Dynamic covalent nanoparticle building blocks

The author thanks the Royal Society of Edinburgh and Scottish Government for a personal research fellowship and gratefully acknowledge the EPSRC (EP/K016342/1) and Leverhulme Trust (RPG-2015-042) for funding our work on dynamic nanomaterials.Rational and generalizable methods for engineering surface functionality will be crucial to realizing the technological potential of nanomaterials. Nanoparticle-bound dynamic covalent exchange combines the error-correcting and environment-responsive features of equilibrium processes with the stability, structural precision and vast diversity of covalent chemistry, defining a new and powerful approach for manipulating structure, function and properties at nanomaterial surfaces. Dynamic covalent nanoparticle (DCNP) building blocks thus present a whole host of possibilities for constructing adaptive systems, devices and materials that incorporate both nanoscale and molecular functional components. At the same time, DCNPs have the potential to reveal fundamental insights regarding dynamic and complex chemical systems confined to nanoscale interfaces.Publisher PDFPeer reviewe

Dynamic covalent assembly and disassembly of nanoparticle aggregates

This work was supported by the EPSRC (EP/K016342/1 and EP/J500549/1), the University of St Andrews and by a Royal Society of Edinburgh/Scottish Government Fellowship (E.R.K.).The quantitative assembly and disassembly of a new type of dynamic covalent nanoparticle (NP) building block is reported. In situ spectroscopic characterization reveals constitutionally adaptive NP-bound monolayers of boronate esters. Ditopic linker molecules are used to produce covalently connected AuNP assemblies, displaying open dendritic morphologies, and which, despite being linked by covalent bonds, can be fully disassembled on application of an appropriate chemical stimulus.PostprintPeer reviewe

A dissipative reaction network drives transient solid-liquid and liquid-liquid phase cycling of nanoparticles

Financial support for this work was provided by the University of St Andrews and EaStCHEM, and the Leverhulme Trust [Grant RPG-2019-155].Transient states maintained by energy dissipation are an essential feature of dynamic systems where structures and functions are regulated by fluxes of energy and matter through chemical reaction networks. Perfected in biology, chemically fueled dissipative networks incorporating nanoscale components allow the unique properties of nanomaterials to be bestowed with spatiotemporal adaptability and chemical responsiveness. We report the transient dispersion of gold nanoparticles in water, powered by dissipation of a chemical fuel. A dispersed state that is generated under nonequilibrium conditions permits fully reversible solid–liquid or liquid–liquid phase transfer. The molecular basis of the out-of-equilibrium process is reversible covalent modification of nanoparticle-bound ligands by a simple inorganic activator. Activator consumption by a coupled dissipative reaction network leads to autonomous cycling between phases. The out-of-equilibrium lifetime is tunable by adjusting pH, and reversible phase cycling is reproducible over several cycles.Publisher PDFPeer reviewe

A general one-step synthesis of alkanethiyl-stabilized gold nanoparticles with control over core size and monolayer functionality

Funding: Engineering and Physical Sciences Research Council - EP/M506631/1, EP/J500549/1, EP/K016342/1; Leverhulme Trust - RPG-2015-042; Army Research Office - W911NF-20-1-0233; University of St Andrews; Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología - AC17-14; European Commission - AC17-14.In spite of widespread interest in the unique size-dependent properties and consequent applications of gold nanoparticles (AuNPs), synthetic protocols that reliably allow for independent tuning of surface chemistry and core size, the two critical determinants of AuNP properties, remain limited. Often, core size is inherently affected by the ligand structure in an unpredictable fashion. Functionalized ligands are commonly introduced using postsynthesis exchange procedures, which can be inefficient and operationally delicate. Here, we report a one-step protocol for preparing monolayer-stabilized AuNPs that is compatible with a wide range of ligand functional groups and also allows for the systematic control of core size. In a single-phase reaction using the mild reducing agent tert-butylamine borane, AuNPs that are compatible with solvents spanning a wide range of polarities from toluene to water can be produced without damaging reactive chemical functionalities within the small-molecule surface-stabilizing ligands. We demonstrate that the rate of reduction, which is easily controlled by adjusting the period over which the reducing agent is added, is a simple parameter that can be used irrespective of the ligand structure to adjust the core size of AuNPs without broadening the size distribution. Core sizes in the range of 2–10 nm can thus be generated. The upper size limit appears to be determined by the nature of each specific ligand/solvent pairing. This protocol produces high quality, functionally sophisticated nanoparticles in a single step. By combining the ability to vary size-related nanoparticle properties with the option to incorporate reactive functional groups at the nanoparticle–solvent interface, it is possible to generate chemically reactive colloidal building blocks from which more complex nanoparticle-based devices and materials may subsequently be constructed.Publisher PDFPeer reviewe

Probing multiscale factors affecting the reactivity of nanoparticle-bound molecules

I. K. M., W. E., E. J. H, S. S. and E. R. K. are grateful for funding from the Leverhulme Trust [RPG-2015-042], the Engineering and Physical Sciences Research Council [EP/K016342/1], the University of St Andrews, and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT) [Ph.D. studentship to SS: EP/L016419/1]. D. M. and P.P thank the Italian Ministry of University Research (MIUR) for funding [RBSI14PBC6].The structures and physicochemical properties of surface-stabilizing molecules play a critical role in defining the properties, interactions, and functionality of hybrid nanomaterials such as monolayer-stabilized nanoparticles. Concurrently, the distinct surface-bound interfacial environment imposes very specific conditions on molecular reactivity and behavior in this setting. Our ability to probe hybrid nanoscale systems experimentally remains limited, yet understanding the consequences of surface confinement on molecular reactivity is crucial for enabling predictive nanoparticle synthon approaches for postsynthesis engineering of nanoparticle surface chemistry and construction of devices and materials from nanoparticle components. Here, we have undertaken an integrated experimental and computational study of the reaction kinetics for nanoparticle-bound hydrazones, which provide a prototypical platform for understanding chemical reactivity in a nanoconfined setting. Systematic variation of just one molecular-scale structural parameter—the distance between reactive site and nanoparticle surface—showed that the surface-bound reactivity is influenced by multiscale effects. Nanoparticle-bound reactions were tracked in situ using 19F NMR spectroscopy, allowing direct comparison to the reactions of analogous substrates in bulk solution. The surface-confined reactions proceed more slowly than their solution-phase counterparts, and kinetic inhibition becomes more significant for reactive sites positioned closer to the nanoparticle surface. Molecular dynamics simulations allowed us to identify distinct supramolecular architectures and unexpected dynamic features of the surface-bound molecules that underpin the experimentally observed trends in reactivity. This study allows us to draw general conclusions regarding interlinked structural and dynamical features across several length scales that influence interfacial reactivity in monolayer-confined environments.PostprintPeer reviewe

Optical trapping of ultrasmooth gold nanoparticles in liquid and air

This work is supported by the UK Engineering and Physical Sciences Research Council for funding through Grant (Nos. EP/P030017/1, EP/J01171X/1, EP/K016342/1, and EP/M506631/1) and the Leverhulme Trust (No. RPG-2015-042).Optical manipulation of gold nanoparticles has emerged as an exciting avenue for studies in nanothermometry, cell poration, optical binding, and optomechanics. However, conventional gold nanoparticles usually depart from a spherical shape, making such studies less controlled and leading to potential artifacts in trapping behavior. We synthesize ultrasmooth gold nanoparticles, which offer improved circularity and monodispersity. In this article, we demonstrate the advantages of such nanoparticles through a series of optical trapping experiments in both liquid and air. Compared to their conventional counterparts, ultrasmooth gold nanoparticles exhibit up to a two-fold and ten-fold reduction in standard deviation for trap stiffness measurements in liquid and air, respectively. They will enable more controlled studies of plasmon mediated light-matter interactions.Publisher PDFPeer reviewe

Probing the interaction of nanoparticles with small molecules in real time via quartz crystal microbalance monitoring

Y. Y. acknowledges University College London (UCL) for the Overseas Research Scholarship and the Graduate Research Scholarship. The project received funding from the European Unions Horizon 2020 research and innovation programme under grant agreement no. 633635 (DIACHEMO) and the EPSRC (grant number EP/J500549/1).Despite extensive advances in the field of molecular recognition, the real-time monitoring of small molecule binding to nanoparticles (NP) remains a challenge. To this end, we report on a versatile approach, based on quartz crystal microbalance with dissipation monitoring, for the stepwise in situ quantification of gold nanoparticle (AuNPs) immobilisation and subsequent uptake and release of binding partners. AuNPs stabilised by thiol-bound ligand shells of prescribed chemical composition were densely immobilised onto gold surfaces via dithiol linkers. The boronate ester formation between salicylic acid derivatives in solution and boronic acids in the AuNP ligand shell was then studied in real time, revealing a drastic effect of both ligand architecture and Lewis base concentration on the interaction strength. The binding kinetics were analysed with frequency response modelling for a thorough comparison of binding parameters including relaxation time as well as association rate constant. The results directly mirror those from previously reported in-depth studies using nuclear magnetic resonance spectroscopy. By achieving quantitative characterisation of selective binding of analytes with molecular weight below 300 Da, this new method enables rapid, low cost, rational screening of AuNP candidates for molecular recognition.Publisher PDFPeer reviewe

Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer

Purpose: This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707