Exploiting topology-directed nanoparticle disassembly for triggered drug delivery

YesThe physical properties of cyclic and linear polymers are markedly different; however, there are few examples which exploit these differences in clinical applications. In this study, we demonstrate that self-assemblies comprised of cyclic-linear graft copolymers are significantly more stable than the equivalent linear-linear graft copolymer assemblies. This difference in stability can be exploited to allow for triggered disassembly by cleavage of just a single bond within the cyclic polymer backbone, via disulfide reduction, in the presence of intracellular levels of l-glutathione. This topological effect was exploited to demonstrate the first example of topology-controlled particle disassembly for the controlled release of an anti-cancer drug in vitro. This approach represents a markedly different strategy for controlled release from polymer nanoparticles and highlights for the first time that a change in polymer topology can be used as a trigger in the design of delivery vehicles. We propose such constructs, which demonstrate disassembly behavior upon a change in polymer topology, could find application in the targeted delivery of therapeutic agents.ERC are acknowledged for support to M.C.A., A.P.D. (grant number: 681559) and R.O.R. (grant number: 615142)

1D vs. 2D shape selectivity in the crystallization-driven self-assembly of polylactide block copolymers

yes2D materials such as graphene, LAPONITE® clays or molybdenum disulfide nanosheets are of extremely high interest to the materials community as a result of their high surface area and controllable surface properties. While several methods to access 2D inorganic materials are known, the investigation of 2D organic nanomaterials is less well developed on account of the lack of ready synthetic accessibility. Crystallization-driven self-assembly (CDSA) has become a powerful method to access a wide range of complex but precisely-defined nanostructures. The preparation of 2D structures, however, particularly those aimed towards biomedical applications, is limited, with few offering biocompatible and biodegradable characteristics as well as control over self-assembly in two dimensions. Herein, in contrast to conventional self-assembly rules, we show that the solubility of polylactide (PLLA)-based amphiphiles in alcohols results in unprecedented shape selectivity based on unimer solubility. We use log Poct analysis to drive solvent selection for the formation of large uniform 2D diamond-shaped platelets, up to several microns in size, using long, soluble coronal blocks. By contrast, less soluble PLLA-containing block copolymers yield cylindrical micelles and mixed morphologies. The methods developed in this work provide a simple and consistently reproducible protocol for the preparation of well-defined 2D organic nanomaterials, whose size and morphology are expected to facilitate potential applications in drug delivery, tissue engineering and in nanocomposites.University of Warwick, Materials GRP, EPSRC, The Royal Society, ER

Exploiting nucleobase-containing materials : from monomers to complex morphologies using RAFT dispersion polymerization

yesThe synthesis of nucleobase-containing polymers was successfully performed by RAFT dispersion polymerization in both chloroform and 1,4-dioxane and self-assembly was induced by the polymerizations. A combination of scattering and microscopy techniques were used to characterize the morphologies. It is found that the morphologies of self-assembled nucleobase-containing polymers are solvent dependent. By varying the DP of the core-forming block, only spherical micelles with internal structures were obtained in chloroform when using only adenine-containing methacrylate or a mixture of adenine-containing methacrylate and thymine-containing methacrylate as monomers. However, higher order structures and morphology transitions were observed in 1,4-dioxane. A sphere-rod-lamella-twisted bilayer transition was observed in this study. Moreover, the kinetics of the dispersion polymerizations were studied in both solvents, suggesting a different formation mechanism in these systems.University of Warwick, Swiss National Science Foundation, EPSRC, Birmingham Science City, Advanatfe West Midlands (AWM), European Regional Development Fund (ERDF), Science City Research Alliance, Higher Education Funding Council for England (HEFCE

Fabrication of crystals from single metal atoms

YesMetal nanocrystals offer new concepts for the design of nanodevices with a range of potential applications. Currently the formation of metal nanocrystals cannot be controlled at the level of individual atoms. Here we describe a new general method for the fabrication of multi-heteroatom-doped graphitic matrices decorated with very small, ångström-sized, three-dimensional (3D)-metal crystals of defined size. We irradiate boron-rich precious-metal-encapsulated self-spreading polymer micelles with electrons and produce, in real time, a doped graphitic support on which individual osmium atoms hop and migrate to form 3D-nanocrystals, as small as 15 Å in diameter, within 1 h. Crystal growth can be observed, quantified and controlled in real time. We also synthesize the first examples of mixed ruthenium–osmium 3D-nanocrystals. This technology not only allows the production of ångström-sized homo- and hetero-crystals, but also provides new experimental insight into the dynamics of nanocrystals and pathways for their assembly from single atoms.We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RDF 2013-14 to NPEB), the Swiss National Science Foundation (Grant No. PA00P2_145308 to NPEB and PBNEP2_142949 to APB), the ERC (Grant No. 247450 to PJS), EPSRC (EP/G004897/1 to RKOR, and EP/F034210/1 to PJS) and Science City (AWM/ERDF) for support. We thank the Wellcome Trust (Grant No. 055663/Z/98/Z) for funding the Electron Microscopy Facility, School of Life Sciences, University of Warwick. We also thank COST Action CM1105 for stimulating discussions, Thomas Wilks for supplying the micelle image for Figure 1, and the Australian Synchrotron and the University of Monash for allocation of time on the SAXS/ WAXS beamline and funding. The 2000FX Gatan Orius digital TEM camera used in this research was funded by Science City: Creating and Characterizing Next Generation Advanced Materials, with support from Advantage West Midlands and part funded by the European Regional Development Fund

Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Peer reviewe

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

Erratum: "A Gravitational-wave Measurement of the Hubble Constant Following the Second Observing Run of Advanced LIGO and Virgo" (2021, ApJ, 909, 218)

[no abstract available