Place Exchange Reaction Research Articles

Furan-containing polymer-coated magnetic nanoparticles using the ‘graft-to’ approach

Coating of magnetic nanoparticles with functional polymers increases the applicability of these nanomaterials. A modular approach to functionalizing these polymer coatings can be achieved using click chemistry. This work reports the synthesis of magnetic nanoparticles coated with a dopamine anchoring group containing polymer with furan groups as side chain residues. Using the ‘graft-to’ approach, polymers are coated onto magnetic nanoparticles using a simple place exchange reaction. Various analytical techniques were used to characterize the polymer-coated nanoparticles for their size and surface composition. Utilization of poly(ethylene glycol) (PEG)-based polymer renders the magnetic nanoparticles water dispersible. The presence of the furan ring on the polymer brushes enables their facile functionalization using a maleimide group-bearing molecule under catalyst-free conditions. A hydrophobic fluorescent dye, used as a model drug, is conjugated onto the nanoparticles using the Diels-Alder reaction. One can anticipate that the facile fabrication and functionalization of these clickable polymer-coated magnetic nanoparticles will be attractive for various biomedical applications.

Ligation of Gold Nanoparticles with Self-Assembling, Coiled-Coil Peptides.

The surface of gold nanoparticles (AuNPs) can be conjugated with a wide range of highly functional biomolecules. A common pitfall when utilizing AuNPs is their tendency to aggregate, especially when their surface is functionalized with ligands of low molecular weight (no steric repulsion) or ligands of neutral charge (no electrostatic repulsion). For biomedical applications, AuNPs that are colloidally stable are desirable because they have a high surface area and thus reactivity, resist sedimentation, and exhibit uniform optical properties. Here, we engineer the surface of AuNPs so that they remain stable when decorated with coiled-coil (CC) peptides while preserving the native polypeptide properties. We achieve this by using a neutral, mixed ligand layer composed of lipoic acid poly(ethylene glycol) and lipoic acid poly(ethylene glycol) maleimide to attach the CCs. Tuning the surface fraction of each component within the mixed ligand layer also allowed us to control the degree of AuNP labeling with CCs. We demonstrate the dynamic surface properties of these CC-AuNPs by performing a place-exchange reaction and their utility by designing an energy-transfer-based caspase-3 sensor. Overall, this study optimizes the surface chemistry of AuNPs to quantitatively present functional biomolecules while maintaining colloid stability.

Facile generation of surface diversity in gold nanoparticles

Surface chemistry is a key determinant of the physico-chemical and biological properties of gold nanoparticles (AuNPs). The introduction of chemical diversity in the surface of AuNPs is usually accomplished by place-exchange reactions using incoming ligands containing the desired terminal functional groups. As an alternative approach, we present here a simple, practical methodology to modify the surface of gold nanoparticles that allows the preparation of AuNPs stabilized with polyethyleneglycol (PEG) ligands with different surface chemistries using AuNPs stabilized with thiol-PEG-amino ligands as starting material. The surface modification reaction involves the acylation of the terminal amino groups in the ligand with an organic acid anhydride in an aqueous buffer. In addition to a full surface modification, this method also allows the synthesis of AuNPs with tailored mixed surfaces, containing two or more different functional groups, each of them at the desired extent. The ease of the experimental conditions for the reaction, purification, and for determining the level of surface modification makes this strategy an attractive alternative to current methods for the preparation of AuNPs with diverse surface chemistry.

Gold nanocarriers for transport of oligonucleotides across brain endothelial cells.

Treatment of diseases that affect the CNS by gene therapy requires delivery of oligonucleotides to target cells within the brain. As the blood brain barrier prevents movement of large biomolecules, current approaches involve direct injection of the oligonucleotides, which is invasive and may have only a localised effect. The aim of this study was to investigate the potential of 2 nm galactose-coated gold nanoparticles (NP-Gal) as a delivery system of oligonucleotides across brain endothelium. DNA oligonucleotides of different types were attached to NP-Gal by the place exchange reaction and were characterised by EMSA (electrophoretic mobility shift assay). Several nanoparticle formulations were created, with single- or double-stranded (20nt or 40nt) DNA oligonucleotides, or with different amounts of DNA attached to the carriers. These nanocarriers were applied to transwell cultures of human brain endothelium in vitro (hCMEC/D3 cell-line) or to a 3D-hydrogel model of the blood-brain barrier including astrocytes. Transfer rates were measured by quantitative electron microscopy for the nanoparticles and qPCR for DNA. Despite the increase in nanoparticle size caused by attachment of oligonucleotides to the NP-Gal carrier, the rates of endocytosis and transcytosis of nanoparticles were both considerably increased when they carried an oligonucleotide cargo. Carriers with 40nt dsDNA were most efficient, accumulating in vesicles, in the cytosol and beneath the basal membrane of the endothelium. The oligonucleotide cargo remained attached to the nanocarriers during transcytosis and the transport rate across the endothelial cells was increased at least 50fold compared with free DNA. The nanoparticles entered the extracellular matrix and were taken up by the astrocytes in biologically functional amounts. Attachment of DNA confers a strong negative charge to the nanoparticles which may explain the enhanced binding to the endothelium and transcytosis by both vesicular transport and the transmembrane/cytosol pathway. These gold nanoparticles have the potential to transport therapeutic amounts of nucleic acids into the CNS.

The Influence of Hydrophilic Decoration on X-ray Excited Luminescence Nanoparticles to Singlet Oxygen Production

(1) Background: Though X-ray excited photodynamic therapy (X-PDT) breakthrough the bottom neck of PDT application in deep tumor by overcoming light penetration depth limitation, the quantum yield of the hydrophilic X-PDT nanoparticles (NPs) still hampered its further application in vivo. Thus, establishing a proper hydrophilic decoration method which can maximally maintain the quantum yield of X-ray excited luminescent NPs is of urgent demand. (2) Methods: We synthesized NaGdF4: [Formula: see text] (NGF) as X-ray excited luminescent NPs and conducted hydrophilic decoration by two hydrophilic ligands, polyethylene glycol-NH2 (PEG) and cysteamine (Cy) via place exchange reaction, and coupled with photosensitizer (MC540) to form a X-PDT nanosystem. We also conducted experiments in vitro and in vivo to evaluate the efficacy of the X-PDT system. (3) Results: Both PEG and Cy decoration NPs presented excellent emission intensity, which could well excite the coupled photosensitizer MC540 to generate significant X-PDT efficacy under low-dose X-ray radiation. Especially for the NGF-Cy-MC540 treatment group, the cell viability reduced to [Formula: see text]% under 0.3[Formula: see text]Gy radiation and [Formula: see text]% under only 0.1[Formula: see text]Gy radiation, which is the lowest radiation dosage in the literature reports so far. In vivo experiment showed about 36% of tumor inhibition rate under 0.3[Formula: see text]Gy X-ray. Besides, no biotoxicity was observed in NGF groups even in high concentrations, demonstrating good biocompatibility. (4) Conclusions: The hydrophilic decoration method by Cy or PEG via place exchange reaction may pave a brand new way and strategy for X-PDT further clinical application.

A modified and simplified method for purification of gold nanoparticles

2 nm gold nanoparticles (AuNPs) have promising applications within drug and protein delivery, bioimaging, and biosensing. By performing ligand place-exchange reactions, AuNPs protected with alkanethiolate ligands can be functionalized to regulate their behaviors. In this reaction, a new ligand is incorporated by mixing a thiol with the AuNPs. To remove the excess new ligand as well as the displaced thiolate, dialysis has previously been the most widely used method. However, this purification method is time-consuming and fails to remove unwanted thiols completely. In this study, we describe a fast and efficient procedure to purify AuNP aqueous solution through liquid-liquid extraction using dichloromethane.•We demonstrate a facile way to purify AuNPs after ligand place-exchange reactions through liquid-liquid extraction.•Liquid-liquid extraction is a simple, inexpensive and efficient method for AuNP purification.•This protocol enables us to completely purify AuNPs in a few hours and can be used as a much quicker and more scaleable valid alternative to dialysis.

Histone-Mimetic Gold Nanoparticles as Versatile Scaffolds for Gene Transfer and Chromatin Analysis.

Histone-inspired polymer assemblies (polyplexes) can regulate gene expression and subcellular transport in plasmids by harnessing the cellular machinery normally used for histone proteins. When grafted to polyplexes, histone tails promote nuclear accumulation, trigger plasmid DNA (pDNA) release, and enhance transcription. Herein, we developed multifunctional gold nanoparticles (AuNPs) decorated by histone motifs as histone-inspired scaffolds with improved pDNA binding, easy bioimaging, and increased potential for gene delivery and chromatin analysis applications. We hypothesized that polycationic AuNPs coupled to histone motifs would mimic the native presentation of these sequences on the histone octamer and thereby create structures with the capacity to both engage native histone effectors and condense pDNA into nucleosome-inspired nanostructures. AuNPs bearing ∼2 nm cores were prepared based on the well-established Brust-Schiffrin two-phase method involving tetrachloroaurate reduction in the presence of 1-pentanethiol. Solid phase peptide synthesis was employed to generate thiolated polycationic ligands and histone tail motifs, and the AuNPs and peptide ligands were combined in a two-step Murray place exchange reaction at various ratios to produce a collection of polycationic AuNPs modified with varying amounts of histone tails. Electron microscopy and thermal analyses demonstrated that these modified AuNPs exhibited tunable biochemical and biophysical properties that closely mimicked the properties of native histones. The histone-mimetic nanoscaffolds efficiently and sequence-specifically engaged histone effectors responsible for activating transcription. In addition, the nanoscaffolds condensed pDNA into complexes with high stability in the presence of physiological concentrations of heparin, a common extracellular polyanion. These combined properties of histone engagement and high stability led to a ∼6-fold enhancement in transfection efficiency as compared with typical polymeric transfection reagents, with the increased transfection efficiency correlated to the presence and amount of histone tails displayed on the surface of the nanoscaffolds. These findings demonstrate the utility of employing a biomimetic materials design approach to develop more effective and stable delivery vehicles for gene transfer and chromatin analysis applications.

Interfacial Au nanoparticle decoration of a disulfide modified G-wire.

The guanine-rich oligonucleotide (GRO), dGGGGTTGGGG (G4T2G4), has the capacity to form a linear supramolecular polymer known as a G-wire. Individual nucleotides of the component GROs can be functionally modified to serve as site-specific attachment points in the G-wire while not interfering with its self-assembling properties. An amine linker modification to an internal thymine base of the GRO, denoted G4TT*G4, serves as a chemically versatile attachment site. In this work, addition of an alkyl disulfide to G4TT*G4 produces the GRO G4TTdG4 enabling binding to gold nanoparticles via place exchange chemistry. G-wires assembled by combining G4T2G4 and G4TTdG4 were stably maintained in an aqueous environment. Disulfide modified G-wires (DS_G-wire) were then covered with dodecanethiol capped gold nanoparticles in an organic solvent via an interfacial place exchange reaction. Tapping Mode AFM and TEM were used to image G-wires decorated with gold nanoparticles. The specificity of the interfacial place exchange reaction was measured using a fluorometric dye displacement from the gold nanoparticles. The results show that a two component DS_G-wire with an amphipathic tether readily self-assemble as shown by PAGE and TM-AFM. The amphipathic disulfide moiety of DS_G-wires facilitates place exchange chemistry with alkylthiol protected Au nanoparticles across an aqueous-organic interface. Interfacial place exchange is an effective strategy for decorating DS_G-wires with Au nanoparticles. The use of modified G-wire self-assembly combined with a high degree of nanoparticle binding specificity presents another strategy for the use of G-wires as a rigid one-dimensional molecular scaffold with potential applications in nanoscale device construction. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.

Dendronized Anionic Gold Nanoparticles: Synthesis, Characterization, and Antiviral Activity.

Anionic carbosilane dendrons decorated with sulfonate functions and one thiol moiety at the focal point have been used to synthesize water-soluble gold nanoparticles (AuNPs) through the direct reaction of dendrons, gold precursor, and reducing agent in water, and also through a place-exchange reaction. These nanoparticles have been characterized by NMR spectroscopy, TEM, thermogravimetric analysis, X-ray photoelectron spectroscopy (XPS), UV/Vis spectroscopy, elemental analysis, and zeta-potential measurements. The interacting ability of the anionic sulfonate functions was investigated by EPR spectroscopy with copper(II) as a probe. Different structures and conformations of the AuNPs modulate the availability of sulfonate and thiol groups for complexation by copper(II). Toxicity assays of AuNPs showed that those produced through direct reaction were less toxic than those obtained by ligand exchange. Inhibition of HIV-1 infection was higher in the case of dendronized AuNPs than in dendrons.

Single-Crystal to Single-Crystal Linker Substitution, Linker Place Exchange, and Transmetalation Reactions in Interpenetrated Pillared-Bilayer Zinc(II) Metal-Organic Frameworks.

A twofold interpenetrated pillared-bilayer framework, {[Zn3 (L)2 (L2 )(DMF)]⋅(18DMF)(6H2 O)}n (1), has been synthesized from the ligands tris(4'-carboxybiphenyl)amine (H3 L) and 1,2-bis(4-pyridyl)ethylene (L2 ). The structure contains [Zn3 (COO)6 ] secondary building units (SBUs), in which three Zn(II) ions are almost linear with carboxylate bridging. This framework undergoes reversible pillar linker substitution reactions at the terminal Zn(II) centers with three different dipyridyl linkers of different lengths to afford three daughter frameworks, 2-4. Frameworks 2-4 are interconvertible through reversible linker substitution reactions. Also, competitive linker-exchange experiments show preferential incorporation of linker L3 in the parent framework 1. The larger linker L5 does not undergo such substitution reactions and framework 5, which contains this linker, can be synthesized solvothermally as a twofold interpenetrated structure. Interestingly, when framework 5 is dipped in a solution of L3 in DMF, linker substitution takes place as before, but linker L5 now moves and diagonally binds two Zn(II) centers to afford 6 as a nonpenetrated single framework. This linker place exchange reaction is unprecedented. All of these reactions take place in a single-crystal to single-crystal (SC-SC) manner, and have been observed directly through X-ray crystallography. In addition, each 3D framework undergoes complete copper(II) transmetalation.

Near-Infrared Emitting CuInSe₂/CuInS₂ Dot Core/Rod Shell Heteronanorods by Sequential Cation Exchange.

The direct synthesis of heteronanocrystals (HNCs) combining different ternary semiconductors is challenging and has not yet been successful. Here, we report a sequential topotactic cation exchange (CE) pathway that yields CuInSe2/CuInS2 dot core/rod shell nanorods with near-infrared luminescence. In our approach, the Cu+ extraction rate is coupled to the In3+ incorporation rate by the use of a stoichiometric trioctylphosphine-InCl3 complex, which fulfills the roles of both In-source and Cu-extracting agent. In this way, Cu+ ions can be extracted by trioctylphosphine ligands only when the In–P bond is broken. This results in readily available In3+ ions at the same surface site from which the Cu+ is extracted, making the process a direct place exchange reaction and shifting the overall energy balance in favor of the CE. Consequently, controlled cation exchange can occur even in large and anisotropic heterostructured nanocrystals with preservation of the size, shape, and heterostructuring of the template NCs into the product NCs. The cation exchange is self-limited, stopping when the ternary core/shell CuInSe2/CuInS2 composition is reached. The method is very versatile, successfully yielding a variety of luminescent CuInX2 (X = S, Se, and Te) quantum dots, nanorods, and HNCs, by using Cd-chalcogenide NCs and HNCs as templates. The approach reported here thus opens up routes toward materials with unprecedented properties, which would otherwise remain inaccessible.

Cooperative Gold Nanoparticle Stabilization by Acetylenic Phosphaalkenes

Acetylenic phosphaalkenes (APAs) are used as a novel type of ligands for the stabilization of gold nanoparticles (AuNP). As demonstrated by a variety of experimental and analytical methods, both structural features of the APA, that is, the P=C as well as the C≡C units are essential for NP stabilization. The presence of intact APAs on the AuNP is demonstrated by surface-enhanced Raman spectroscopy (SERS), and first principle calculations indicate that bonding occurs most likely at defect sites on the Au surface. AuNP-bound APAs are in chemical equilibrium with free APAs in solution, leading to a dynamic behavior that can be explored for facile place-exchange reactions with other types of anchor groups such as thiols or more weakly binding phosphine ligands.

Structure–function relationships affecting the sensing mechanism of monolayer-protected cluster doped xerogel amperometric glucose biosensors

A systematic study of the structure–function relationships critical to understanding the sensing mechanism of 1st generation amperometric glucose biosensors with an embedded nanoparticle (NP) network is presented. Xerogel-based films featuring embedded glucose oxidase enzyme and doped with alkanethiolate-protected gold NPs, known as monolayer protected clusters (MPCs), exhibit significantly enhanced performance compared to analogous systems without NPs including higher sensitivity, faster response time, and extended linear/dynamic ranges. The proposed mechanism involves diffusion of the glucose to glucose oxidase within the xerogel, enzymatic reaction production of H2O2 with subsequent diffusion to the embedded network of MPCs where it is oxidized, an event immediately reported via fast electron transfer (ET) through the MPC system to the working electrode. Various aspects of the film construct and strategy are systematically probed using amperometry, voltammetry, and solid-state electronic conductivity measurements, including the effects of MPC peripheral chain length, MPC functionalization via place-exchange reaction, MPC core size, and the MPC density or concentration within the xerogel composite films. The collective results of these experiments support the proposed mechanism and identify interparticle spacing and the electronic communication through the MPC network is the most significant factor in the sensing scheme with the diffusional aspects of the mechanism that may be affected by film/MPC hydrophobicity and functionality (i.e., glucose and H2O2 diffusion) shown to be less substantial contributors to the overall enhanced performance. Understanding the structure–function relationships of effective sensing schemes allows for the employment of the strategy for future biosensor design toward clinically relevant targets.

Synthesis of small water-soluble diazirine-functionalized gold nanoparticles and their photochemical modification

Dual water and organic solvent soluble 3-aryl-3-(trifluormethyl) diazirine-functionalized gold nanoparticles (AuNPs) were prepared through a place exchange reaction from triethylene glycol monomethyl ether (EG3-Me) capped AuNPs. These nanoparticles were fully characterized using 1H and 19F nuclear magnetic resonance (NMR) spectroscopy, transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS). TGA along with 1H NMR data allowed the determination of 15% incorporation of diazirine (Diaz) ligands onto mixed monolayer AuNPs, while TEM images showed an average diameter of 2.3 ± 0.5 nm. This information led to the estimated molecular formula of Au400 (S-EG4-Diaz)40 (S-EG3-Me)230 for these AuNPs. It is noteworthy that high-resolution XPS was a powerful tool for quantitative analysis. Irradiation of the diazirine capped AuNPs resulted in nitrogen extrusion and the formation of a highly reactive carbene with evidence of a portion of the reaction proceeding via the diazo intermediate and thus requiring a second photon for activation. The carbene species generated was utilized to tether the attached AuNPs via insertion into C=C or O–H functionality inherent on various substrates. Here, we demonstrated that photolysis of the diazirine modified AuNPs in the presence of a variety of model carbene scavengers led to clean and efficient insertion products while maintaining their solubility in polar solvents.

Differential reactivity of the inner and outer positions of Au25(SCH2CH2Ph)18 dimeric staples under place exchange conditions.

The kinetic analysis of the place exchange reaction on the neutral Au25(SCH2CH2Ph)18 cluster by using 4-fluorobenzylthiol and a series of substituted arylthiols allowed us to establish, for the first time, that the selectivity for the inner and outer positions of the dimeric staples of the cluster can be modulated by using incoming thiols with different structures.

Light-Triggered Thiol-Exchange on Gold Nanoparticles at Low Micromolar Concentrations in Water

The place-exchange reaction of thiol-containing peptides in a cationic monolayer on gold nanoparticles occurs very rapidly at low micromolar concentrations in water with excellent control over the degree of substitution. The driving force for this process is the binding of anionic peptides to a cationic monolayer surface which causes a strong increase in the local concentration of thiols. The place-exchange reaction can be triggered by light using a photolabile protecting group on the thiol moiety.

Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs.

The therapeutic approach for the treatment of HIV infection is based on the highly active antiretroviral therapy (HAART), a cocktail of antiretroviral drugs. Notwithstanding HAART has shown different drawbacks like toxic side effects and the emergence of viral multidrug resistance. Nanotechnology offers new tools to improve HIV drug treatment and prevention. In this scenario, gold nanoparticles are an interesting chemical tool to design and prepare smart and efficient drug-delivery systems. Here we describe the preparation and antiviral activity of carbohydrate-coated gold nanoparticles loaded with anti-HIV prodrug candidates. The nucleoside reverse transcriptase inhibitors abacavir and lamivudine have been converted to the corresponding thiol-ending ester derivatives and then conjugated to ~3 nm glucose-coated gold nanoparticles by means of “thiol-for-thiol” ligand place exchange reactions. The drugs-containing glyconanoparticles were characterized and the pH-mediated release of the drug from the nanoparticle has been determined. The antiviral activity was tested by evaluating the replication of NL4-3 HIV in TZM-bl infected cells. The proof-of-principle presented in this work aims to introduce gold glyconanoparticles as a new multifunctional drug-delivery system in the therapy against HIV.

Exchange reactions between alkanethiolates and alkaneselenols on Au{111}.

When alkanethiolate self-assembled monolayers on Au{111} are exchanged with alkaneselenols from solution, replacement of thiolates by selenols is rapid and complete, and is well described by perimeter-dependent island growth kinetics. The monolayer structures change as selenolate coverage increases, from being epitaxial and consistent with the initial thiolate structure to being characteristic of selenolate monolayer structures. At room temperature and at positive sample bias in scanning tunneling microscopy, the selenolate-gold attachment is labile, and molecules exchange positions with neighboring thiolates. The scanning tunneling microscope probe can be used to induce these place-exchange reactions.

On the Size Evolution of Monolayer-Protected Gold Clusters during Ligand Place-Exchange Reactions: The Effect of Solvents

Ligand place-exchange (LPE) reactions are extensively applied for the post-functionalization of monolayer-protected gold clusters (MPCs) by using excessive incoming ligands to displace initial ones. However, the modified MPCs are often enlarged or degraded; this results in ill-defined size-dependent properties. The growth of MPCs essentially involves an unprotected surface that is subsequently has gold atoms added or is fused with other gold cores owing to collision. Reported herein is a guideline for the selection of solvents to suppress unwanted MPC growth. Favorable solvents are those with significant affinity to gold or with low solubility for desorbed ligands because these properties retard LPE reactions and minimize the time available for unprotected gold cores. This finding provides a general and convenient approach to regulate the size of functionalized MPCs.

Luminescent ‘On-Off’ CdSe/ZnS Quantum Dot Chemodosimeter for Hydroxide Based on Photoinduced Electron Transfer from a Carboxylate Moiety

A CdSe-ZnS quantum dot (QD) has been surface functionalised by a place exchange reaction with p-mercaptomethyl benzoate synthesized by a three-step procedure. The resulting lumophore-spacer-receptor QD-conjugate was characterized by IR, UV-visible and fluorescence spectroscopy. The emission profile of the QD reveals a narrow emission peak centred at 542nm. Addition of hydroxide to the solution containing the QD-conjugate results in quenching of the original fluorescence, which is attributed to a photoinduced electron transfer reaction from the electron-rich benzoate moiety to the QD valence band. This is the first reported example of fluorescent quenching of a CdSe-ZnS QD luminescence by an aryl carboxylate moiety.