediated scaffolds are useful tools for
generating multifunctional nanomedicines with potential activity in
cancer
A Hybrid ProteinâPolymer 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 FcÎł 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