Dithiol Linkers Research Articles

Rapid formation of gold core-satellite nanostructures using Turkevich-synthesized satellites and dithiol linkers: the do's and don'ts for successful assembly.

Turkevich syntheses represent a foundational approach for forming colloids of monodisperse gold nanoparticles where the use of these structures as building blocks when forming multicomponent nanoassemblies is pervasive. The core-satellite motif, which is characterized by a central core structure onto which satellite structures are tethered, distinguishes itself in that it can realize numerous plasmonic nanogaps with nanometer scale widths. Established procedures for assembling these multicomponent structures are, to a large extent, empirically driven, time-consuming, difficult to reproduce, and in need of a strong mechanistic underpinning relating to the close-range electrostatic interactions needed to secure satellite structures onto core materials. Described herein is a rapid, repeatable procedure for assembling core-satellite structures using Turkevich-grown satellites and dithiol linkers. With this successful procedure acting as a baseline for benchmarking modified procedures, a rather complex parameter space is understood in terms of timeline requirements for various processing steps and an analysis of the factors that prove consequential to assembly. It is shown that seemingly innocuous procedures realize sparsely populated cores whereas cores initially obstructed with commonly used capping agents lead to few disruptions to satellite attachment. Once these factors are placed under control, then it is the ionic strength imposed by the reaction biproducts of the Turkevich synthesis that is the critical factor in assembly because they decide the spatial extent of the electrical double layer surrounding each colloidal nanoparticle. With this understanding, it is possible to control the ionic strength through the addition or subtraction of various ionic species and assert control over the assembly process. The work, hence, advances the rules for a robust core-satellite assembly process and, in a broader sense, contributes to the knowhow required for the precise, programmable, and controllable assembly of multicomponent systems.

One Step Encapsulation of Mesenchymal Stromal Cells in PEG Norbornene Microgels for Therapeutic Actions.

Cell therapies require control over the cellular response under standardized conditions to ensure continuous delivery of therapeutic agents. Cell encapsulation in biomaterials can be particularly effective at providing cells with a uniformly supportive and permissive cell microenvironment. In this study, two microfluidic droplet device designs were used to successfully encapsulate equine mesenchymal stromal cells (MSCs) into photopolymerized polyethylene glycol norbornene (PEGNB) microscale (∼100-200 μm) hydrogel particles (microgels) in a single on-chip step. To overcome the slow cross-linking kinetics of thiol-ene reactions, long dithiol linkers were used in combination with a polymerization chamber customized to achieve precise retention time for microgels while maintaining cytocompatibility. Thus, homogeneous cell-laden microgels could be continuously fabricated in a high-throughput fashion. Varying linker length mediated both the gel formation rate and material physical properties (stiffness, mass transport, and mesh size) of fabricated microgels. Postencapsulation cell viability and therapeutic indicators of MSCs were evaluated over 14 days, during which the viability remained at least 90%. Gene expression of selected cytokines was not adversely affected by microencapsulation compared to monolayer MSCs. Notably, PEGNB-3.5k microgels rendered significant elevation in FGF-2 and TGF-β on the transcription level, and conditioned media collected from these cultures showed robust promotion in the migration and proliferation of fibroblasts. Collectively, standardized MSC on-chip encapsulation will lead to informed and precise translation to clinical studies, ultimately advancing a variety of tissue engineering and regenerative medicine practices.

Controlling the spacing of the linked graphene oxide system with dithiol linkers under confinement.

2D nanoscale confined systems exhibit behavior that is markedly different from that observed at the macroscale. Confinement can be tuned by controlling the interlayer spacing between confining layers using organic dithiol linkers. Adjusting spacing and selective intercalation have important impacts for catalysis, superconductivity, spin engineering, sodium ion batteries, 2D magnets, optoelectronics, and many other applications. In this study, we report how reaction conditions and organic linkers can be used to create variable, reproducible spacings between graphene oxide to provide confinement systems. We determined the conditions under which the spacing can be variably adjusted by the type of linker used, the concentration of the linker, and the reaction conditions. Employing dithiol linkers of different lengths, such as three (TPDT) and four (QPDT) aromatic rings, we can adjust the spacing between graphene oxide layers under varied reaction conditions. Here, we show that by varying dithiol linker length and using different reaction conditions, we can reproducibly control the spacing between graphene oxide layers from 0.37 nm to over 0.50 nm.

Development of Bio-Functionalized, Raman Responsive, and Potentially Excretable Gold Nanoclusters.

Gold nanoparticles (AuNPs) are used experimentally for non-invasive in vivo Raman monitoring because they show a strong absorbance in the phototherapeutic window (650–850 nm), a feature that is accompanied by a particle size in excess of 100 nm. However, these AuNPs cannot be used clinically because they are likely to persist in mammalian systems and resist excretion. In this work, clustered ultrasmall (sub-5 nm) AuNP constructs for in vivo Raman diagnostic monitoring, which are also suitable for mammalian excretion, were synthesized and characterized. Sub-5 nm octadecyl amine (ODA)-coated AuNPs were clustered using a labile dithiol linker: ethylene glycol bis-mercaptoacetate (EGBMA). Upon clustering via a controlled reaction and finally coating with a polymeric amphiphile, a strong absorbance in the phototherapeutic window was demonstrated, thus showing the potential suitability of the construct for non-invasive in vivo detection and monitoring. The clusters, when labelled with a biphenyl-4-thiol (BPT) Raman tag, were shown to elicit a specific Raman response in plasma and to disaggregate back to sub-5 nm particles under physiological conditions (37 °C, 0.8 mM glutathione, pH 7.4). These data demonstrate the potential of these new AuNP clusters (Raman NanoTheranostics—RaNT) for in vivo applications while being in the excretable size window.

Highly Sensitive Strain Sensors Based on Molecules-Gold Nanoparticles Networks for High-Resolution Human Pulse Analysis.

High-performance flexible strain sensors are key components for the next generation of wearable health monitoring devices. Here, the authors have fabricated a novel strain sensor based on gold nanoparticles (AuNPs) interconnected by flexible and responsive molecular linkers. The combination of conductive AuNPs (25 nm in diameter) with tetra(ethylene glycol) dithiol (SH-TEG-SH) linkers yields a covalent 3D network which can be directly deposited onto prepatterned flexible supports exposing interdigitated Au electrodes. The electrically insulating nature of the linkers effectively defines the tunneling modulated charge transfer through the AuNPs network. When compressive/tensile strain is applied, the molecular linkers adopt a compressed/stretched conformation thus decreasing/increasing the interparticle distance, ultimately yielding an exponential increase/decrease of the tunneling current when voltage is applied. The strain sensor displays state-of-the-art performances including a highly sensitive response to both tensile and compressive strain, as quantified by a high gauge factor (GF≈126) combined with other superior sensing properties like high flexibility, short response time (16.1 ms), and good robustness (>2000 cycles). Finally, the applicability of the device for health monitoring is demonstrated: high-resolution artery pulse waves are acquired by placing the strain sensor onto the skin allowing the extraction of important physical parameters for human-health assessment.

Programmable Self-Assembly of Gold Nanoarrows via Regioselective Adsorption.

Programing the self-assembly of colloidal nanoparticles into predetermined superstructures represents an attractive strategy to realize functional assemblies and novel nanodevices, but it remains a challenge. Herein, gold nanoarrows (GNAs) showing a distinct convex-concave structure were employed as unique building blocks for programmable self-assembly involving multiple assembly modes. Regioselective adsorption of 1,10-decanedithiol on the vertexes, edges, and facets of GNAs allowed for programmable self-assembly of GNAs with five distinct assembly modes, and regioselective blocking with 1-dodecanethiol followed by adsorption of 1,10-decanedithiol gave rise to programmable self-assembly with six assembly modes including three novel wing-engaged modes. The assembly mode was essentially determined by regioselective adsorption of the dithiol linker dictated by the local curvature together with the shape complementarity of GNAs. This approach reveals how the geometric morphology of nanoparticles affects their regioselective functionalization and drives their self-assembly.

Fluorinated Polymers via Para-Fluoro-Thiol and Thiol-Bromo Click Step Growth Polymerization.

Click reactions are utilized widely to modify chain ends and side groups of polymers while click polymerizations based on step-growth polymerization of bifunctional monomers have recently attracted increased attention of polymer chemists. Herein, the combination of two highly efficient click reactions, namely para-fluoro-thiol click and thiol-bromo substitution reactions, is demonstrated to form fluorinated polymers with tuned hydrophobicity owing to the nature of the dithiol linker compound. The key compound in this study is 2,3,4,5,6-pentafluoro benzyl bromide that provides the combination of thiol click reactions. The thiols used here are 4,4-thiobisbenzenthiol, 2,2'-(ethylenedioxy) diethanethiol, and 1,2-ethanedithiol that allow tuning of the properties of obtained polymers. The step-growth click reaction conditions are optimized by screening the effect of reaction temperature, base, solvent, and stochiometric ratio of the compounds. Thermal properties and hydrophobicity of synthesized polymers are determined via water contact angle, thermogravimetric analysis and differential scanning calorimetry measurements, showing thermal stability up to 300 °C, glass transition temperatures ranging from -25 to 82 °C and water contact angles ranging from 55 to 90 °C.

A Simple and Versatile Method for the Construction of Nearly Ideal Polymer Networks.

Polymer networks usually contain numerous inhomogeneities that deteriorate their physical properties and should be eliminated to create reliable, high-performance materials. A simple method is introduced for the production of nearly ideal networks from various vinyl polymers through controlled polymerization and subsequent crosslinking. Monodisperse star polymers with bromide end groups were synthesized by atom-transfer radical polymerization and end-linked with dithiol linkers using thiol-bromide chemistry. This simple procedure formed nearly ideal polymer networks, as revealed from elasticity of the formed gel and model conjugation reactions involving linear polymers. The versatility of this method was demonstrated by preparing networks of common vinyl polymers, including polyacrylates, polymethacrylate, and polystyrene. This method can be used to prepare multiple functional nearly ideal gels and elastomers and to explore fundamental aspects of polymer networks.

A Simple and Versatile Method for the Construction of Nearly Ideal Polymer Networks

AbstractPolymer networks usually contain numerous inhomogeneities that deteriorate their physical properties and should be eliminated to create reliable, high‐performance materials. A simple method is introduced for the production of nearly ideal networks from various vinyl polymers through controlled polymerization and subsequent crosslinking. Monodisperse star polymers with bromide end groups were synthesized by atom‐transfer radical polymerization and end‐linked with dithiol linkers using thiol–bromide chemistry. This simple procedure formed nearly ideal polymer networks, as revealed from elasticity of the formed gel and model conjugation reactions involving linear polymers. The versatility of this method was demonstrated by preparing networks of common vinyl polymers, including polyacrylates, polymethacrylate, and polystyrene. This method can be used to prepare multiple functional nearly ideal gels and elastomers and to explore fundamental aspects of polymer networks.

Facile Preparation of Cucurbit[6]uril-Based Polymer Nanocapsules for Targeted Photodynamic Therapy.

Covalently self-assembled polymer nanocapsules (NCs) based on cucurbit[6]uril have been previously prepared and their applications in payload delivery and bioimaging have been demonstrated, showing significant potentials. However, the preparation of these NCs often requires laborious and tedious multistep reactions, including a low-yield conversion of perhydroxycucurbit[6]uril to perallyloxycucurbit[6]uril, subsequent photopolymerization of perallyloxycucurbit[6]uril with dithiol linkers, and two additional steps of treatment to remove disulfide loops and create cationic sulfoniums. Herein, we report a novel, facile approach leading to cucurbit[6]uril-based polymer NCs via direct alkylation of perhydroxycucurbit[6]uril with a ditopic linker, thereby saving significant time and efforts, which may lead to significant expansion in investigations of these unique materials in various applications, particularly biomedical sciences. As a proof of concept, we have further demonstrated that a photosensitive therapeutic payload, such as chlorin e6, may get encapsulated inside the NCs for improved, targeted photodynamic therapy against cancer cells.

Dithiol-Induced Oligomerization of Thiol-Protected Gold Nanoclusters.

Controlled synthesis of nanostructure oligomers requires detailed understanding of their wet chemistry and the forces driving the polymerization process. In this paper, we report the main factors affecting the reaction yields of a dithiol-induced synthesis of covalently bound nanocluster dimers and oligomers and present a detailed analysis of possible reaction mechanisms. We synthesize the nanocluster oligomers using monodisperse para-mercaptobenzoic acid (p-MBA)-protected gold nanoclusters with a nominal composition of Au∼250(p-MBA)n to minimize ensemble effects on size, shape, and surface structure. Ligand exchange was performed on the nanoclusters with five different dithiol linkers: 5,5′-bis(mercaptomethyl)-2,2′-bipyridine, 4,4″-thiobisbenzenethiol, benzene-1,4-dithiol, 1,4-benzenedimethanethiol, and dimercaptostilbene. Oligomer yields depend strongly on the used dithiol and on the dithiol-to-nanocluster ratio. Detailed analysis of the reaction yields in combination with simulations suggests that the system reaches a dynamic equilibrium, where ligand exchange happens continuously forming and breaking nanocluster oligomers that are bound together by short chains of disulfide-bridged dithiols. Despite the dynamic nature of the system, dithiol-induced polymerization of nanoclusters is a general and straightforward approach to produce dimers and larger oligomers of thiol-protected nanoclusters. Our work provides physical insight into, offers tools for, and reveals challenges in the controlled synthesis of covalently bound nanoparticle assemblies.

Covalently bonded multimers of Au25(SBut)18 as a conjugated system.

Aromatic dithiol linkers were used to prepare aggregates of Au25(SR)18 clusters (SR: thiolate) via ligand exchange reactions. Fractions of different aggregate sizes were separated by size exclusion chromatography (SEC). The aggregates were characterized by UV-vis absorption spectroscopy, matrix assisted laser desorption ionization (MALDI) mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy (including diffusion-ordered spectroscopy, DOSY) and small angle X-ray scattering (SAXS). At a 2 : 1 cluster : dithiol ratio, small aggregates (dimers, trimers) and also larger aggregates consisting of 10-20 Au25 clusters were formed, according to DOSY, besides unreacted (monomeric) Au25(SR)18. MALDI mass spectrometry shows signals consistent with dimers and trimers (doubly charged). The SAXS curves for the small aggregates can be well fitted by a pearl-necklace model. For the bigger aggregates the SAXS curves evidence a characteristic separation distance between the clusters within the aggregates, which is imposed by the length of the linker. The SAXS curves of these larger aggregates can be well fitted with a core-shell sphere model with a sticky hard-sphere structure factor, in agreement with closely packed aggregates. The absorption spectra of smaller aggregates resemble those of individual Au25(SR)18 clusters; however, and most importantly, the larger aggregates show completely different, less structured spectra with a new band emerging at 840 nm. We assign this drastic change in the absorption spectra and the new band to the electronic coupling between the clusters through the all aromatic linker. In accordance with this view, the aggregates formed with a linker containing methylene groups, thus breaking conjugation, do not show the band at 840 nm. By the addition of monothiols to the larger aggregates their size can be reduced through an "unlinking" reaction. This reaction also affects the band at 840 nm, which moves to higher energy when reducing the aggregate size, as would be expected within a particle in a box model. The electronic coupling between the clusters through the linker is the basis for future applications in nanoelectronics.

Size-Controllable Gold Nanopores with High SERS Activity.

Nanopore structures have been successfully employed in next-generation DNA sequencing. For more complicated protein which normally contains 20 different amino acids, identifying the fluctuation of ionic current caused by different amino acids appears inadequate for protein sequencing. Therefore, it is highly desirable to develop size-controllable nanopores with optical activity that can provide additional structural information. Herein, we discovered the novel nanopore properties of the self-assembled ultramicroelectrodes originally developed by Bard and co-workers. Using a slightly modified method, the self-assembly of 7 ± 1 nm gold nanoparticles (AuNPs) can be precisely controlled to form a gold nanoporous sphere (GPS) on the tip of a glass capillary. Different dithiol linker molecules (1,3-propanedithiol, C3; 1,6-hexanedithiol, C6; and 1,9-nonanedithiol, C9) reproducibly led to rather similar nanopore sizes (5.07 ± 0.02, 5.13 ± 0.02, and 5.25 ± 0.01 nm), respectively. The GPS nanostructures were found to exhibit high ionic current rectification as well as surface-enhanced Raman scattering (SERS) activity due to the presence of nanopores and numerous "hot spots" among the cross-linked AuNPs on the surface of GPS. The rectification effect of the small nanopores was observed even under high concentration of electrolyte (290 mM), along with SERS enhancement factors well above 1 × 105. The GPS nanostructures were successfully applied for SERS-based detection of glutathione from a single HeLa cell.

Tunable, Injectable Hydrogels Based on Peptide-Cross-Linked, Cyclized Polymer Nanoparticles for Neural Progenitor Cell Delivery.

A PEG-based cyclized vinyl polymer was synthesized via one-step RAFT polymerization and used as a precursor of injectable hydrogels. Dithiol linkers including laminin-derived peptides containing IKVAV and YIGSR sequences and DTT were used for gelation. Fast and adjustable gelation rate was achieved through nucleophile-initiated thiol-Michael reaction under physiological conditions. Low swelling ratio and moderate degradation rate of the formed hydrogels were observed. 3D encapsulation of neural progenitor cells in the synthetic hydrogel showed good cell viability over 8 days. The long-term cell survival and proliferation were promoted by the introduction of laminin-derived peptides. This hydrogel platform based on peptide-cross-linked, cyclized vinyl polymers can be used as a universal hydrogel template for 3D cell encapsulation.

Stepwise Light-Induced Dual Compaction of Single-Chain Nanoparticles.

A photochemical strategy for the sequential dual compaction of single polymer chains is introduced. Two photoreactive methacrylates, with side chains bearing either a phenacyl sulfide (PS) or an α-methylbenzaldehyde (photoenol, PE) moiety, are selectively incorporated by one-pot iterative reversible-addition fragmentation chain transfer copolymerization into the outer blocks of a well-defined poly(methyl methacrylate) based ABC triblock copolymer possessing a nonfunctional spacer block (Mn = 23 400 g mol-1 , Đ = 1.2; ≈15 units of each photoreactive moieties of each type) as well as in model statistical copolymers bearing only one type of photoreactive unit. Upon UVA irradiation, PS and PE lead to highly reactive thioaldehydes and o-quinodimethanes, which rapidly react with dithiol and diacrylate linkers, respectively. The monomerfunctional copolymers are employed to establish the conditions for controlled intramolecular photo-crosslinking, which are subsequently applied to the bifunctional triblock copolymer. All compaction/folding experiments are monitored by size-exclusion chromatography and dynamic light scattering. The dual compaction consists of two events of dissimilar amplitude: the first folding step reveals a large reduction in hydrodynamic diameters, while the second compaction lead to a far less pronounced reduction of the single-chain nanoparticles size, consistent with the reduced degrees of freedom available after the first covalent compaction step.

Highly Sensitive Plasmonic Optical Sensors Based on Gold Core-Satellite Nanostructures Immobilized on Glass Substrates.

Fabrication of discrete nanostructures consisting of noble metal nanoparticles immobilized on substrates is challenging because of structural complexity but important for chip-based plasmonic sensor technology. Here we report optical sensing capabilities of core-satellite nanostructures made of gold nanoparticles immobilized on glass substrate, which were fabricated by combining stepwise interconnection of gold nanoparticles through dithiol linkers and surface treatment using vacuum ultraviolet light. The nanostructures exhibit large changes in coupled plasmon resonance peak upon surrounding refractive index, with sensitibity of ca. 350 nm RIU(-1), thus providing highly sensitive optical sensors for determining the surrounding refractive index and detecting organic vapors.

Structure and Function of Photosystem I-[FeFe] Hydrogenase Protein Fusions: An All-Atom Molecular Dynamics Study.

All-atom molecular dynamics (MD) simulation was used to study the solution dynamics and protein-protein interactions of protein fusions of photosystem I (PSI) from Thermosynechococcus elongatus and an [FeFe]-hydrogenase (FeFe H2ase) from Clostridium pasteurianum, a unique complex capable of photocatalytic hydrogen production. This study involved fusions of these two proteins via dithiol linkers of different length including decanedithiol, octanedithiol, and hexanedithiol, for which experimental data had previously been obtained. Evaluation of root-mean-squared deviations (RMSDs) relative to the respective crystal structures of PSI and the FeFe H2ase shows that these fusion complexes approach stable equilibrium conformations during the MD simulations. Investigating protein mobility via root-mean-squared fluctuations (RMSFs) reveals that tethering via the shortest hexanedithiol linker results in increased atomic fluctuations of both PSI and the hydrogenase in these fusion complexes. Evaluation of the inter- and intraprotein electron transfer distances in these fusion complexes indicates that the structural changes in the FeFe H2ase arising from ligation to PSI via the shortest hexanedithiol linker may hinder electron transport in the hydrogenase, thus providing a molecular level explanation for the observation that the medium-length octanedithiol linker gives the highest hydrogen production rate.

Gold Nanoparticle Satellite Nanostructures on a Glass Substrate for Dual-responsive Optical Sensing of Organic Liquids

Abstract Core–satellite nanostructures made of gold nanoparticles were fabricated on glass substrates by controlled immobilization of the nanoparticles and VUV irradiation. Coupled SPR absorption between core and satellite nanoparticles was observed, depending on the length of the dithiol linkers. These satellite nanostructures provide an improved selectivity for distinguishing various liquids using single and coupled SPR absorption in a dual-responsive manner.

Hollow nanotubular toroidal polymer microrings

Despite the remarkable progress made in the self-assembly of nano- and microscale architectures with well-defined sizes and shapes, a self-organization-based synthesis of hollow toroids has, so far, proved to be elusive. Here, we report the synthesis of polymer microrings made from rectangular, flat and rigid-core monomers with anisotropically predisposed alkene groups, which are crosslinked with each other by dithiol linkers using thiol-ene photopolymerization. The resulting hollow toroidal structures are shape-persistent and mechanically robust in solution. In addition, their size can be tuned by controlling the initial monomer concentrations, an observation that is supported by a theoretical analysis. These hollow microrings can encapsulate guest molecules in the intratoroidal nanospace, and their peripheries can act as templates for circular arrays of metal nanoparticles.

Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides.

Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the SNAr reaction between cysteine thiolates and a new generation of highly reactive perfluoroaromatic small molecule linkers. This strategy enabled us to simultaneously "scan" two cysteine residues positioned from i, i + 1 to i, i + 14 sites in a polypeptide, producing 98 macrocyclic products from reactions of 14 peptides with 7 linkers. A complementary reverse strategy was developed; cysteine residues within the polypeptide were first modified with non-bridging perfluoroaryl moieties and then commercially available dithiol linkers were used for macrocyclization. The highly convergent, site-independent, and modular nature of these two strategies coupled with the unique chemoselectivity of a SNAr transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.