Nanoscale Hafnium Metal-Organic Frameworks Enhance Radiotherapeutic Effects by Upregulation of Type I Interferon and TLR7 Expression.

Recent preclinical and clinical studies have highlighted the improved outcomes of combination radiotherapy and immunotherapy. Concurrently, the development of high-Z metallic nanoparticles as radiation dose enhancers has been explored to widen the therapeutic window of radiotherapy and potentially enhance immune activation. In this study, folate-modified hafnium-based metal-organic frameworks (HfMOF-PEG-FA) are evaluated in combination with imiquimod, a TLR7 agonist, as a well-defined interferon regulatory factor (IRF) stimulator for local antitumor immunotherapy. The enhancement of radiation dose deposition by HfMOF-PEG-FA and subsequent generation of reactive oxygen species (ROS) deregulates cell proliferation and increases apoptosis. HfMOF-PEG-FA loaded with imiquimod (HfMOF-PEG-FA@IMQ) increases DNA double-strand breaks and cell death, including apoptosis, necrosis, and calreticulin exposure, in response to X-ray irradiation. Treatment with this multipronged therapy promotes IRF stimulation for subsequent interferon production within tumor cells themselves. The novel observation is reported that HfMOF itself increases TLR7 expression, unexpectedly pairing immune agonist and receptor upregulation in a tumor intrinsic manner, and supporting the synergistic effect observed with the γH2AX assay. T-cell analysis of CT26 tumors following intratumoral administration of HfMOF-PEG-FA@IMQ with radiotherapy reveals a promising antitumor response, characterized by an increase in CD8+ and proliferative T cells.

Synthesis of Radioluminescent CaF2:Ln Core, Mesoporous Silica Shell Nanoparticles for Use in X-ray Based Theranostics.

X-ray radiotherapy is a common method of treating cancerous tumors or other malignant lesions. The side effects of this treatment, however, can be deleterious to patient quality of life if critical tissues are affected. To potentially lower the effective doses of radiation and negative side-effects, new classes of nanoparticles are being developed to enhance reactive oxygen species production during irradiation. This report presents the synthesis and radiotherapeutic efficacy evaluation of a new nanoparticle formulation designed for this purpose, composed of a CaF2 core, mesoporous silica shell, and polyethylene glycol coating. The construct was additionally doped with Tb and Eu during the CaF2 core synthesis to prepare nanoparticles (NPs) with X-ray luminescent properties for potential application in fluorescence imaging. The mesoporous silica shell was added to provide the opportunity for small molecule loading, and the polyethylene glycol coating was added to impart aqueous solubility and biocompatibility. The potential of these nanomaterials to act as radiosensitizers for enhancing X-ray radiotherapy was supported by reactive oxygen species generation assays. Further, in vitro experiments indicate biocompatibility and enhanced cellular damage during X-ray radiotherapy.

Lanthanide Metal-Organic Frameworks for Multispectral Radioluminescent Imaging.

In this report, we describe the X-ray luminescent properties of two lanthanide-based nanoscale metal-frameworks (nMOFs) and their potential as novel platforms for optical molecular imaging techniques such as X-ray excited radioluminescence (RL) imaging. Upon X-ray irradiation, the nMOFs display sharp tunable emission peaks that span the visible to near-infrared spectral region (∼400-700 nm) based on the identity of the metal (Eu, Tb, or Eu/Tb). Surface modification of the nMOFs with polyethylene glycol (PEG) resulted in nanoparticles with enhanced aqueous stability that demonstrated both cyto- and hemo-compatibility important prerequisites for biological applications. Importantly, this is the first report to document and investigate the radioluminescent properties of lanthanide nMOFs. Taken together, the observed radioluminescent properties and low in vitro toxicity demonstrated by the nMOFs render them promising candidates for in vivo translation.

Facile Synthesis of Ligand-Free Iridium Nanoparticles and Their In Vitro Biocompatibility.

High-density inorganic nanoparticles have shown promise in medical applications that utilize radiation including X-ray imaging and as radiation dose enhancers for radiotherapy. We have developed an aqueous synthetic method to produce small (~ 2 nm) iridium nanoparticles (IrNPs) by reduction of iridium(III) chloride using a borohydride reducing agent. Unlike other solution-based synthesis methods, uniform and monodispersed IrNPs are produced without the use of surfactants or other solubilizing ligands. These nanoparticles are highly crystalline as observed by X-ray diffraction and high-resolution transmission electron microscopy (TEM). In vitro metabolic toxicity assays using hepatocyte and macrophage cells demonstrate that both IrNPs and iridium(III) chloride are well tolerated at concentrations of up to 10 µM iridium. Furthermore, the IrNPs were assessed in a hemolytic assay and found to have no significant impact on red blood cells when exposed to concentrations up to 100 µM. Overall, these results support the potential for the in vivo application of this nanomaterial.

Creation and Annihilation of Charge Traps in Silicon Nanocrystals: Experimental Visualization and Spectroscopy.

Recent studies have shown the presence of an amorphous surface layer in nominally crystalline silicon nanocrystals (SiNCs) produced by some of the most common synthetic techniques. The amorphous surface layer can serve as a source of deep charge traps, which can dramatically affect the electronic and photophysical properties of SiNCs. We present results of a scanning tunneling microscopy/scanning tunneling spectroscopy (STM/STS) study of individual intragap states observed on the surfaces of hydrogen-passivated SiNCs deposited on the Au(111) surface. STS measurements show that intragap states can be formed reversibly when appropriate voltage-current pulses are applied to individual SiNCs. Analysis of STS spectra suggests that the observed intragap states are formed via self-trapping of charge carriers injected into SiNCs from the STM tip. Our results provide a direct visualization of the charge trap formation in individual SiNCs, a level of detail which until now had been achieved only in theoretical studies.

Communication: Visualization and spectroscopy of defects induced by dehydrogenation in individual silicon nanocrystals.

We present results of a scanning tunneling spectroscopy (STS) study of the impact of dehydrogenation on the electronic structures of hydrogen-passivated silicon nanocrystals (SiNCs) supported on the Au(111) surface. Gradual dehydrogenation is achieved by injecting high-energy electrons into individual SiNCs, which results, initially, in reduction of the electronic bandgap, and eventually produces midgap electronic states. We use theoretical calculations to show that the STS spectra of midgap states are consistent with the presence of silicon dangling bonds, which are found in different charge states. Our calculations also suggest that the observed initial reduction of the electronic bandgap is attributable to the SiNC surface reconstruction induced by conversion of surface dihydrides to monohydrides due to hydrogen desorption. Our results thus provide the first visualization of the SiNC electronic structure evolution induced by dehydrogenation and provide direct evidence for the existence of diverse dangling bond states on the SiNC surfaces.

Mapping of Defects in Individual Silicon Nanocrystals Using Real-Space Spectroscopy.

The photophysical properties of silicon semiconductor nanocrystals (SiNCs) are extremely sensitive to the presence of surface chemical defects, many of which are easily produced by oxidation under ambient conditions. The diversity of chemical structures of such defects and the lack of tools capable of probing individual defects continue to impede understanding of the roles of these defects in SiNC photophysics. We use scanning tunneling spectroscopy to study the impact of surface defects on the electronic structures of hydrogen-passivated SiNCs supported on the Au(111) surface. Spatial maps of the local electronic density of states (LDOS) produced by our measurements allowed us to identify locally enhanced defect-induced states as well as quantum-confined states delocalized throughout the SiNC volume. We use theoretical calculations to show that the LDOS spectra associated with the observed defects are attributable to Si-O-Si bridged oxygen or Si-OH surface defects.

Synthesis, X-ray Opacity, and Biological Compatibility of Ultra-High Payload Elemental Bismuth Nanoparticle X-ray Contrast Agents.

Inorganic nanoscale X-ray contrast agents (XCAs) offer many potential advantages over currently used intravascular molecular contrast agents, including longer circulation and retention times, lower administration volumes, and greater potential for site directed imaging. Elemental bismuth nanoparticles (BiNPs) are particularly attractive candidate XCAs due to the low cost, the high atomic number and high density of bismuth, and the likelihood that BiNPs will oxidatively decompose to biocompatible bismuth(III) ions at controlled rates for renal excretion. Herein we describe the synthesis of ultrahigh payload BiNPs in 1,2-propanediol using a borane reducing agent and glucose as a biocompatible surface stabilizer. Both synthetic solvent (1,2-propanediol) and surfactant (glucose) are evident on the BiNP surfaces when analyzed by 1H NMR and FT-IR spectroscopies. These particles contain ∼6 million Bi atoms per NP and have large inorganic cores (74 nm by TEM) compared to their hydrodynamic size (86 nm by DLS). Thus, the dense BiNP core constitutes the majority (∼60%) of each particle's volume, a necessary property to realize the full potential of nanoscale XCAs. Using quantitative computed tomography in phantom and in vitro imaging studies, we demonstrate that these BiNPs have greater X-ray opacity than clinical small molecule iodinated contrast agents at the same concentrations. We furthermore demonstrate a favorable biocompatibility profile for these BiNPs in vitro. Altogether, these studies indicate that these ultrahigh payload BiNPs, synthesized from known biocompatible components, have promising physical and cytotoxicological properties for use as XCAs.

Complementary microscopy techniques applied for optimizing the structure and performance of graphene-based hybrids.

To improve the performance of graphene and to extend its potential applications, one of the most effective efforts is to hybridize graphene with one or more metal/metal oxide nanocrystals (NCs). In this paper, we demonstrate the complementary techniques of X-ray diffraction, high resolution electron microscopy (HREM), energy-dispersive X-ray spectroscopy (EDX), and energy-filtered transmission electron microscopy (EFTEM), which enables us to optimize the synthetic conditions, improve the quality of attached NCs, and tailor the performance of graphene-based hybrids for green energy related applications. Specifically, we explored the EFTEM technique to characterize two graphene-based composites. For the first sample of graphene/CoO(x), we present how the oxygen elemental map can identify that the oxidization of attached cobalt NCs most likely occurred during post treatments, rather than during the solvothermal reaction; for the second sample of graphene/(Mn, Co, Ni)O(x), we demonstrate how two-dimensional elemental mapping can differentiate the distribution of Mn, Co, and Ni on the surface of graphene. The results indicate that the EFTEM technique can supply very valuable and indispensable information, which contributes to comprehensive evaluation of structure and performance of graphene based hybrids.

One-step Melt Synthesis of Water Soluble, Photoluminescent, Surface-Oxidized Silicon Nanoparticles for Cellular Imaging Applications.

We have developed a versatile, one-step melt synthesis of water-soluble, highly emissive silicon nanoparticles using bi-functional, low-melting solids (such as glutaric acid) as reaction media. Characterization through transmission electron microscopy, selected area electron diffraction, X-ray photoelectron spectroscopy, and Raman spectroscopy shows that the one-step melt synthesis produces nanoscale Si cores surrounded by a silicon oxide shell. Analysis of the nanoparticle surface using FT-IR, zeta potential, and gel electrophoresis indicates that the bi-functional ligand used in the one-step synthesis is grafted onto the nanoparticle, which allows for tuning of the particle surface charge, solubility, and functionality. Photoluminescence spectra of the as-prepared glutaric acid-synthesized silicon nanoparticles show an intense blue-green emission with a short (ns) lifetime suitable for biological imaging. These nanoparticles are found to be stable in biological media and have been used to examine cellular uptake and distribution in live N2a cells.

Structural diversity and thermochromic properties of iodobismuthate materials containing d-metal coordination cations: observation of a high symmetry [Bi3I11]2- anion and of isolated I- anions.

Six new inorganic-organic salts, all containing iodobismuthate anions and d-metal coordination cations, were synthesized solvothermally from reactions of bismuth iodide, a transition metal (M) nitrate salt (M = Co, Fe or Zn), and a heterocyclic, chelating organic ligand: 1,10-phenanthroline (1,10-phen), 3,4,7,8-tetramethyl-1,10-phenanthroline (TMphen), or 2,2':6',2''-terpyridine (tpy). All six compounds were structurally analyzed by single crystal X-ray diffraction, including variable temperature crystallographic analysis to monitor for structural changes. Furthermore, those containing novel anions and achieved in high yield were additionally characterized by solid-state UV visible spectroscopy at room temperature. [Co(1,10-phen)(3)][Bi(3)I(11)] (1), [Fe(1,10-phen)(3)][Bi(3)I(11)] (2), and [Zn(1,10-phen)(3)][Bi(3)I(11)] (3) are isostructural. They crystallize in the monoclinic space group P2(1)/n and contain the unprecedented iodobismuthate anion, [Bi(3)I(11)](2-), which exhibits near D(3h) symmetry and has an unusual arrangement of three cis face-sharing BiI(6) octahedra. [Co(TMPhen)(3)](2)[Bi(2)I(9)][I] (4), which crystallizes in the trigonal space group P-31c, and [Co(tpy)(2)](2)[Bi(2)I(9)][I] (5) and [Zn(tpy)(2)](2)[Bi(2)I(9)][I] (6), which are isostructural and crystallize in the monoclinic space group C2/c, contain the discrete binuclear [Bi(2)I(9)](3-) anion, common in previously reported iodobismuthate compounds. In addition they contain unusual isolated I(-) anions, which are rarely encountered in iodobismuthate phases. Compounds 1-6 show constitutional similarities while utilizing different organic ligands and illustrate the sensitive dependence of reaction conditions on the identity of the halometalate anion formed. Additionally, all six compounds and the starting material BiI(3) are thermochromic; the origin of this behavior is spectroscopically and crystallographically investigated.

A versatile low temperature synthetic route to Zintl phase precursors: Na4Si4, Na4Ge4 and K4Ge4 as examples.

Na(4)Si(4) and Na(4)Ge(4) are ideal chemical precursors for inorganic clathrate structures, clusters, and nanocrystals. The monoclinic Zintl phases, Na(4)Si(4) and Na(4)Ge(4), contain isolated homo-tetrahedranide [Si(4)](4-) and [Ge(4)](4-) clusters surrounded by alkali metal cations. In this study, a simple scalable route has been applied to prepare Zintl phases of composition Na(4)Si(4) and Na(4)Ge(4) using the reaction between NaH and Si or Ge at low temperature (420 degrees C for Na(4)Si(4) and 270 degrees C for Na(4)Ge(4)). The method was also applied to K(4)Ge(4), using KH and Ge as raw materials, to show the versatility of this approach. The influence of specific reaction conditions on the purity of these Zintl phases has been studied by controlling five factors: the method of reagent mixing (manual or ball milled), the stoichiometry between raw materials, the reaction temperature, the heating time and the gas flow rate. Moderate ball-milling and excess NaH or KH facilitate the formation of pure Na(4)Si(4), Na(4)Ge(4) or K(4)Ge(4) at 420 degrees C (Na(4)Si(4)) or 270 degrees C (both M(4)Ge(4) compounds, M = Na, K). TG/DSC analysis of the reaction of NaH and Ge indicates that ball milling reduces the temperature for reaction and confirms the formation temperature. This method provides large quantities of high quality Na(4)Si(4) and Na(4)Ge(4) without the need for specialized laboratory equipment, such as Schlenk lines, niobium/tantalum containers, or an arc welder, thereby expanding the accessibility and chemical utility of these phases by making them more convenient to prepare. This new synthetic method may also be extended to lithium-containing Zintl phases (LiH is commercially available) as well as to alkali metal-tetrel Zintl compounds of other compositions, e.g. K(4)Ge(9).

Magnetic properties and negative colossal magnetoresistance of the rare earth Zintl phase EuIn2As2.

Large, high quality single crystals of a new Zintl phase, EuIn(2)As(2), have been synthesized from a reactive indium flux. EuIn(2)As(2) is isostructural to the recently reported phase EuIn(2)P(2), and it is only the second reported member of the group of compounds with formula AM(2)X(2) (A = alkali, alkaline earth, or rare earth cation; M = transition or post-transition metal; and X = Group 14 or 15 element) that crystallizes in the hexagonal space group P6(3)/mmc (a = 4.2067(3) A, c = 17.889(2) A and Z = 2). The structure type contains layers of A(2+) cations separated by [M(2)X(2)](2-) layers along the crystallographic c-axis. Crystals of the title compound were mounted for magnetic measurements, with the crystallographic c-axis oriented either parallel or perpendicular to the direction of the applied field. The collective magnetization versus temperature and field data indicate two magnetic exchange interactions near 16 K, one involving Eu(2+)...Eu(2+) intralayer coupling and the other involving Eu(2+)...Eu(2+) coupling between layers. EuIn(2)As(2) is metallic and magnetoresistive, as is the isostructural phosphide, and both compounds have coincident resistivity and magnetic ordering transitions, consistent with the observation of colossal magnetoresistance. Negative colossal magnetoresistance (MR = {[rho(H) - rho(0)]/rho(H)} x 100%) of up to -143% (at T = 17.5 K, H = 5 T) is observed for EuIn(2)As(2), approximately half of that observed for the more resistive phosphide, which has a higher magnetic ordering temperature and local moment coupling strength.

A new 2-carboxylate-substituted 4,4'-bipyridine ligand: coordination chemistry of 4,4'-bipyridine-2-carboxylic acid and its synthetic intermediate 2-methyl-4,4'-bipyridine.

The first monocarboxylate-substituted 4,4'-bipyridine ligand, 4,4'-bipyridine-2-carboxylic acid (4-(pyridin-4-yl)pyridine-2-carboxylic acid (PPCAH)), has been successfully synthesized from 4,4'-bipyridine. Reactions with transition metals zinc and manganese were used to establish the coordination characteristics of the product, 4,4'-bipyridine-2-carboxylic acid, and of the synthetic intermediate, 2-methyl-4,4'-bipyridine, by single-crystal X-ray diffraction. The ligand PPCAH is useful for the formation of metal-containing building blocks that can be used in the assembly of mixed-metal framework materials. The synthesis and structure of one such mixed-metal coordination polymer, Cu(PPCA)(2)HgI(2), is also presented.

Tetrakis[2-(2-pyridyl)pyridinium] tetra-mu3-iodo-hexa-mu2-iodo-dodecaiodohexabismuthate and bis[tris(2,2'-bipyridine)ruthenium(II)] di-mu4-iodo-octa-mu2-iodo-dodecaiodohexabismuthate.

Crystals of the title compounds were grown solvothermally in an ethanol-water solvent mixture using ruthenium triiodide, 2,2'-bipyridine and bismuth triiodide as starting materials. Tetrakis[2-(2-pyridyl)pyridinium] tetra-mu3-iodo-hexa-mu2-iodo-dodecaiodohexabismuthate, (C10H9N2)4[Bi6I22], crystallizes in the triclinic space group P-1 and is the major reaction product. The asymmetric unit of this compound consists of half a centrosymmetric [Bi6I22]4- anion and two independent 2,2'-bipyridinium cations. The minor product of the reaction is bis[tris(2,2'-bipyridine)ruthenium(II)] di-mu4-iodo-octa-mu2-iodo-dodecaiodohexabismuthate, [Ru(C10H8N2)3]2[Bi6I22], which also crystallizes in the triclinic space group P-1. For this compound, the asymmetric unit consists of one full [Ru(2,2'-bipyridine)3]2+ cation and half a centrosymmetric [Bi6I22]4- anion. Although both compounds contain a centrosymmetric [Bi6I22]4- anion, the polyhedral arrangement of the distorted BiI6 octahedra in the two compounds is quite different, and the anion of the latter compound has not previously been observed in iodobismuthate chemistry.

Non-interpenetrated square-grid coordination polymers synthesized using an extremely long N,N'-type ligand.

Four new, non-interpenetrated square-grid coordination polymers, namely [Mn(L)2(NO3)2]infinity (1), [[Cd(L)2(NO3)2].solvate]infinity (2), [Cd(L)2(NO3)2]infinity (3), and [[Zn(L)2](BF4)2.(C6H6)2.564.(DMF)1.576.(MeOH, H2O)3.454]infinity (4), were synthesized using the new, extremely long N,N'-type ligand: 2,5-bis(4'-(imidazol-1-yl)benzyl)-3,4-diaza-2,4-hexadiene (L). The reaction of Cd(NO3)2 with L leads to two novel structures sharing the same framework composition, [Cd(L)2(NO3)2]infinity, which have different arrangements of L around the metal centers. Both the channel-containing structure and the nonporous structure can be formed by choice of the appropriate solvent system. Moreover, the less stable, channel-containing form readily converts into the more stable, condensed structure upon removal of the guest molecules from the channels.

A three-dimensional, noninterpenetrating metal--organic framework with the moganite topology: a simple (4(2)x6(2)x8(2))(4x6(4)x8)(2) net containing two kinds of topologically nonequivalent points.

Self assembly of Cu(2+) with the multifunctional ligand 2-(4-pyridyl)thiazole-4-carboxylic acid (Pytac) affords the neutral 3D coordination polymer [Cu(3)(Pytac)(6)](H(2)O)(14) (hereafter, SZL-1), which has the rare moganite topology. The mineral moganite has a topology that is closely related to the well-known quartz topology, but the two topologies are differentiated by the number of topologically inequivalent nodes. Whereas only one kind of node is present in quartz, two types of topologically inequivalent nodes are present in moganite. The title compound, which has three vertices in its repeat unit, has two types of topologically inequivalent nodes with the overall vertex symbol (4(2)x6(2)x8(2))(4x6(4)x8)(2) corresponding to the moganite net. Prior to this report, few metal-organic framework materials (MOFs) have been found to contain more than one type of node, and SZL-1 is the first MOF with the moganite topology.

Preparation and characterization of novel inorganic-organic hybrid materials containing rare, mixed-halide anions of bismuth(III).

Three new hybrid inorganic-organic salts containing novel mixed haloanions of bismuth were synthesized by the solvothermal reaction of bismuth iodide with a haloacid, HX (X = Cl or Br), and the alkylamine 4,4'-trimethylenedipiperidine (TMDP). All three compounds were structurally characterized by single-crystal X-ray diffraction. Reaction of TMDP and BiI(3) with HCl yielded two crystalline products: [H(2)TMDP](2)[(Bi(2)I(9))(BiCl(2)I(2))] (1, major yield) and [H(2)TMDP](2)[Bi(2)Cl(10-x)I(x)] (2, x = 3.83, minor yield). Compound 1 crystallizes in the monoclinic space group Cc (a = 22.8586(11) A, b = 15.5878(7) A, c = 17.6793(9) A, beta = 118.7010(10) degrees , Z = 4) and contains the mononuclear mixed-halide anion BiCl(2)I(2)(-) in addition to a face-sharing bioctahedral Bi(2)I(9)(3)(-) anion and two independent H(2)TMDP(2+) cations. The BiCl(2)I(2)(-) anion has a sawhorse geometry (equatorially vacant trigonal bipyramidal geometry) that is not commonly observed in bismuth chemistry. Compound 2 crystallizes in the monoclinic space group P2(1)/c (a = 14.9471(7) A, b = 12.7622(6) A, c = 13.3381(7) A, beta = 116.1030(10) degrees , Z = 2) and contains an edge-sharing bioctahedral mixed-halide anion in which iodide occupies one and chloride occupies two of the five crystallographically independent halide sites. The remaining two sites have mixed-chloride and -iodide occupancy. Reaction of TMDP and BiI(3) with HBr yielded the crystalline product [H(2)TMDP][BiBr(5-x)I(x)] (3, x = 0.99), which contains, in addition to the organic cation, a polymeric, mixed-haloanion of bismuth(III). Compound 3 crystallizes in the chiral, orthorhombic space group P2(1)2(1)2(1) (a = 8.5189(5) A, b = 14.8988(9) A, c = 17.9984(11) A, Z = 4) and consists of an H(2)TMDP(2+) cation in addition to the anion, which is built up of corner-sharing BiX(6) octahedra. Of the five crystallographically independent halide sites in this anion, two are occupied solely by Br and the remaining three have mixed-bromide and -iodide occupancy. Other anion stoichiometries have been observed crystallographically for 3, as the specific stoichiometry is dependent on the relative concentration of the haloacid starting material used.

Assembly of large simple 1D and rare polycatenated 3D molecular ladders from T-shaped building blocks containing a new, long N,N'-bidentate ligand.

Molecular ladders [Co(2)(nbpy4)(3)(NO(3))(4)]*solvents and [Cd(2)(nbpy4)(3)(NO(3))(4)](nbpy4 =N,N'-bis-(4-pyridinylmethylene)-1,5-naphthalenediamine) were synthesized via self-assembly; the former is a large, simple, noninterpenetrated 1D ladder that contains guest solvent molecules between the rungs, while the latter exists as 1D ladders in a rare four-fold interlocked 3D structure.