Biodistribution and toxicity of engineered gold nanoparticles: a review of in vitro and in vivo studies

Recent advances in wet chemical synthesis and biomolecular functionalization of gold nanoparticles have led to a dramatic expansion of their potential biomedical applications, including biosensorics, bioimaging, photothermal therapy, and targeted drug delivery. As the range of gold nanoparticle types and their applications continues to increase, human safety concerns are gaining attention, which makes it necessary to better understand the potential toxicity hazards of these novel materials. Whereas about 80 reports on the in vivo biodistribution and in vitro cell toxicity of gold nanoparticles are available in the literature, there is lack of correlation between both fields and there is no clear understanding of intrinsic nanoparticle effects. At present, the major obstacle is the significant discrepancy in experimental conditions under which biodistribution and toxicity effects have been evaluated. This critical review presents a detailed analysis of data on the in vitro and in vivo biodistribution and toxicity of most popular gold nanoparticles, including atomic clusters and colloidal particles of diameters from 1 to 200 nm, gold nanoshells, nanorods, and nanowires. Emphasis is placed on the systematization of data over particle types and parameters, particle surface functionalization, animal and cell models, organs examined, doses applied, the type of particle administration and the time of examination, assays for evaluating gold particle toxicity, and methods for determining the gold concentration in organs and distribution of particles over cells. On the basis of a critical analysis of data, we arrive at some general conclusions on key nanoparticle parameters, methods of particle surface modification, and doses administered that determine the type and kinetics of biodistribution and toxicity at cellular and organismal levels (197 references).     

Anomeric effect in N-azidomethylpyrrolidine: gas-phase electron diffraction and theoretical study

Gas-phase electron-diffraction data and high-level quantum chemical calculations have been used to study the conformational behaviour of N-azidomethylpyrrolidine. The two most stable conformers with a relative abundance of about 80% at 298 K possess gauche orientation of the azidomethyl group around the C-N(pyr) bond (C-N(azido)gauche with respect to the endocyclic N(pyr)-C bond). This orientation is a strong manifestation of an anomeric effect. The influence of the anomeric effect is also reflected in shortening of the C-N(pyr) bond and lengthening of the C-N(azido) bond as compared to such bonds in other compounds.     

Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Four putative functionalized α‐chloroakyllithiums RCH₂CHLiCl, where R=CHCH₂ ( 18 a ), CCH ( 18 b ), CH₂OBn ( 18 c ), and CH[O(CH₂)₂O] ( 18 d ), were generated in situ by sulfoxide–lithium exchange from α‐chlorosulfoxides, and investigated for the stereospecific reagent‐controlled homologation (StReCH) of phenethyl and 2‐chloropyrid‐5‐yl ( 17 ) pinacol boronic esters. Deuterium labeling experiments revealed that α‐chloroalkyllithiums are quenched by proton transfer from their α‐chlorosulfoxide precursors and it was established that this effect compromises the yield of StReCH reactions. Use of α‐deuterated α‐chlorosulfoxides was discovered to ameliorate the problem by retarding the rate of acid‐base chemistry between the carbenoid and its precursor. Carbenoids 18 a and 18 b showed poor StReCH efficacy, particularly the propargyl group bearing carbenoid 18 b , the instability of which was attributed to a facile 1,2‐hydride shift. By contrast, 18 d , a carbenoid that benefits from a stabilizing interaction between O and Li atoms gave good StReCH yields. Boronate 17 was chain extended by carbenoids 18 a , 18 b , and 18 d in 16, 0, and 68 % yield, respectively; α‐deuterated isotopomers D ‐ 18 a and D ‐ 18 d gave yields of 33 and 79 % for the same reaction. Double StReCH of 17 was pursued to target contiguous stereodiads appropriate for the total synthesis of (?)‐epibatidine ( 15 ). One‐pot double StReCH of boronate 17 by two exposures to (S)‐D ‐ 18 a (≤66 % ee), followed by work‐up with KOOH, gave the expected stereodiad product in 16 % yield (d.r.～67:33). The comparable reaction using two exposures to (S)‐D ‐ 18 d (≤90 % ee) delivered the expected bisacetal containing stereodiad (R,R)‐DD ‐ 48 in 40 % yield (≥98 % ee, d.r.=85:15). Double StReCH of 17 using (S)‐D ‐ 18 d (≤90 % ee) followed by (R)‐D ‐ 18 d (≤90 % ee) likewise gave (R,S)‐DD ‐ 48 in 49 % yield (≥97 % ee, d.r.=79:21). (R,S)‐DD ‐ 48 was converted to a dideuterated isotopomer of a synthetic intermediate in Corey’s synthesis of 15 .     

CeAgAs2 — a New Derivative of the HfCuSi2 Type of Structure: Synthesis,Crystal Structure and Magnetic Properties

Single crystals of CeAgAs₂ have been obtained by chemical transport reactions starting from a pre‐reacted powder sample. The crystal structure was solved using X‐ray diffraction (space group Pmca, No. 57, a = 5.7586(4) Å, b = 5.7852(4) Å, c = 21.066(3) Å, Z = 8) and refined to a residual of R(F) = 0.029 for 46 refined parameters and 1020 reflections. The structure of CeAgAs₂ represents a new distorted and ordered variant of the HfCuSi₂ type. The characteristic feature of this structure are infinite cis‐trans chains of As atoms with As—As distances of 2.563(1) Å and 2.601(1) Å. CeAgAs₂ is paramagnetic (μ_eff = 2.37 μ_B, θ = —10.5(2) K), with antiferromagnetic ordering at 5.5(2) K and exhibits a metamagnetic transition starting at 4.6 kOe and T = 1.8 K.     

Self-assembled E(2)L(3) cryptands (E = P, As, Sb, Bi): transmetalation, homo- and heterometallic assemblies, and conformational isomerism

A series of Group 15-containing homometallic (E(2)L(3), E = P, As, Sb, Bi) and heterometallic (AsSbL(3), AsBiL(3), PSbL(3)) supramolecular cryptands were prepared by the self-assembly of pnictogen halides with dithiolate ligand or by direct transmetalation from a heavier congener. Structural characterization by single crystal X-ray diffraction shows that the E-S bond distances and S-E-S bond angles are significantly affected by the identity of the pnictogen. (1)H NMR spectroscopy reveals that the homometallic cryptands are dynamic in solution: surprisingly one ligand "flips", perturbing the C(3) symmetry of the complex and giving a new asymmetric conformer. Density functional theory calculations were carried out on both the symmetric and the asymmetric conformations of the cryptands, and the energies were compared to those observed by NMR spectroscopy. It was found that the relative stability of the asymmetric cryptand to its symmetric conformer increases with increasing size of the Group 15 element. Finally, it is reported that if two metals are present during the self-assembly process, heterometallic cryptands form. These supramolecular cryptands are reminiscent of their organic analogues, but result from a self-assembly process rather than a stepwise synthesis. Surprisingly, they possess conformational isomerism and exhibit dynamic transmetalation in their reactivity which provides access to otherwise unattainable assemblies.     

A model proton-transfer system in the condensed phase: NH4(+)OOH(-), a crystal with short intermolecular H-bonds

The crystal structure of NH(4)(+)OOH(-) is determined from single-crystal x-ray data obtained at 150 K. The crystal belongs to the space group P2(1)/c and has four molecules in a unit cell. The structure consists of discrete NH(4)(+) and OOH(-) ions. The OOH(-) ions are linked by short hydrogen bonds (2.533 A?) to form parallel infinite chains. The ammonium ions form links between these chains (the N?O distances vary from 2.714 to 2.855 A?) giving a three-dimensional network. The harmonic IR spectrum and H-bond energies are computed at the Perdew-Burke-Ernzerhof (PBE)/6-31G(??) level with periodic boundary conditions. A detailed analysis of the shared (bridging) protons' dynamics is obtained from the CPMD simulations at different temperatures. PBE functional with plane-wave basis set (110 Ry) is used. At 10 K the shared proton sits near the oxygen atom, only a few proton jumps along the chain are detected at 70 K while at 270 K numerous proton jumps exist in the trajectory. The local-minimum structure of the space group Cc is localized. It appears as a result of proton transfer along a chain. This process is endothermic (～2?kJ/mol) and is described as P2(1)/c?2Cc. The computed IR spectrum at 10 K is close to the harmonic one, the numerous bands appear at 70 K while at 270 K it shows a very broad absorption band that covers frequencies from about 1000 to 3000?cm(-1). The advantages of the NH(4)(+)OOH(-) crystal as a promising model for the experimental and DFT based molecular dynamics simulation studies of proton transfer along the chain are discussed.     

Growth of metal-organic frameworks on polymer surfaces

Polymer substrates have been functionalized with a MOF material (MIL-47) synthesized directly on polyacrylonitrile using in situ microwave irradiation. The growth of MIL-47 on these substrates was studied as a function of microwave irradiation time using scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The conversion of nitrile to carboxylic acid groups on the PAN surface was necessary for the growth of MIL-47 on the substrate. MIL-47 crystals grew over time at the expense of a related disordered precursor phase, which lacks the long-range order of MIL-47. This work paves the way for the development of a new class of hybrid MOF-polymer materials that will extend the applications of MOFs to fields such as membrane separations, filtration, and protective textiles.     

Photochemical Reduction of Carbon Dioxide Catalyzed by a Ruthenium‐Substituted Polyoxometalate

A polyoxometalate of the Keggin structure substituted with Ru^III, ⁶Q₅[Ru^III(H₂O)SiW₁₁O₃₉] in which ⁶Q=(C₆H₁₃)₄N⁺, catalyzed the photoreduction of CO₂ to CO with tertiary amines, preferentially Et₃N, as reducing agents. A study of the coordination of CO₂ to ⁶Q₅[Ru^III(H₂O)SiW₁₁O₃₉] showed that 1) upon addition of CO₂ the UV/Vis spectrum changed, 2) a rhombic signal was obtained in the EPR spectrum (g_x=2.146, g_y=2.100, and g_z=1.935), and 3) the ¹³C NMR spectrum had a broadened peak of bound CO₂ at 105.78 ppm (Δ_1/2=122 Hz). It was concluded that CO₂ coordinates to the Ru^III active site in both the presence and absence of Et₃N to yield ⁶Q₅[Ru^III(CO₂)SiW₁₁O₃₉]. Electrochemical measurements showed the reduction of Ru^III to Ru^II in ⁶Q₅[Ru^III(CO₂)SiW₁₁O₃₉] at ?0.31 V versus SCE, but no such reduction was observed for ⁶Q₅[Ru^III(H₂O)SiW₁₁O₃₉]. DFT‐calculated geometries optimized at the M06/PC1//PBE/AUG‐PC1//PBE/PC1‐DF level of theory showed that CO₂ is preferably coordinated in a side‐on manner to Ru^III in the polyoxometalate through formation of a Ru? O bond, further stabilized by the interaction of the electrophilic carbon atom of CO₂ to an oxygen atom of the polyoxometalate. The end‐on CO₂ bonding to Ru^III is energetically less favorable but CO₂ is considerably bent, thus favoring nucleophilic attack at the carbon atom and thereby stabilizing the carbon sp² hybridization state. Formation of a O₂C–NMe₃ zwitterion, in turn, causes bending of CO₂ and enhances the carbon sp² hybridization. The synergetic effect of these two interactions stabilizes both Ru–O and C–N interactions and probably determines the promotional effect of an amine on the activation of CO₂ by [Ru^III(H₂O)SiW₁₁O₃₉]^5?. Electronic structure analysis showed that the polyoxometalate takes part in the activation of both CO₂ and Et₃N. A mechanistic pathway for photoreduction of CO₂ is suggested based on the experimental and computed results.     

β-Amino alcohol selectors for enantioselective separation of amino acids by ligand-exchange capillary zone electrophoresis in a low molecular weight organogel

A new family of copper ligand-exchange selectors, L- or D-β-amino alcohols, is employed for the chiral separation of D,L-dansyl-amino acids, unmodified amino acid racemates, phenylalanine and tryptophan, and β-blocker L,D-propranolol by SDS-micellar electrokinetic chromatography and by electrophoretic chromatography in a low molecular weight organogel (LMOG)-filled capillary. The LMOG comprised a self-assembled fibrillar gel of trans-(1S,2S)-1,2-bis-(dodecylamido) cyclohexane in methanol. The di-L-valinol-copper complex exhibited the best performance on LMOG-CE compared with all other β-amino alcohol-copper selectors. The dependence of chiral resolution on the pH*, the ratio between the copper and the L-valinol ligand and the concentration of added selector complex in the run buffer were investigated revealing a marked difference between the activity of the copper-valinol and the previously studied copper-valine selector. The optimal separation conditions were achieved using a 2:1 valinol/copper ratio, in accordance with the 2:1 structure of the complex, which was proven by single crystal and powder X-ray diffractions and by elemental analysis. Unlike the copper-valine selectors that could be used only under acidic conditions (pH* 3.5), the copper-valinol selectors could be used under near-neutral conditions and even at pH* 9.1. A comparison between SDS-micellar electrokinetic chromatography and LMOG-CE under otherwise identical conditions revealed a significant superior separation on the LMOG-filled capillaries.