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)

Decreasing rates of disorganised attachment in infants and young children, who are at risk of developing, or who already have disorganised attachment. A systematic review and meta-analysis of early parenting interventions

BACKGROUND: Disorganised attachment patterns in infants have been linked to later psychopathology. Services have variable practices for identifying and providing interventions for families of children with disorganised attachment patterns, which is the attachment pattern leading to most future psychopathology. Several recent government reports have highlighted the need for better parenting interventions in at risk groups. OBJECTIVES: The objective of this review and meta-analysis was to evaluate the clinical effectiveness of available parenting interventions for families of children at high risk of developing, or already showing, a disorganised pattern of attachment. METHODS: Population: Studies were included if they involved parents or caregivers of young children with a mean age under 13 years who had a disorganised classification of attachment or were identified as at high risk of developing such problems. Included interventions were aimed at parents or caregivers (e.g. foster carers) seeking to improve attachment. Comparators included an alternative intervention, an attention control, treatment as usual or no intervention. The primary outcome was a disorganised pattern in childhood measured using a validated attachment instrument. Studies that did not use a true Randomised Controlled Trial (RCT) design were excluded from the review. Both published and unpublished papers were included, there were no restrictions on years since publication and foreign language papers were included where translation services could be accessed within necessary timescales. RESULTS: A comprehensive search of relevant databases yielded 15,298 papers. This paper reports a systematic review as part of an NIHR HTA study identifying studies pre-2012, updated to include all papers to October 2016. Two independent reviewers undertook two stage screening and data extraction of the included studies at all stages. A Cochrane quality assessment was carried out to assess the risk of bias. In total, fourteen studies were included in the review. In a meta-analysis of these fourteen studies the interventions saw less disorganised attachment at outcome compared to the control (OR = 0.50, (0.32, 0.77), p = 0.008). The majority of the interventions targeted maternal sensitivity. We carried out exploratory analyses to examine factors that may influence treatment outcome but these should be treated with caution given that we were limited by small numbers of studies. CONCLUSIONS: Parenting interventions that target parental sensitivity show promise in reducing disorganised attachment. This is limited by few high quality studies and the fact that most studies are with mothers. More high quality randomised controlled trials are required to elucidate this further

Daily mood, partner support, sexual interest, and sexual activity among adolescent women

This is a post print version of the article. The official published version can be accessed from the link below.Objective: to examine day-to-day associations of coitus, sexual interest, partner emotional support, negative mood and positive mood among adolescent women. Methods: Women (ages 14 – 17 at enrollment; N=146) enrolled from one of three adolescent primary care clinics completed up to five 84-day diaries over a 27-month period. The diaries assessed partner interactions, sexual activity, substance use and mood. Partner-specific measures assessed on each day included partner emotional support (4 items; alpha = 0.94), argument with a partner (no/yes) and coitus (no/yes). Within-day measures assessed marijuana use (no/yes), Positive Mood (3-items; alpha = 0. 86); Negative Mood (3-items; alpha = 0.82) and Sexual Interest (1-item). Lagged measures of mood and sexual activity were included in multivariate models to control for recent mood and sexual behavior effects on current day mood and coitus. Two main analyses were conducted: coitus as a predictor of positive and negative mood; and the role of positive and negative mood as predictors of coitus. Analyses were conducted by multivariate mixed effect regression and mixed effect logistic regression models. Results: Data represent 28,376 days from 146 participants. The average number of diary days was 194 days per participant. Sexual activity was reported on 8.3% of days, with condoms used for 27.0% of these coital events. Marijuana was used on 11% of days. Significant predictors of positive mood on a given day included partner support, marijuana use, and coitus. Negative mood was associated with having an argument with a partner and with prior day coitus. Predictors of coitus on a given day included age (Odds ratio = 1.22), increased coital frequency in previous week (OR = 1.49), coitus on the previous day (1.21), increased same-day sexual interest (OR = 2.8) and decreased same-day negative mood (OR = 0.92). Conclusions: The data demonstrate complex associations of sexual interest, mood, partner interactions and sexual activity

Gaia: Establishing the world’s first climate Command and Control (C2) centre

Establishing Gaia, a Command-and-Control Centre focused on climate activity, based in Wales. It aims to apply command and control principles to the evolving map of climate data and explore how such data can be integrated with policy, and with other information: resources and vulnerabilities to influence behaviour change on a regional and national level

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

Arene ruthenium dithiolato-carborane complexes for boron neutron capture theory (BNCT)

YesWe report the effect of low-energy thermal neutron irradiation on the antiproliferative activities of a highly hydrophobic organometallic arene ruthenium dithiolatoecarborane complex [Ru(p-cymene) (1,2- dicarba-closo-dodecarborane-1,2-dithiolato)] (1), and of its formulation in Pluronic® triblock copolymer P123 coreeshell micelles (RuMs). Complex 1 was highly active, with and without neutron irradiation, towards human ovarian cancer cells (A2780; IC50 0.14 mM and 0.17 mM, respectively) and cisplatinresistant human ovarian cancer cells (A2780cisR; IC50 0.05 and 0.13 mM, respectively). Complex 1 was particularly sensitive to neutron irradiation in A2780cisR cells (2.6 more potent after irradiation compared to non-irradiation). Although less potent, the encapsulated complex 1 as RuMs nanoparticles resulted in higher cellular accumulation (2.5 ), and was sensitive to neutron irradiation in A2780 cells (1.4 more potent upon irradiation compared to non-irradiation).We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RD14102 to NPEB), the University of Birmingham/EPSRC Follow-on- Fund (Grant No UOBFOF026 to BP), the ERC (Grant No. 247450 to PJS), EPSRC (EP/F034210/1 to PJS)

Precious metal carborane polymer nanoparticles: characterisation of micellar formulations and anticancer activity

YesWe report the encapsulation of highly hydrophobic 16-electron organometallic ruthenium and osmium carborane complexes [Ru/Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolate)] (1 and 2) in Pluronic® triblock copolymer P123 core–shell micelles. The spherical nanoparticles RuMs and OsMs, dispersed in water, were characterized by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and synchrotron small-angle X-ray scattering (SAXS; diameter ca. 15 and 19 nm, respectively). Complexes 1 and 2 were highly active towards A2780 human ovarian cancer cells (IC50 0.17 and 2.50 μM, respectively) and the encapsulated complexes, as RuMs and OsMs nanoparticles, were less potent (IC50 6.69 μM and 117.5 μM, respectively), but more selective towards cancer cells compared to normal cells.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 APB, and EP/F034210/1 to PJS), Institute of Advanced Study (IAS) – University of Warwick (Fellowship to JJSB), and Science City (AWM/ERDF) for support. We thank the Wellcome Trust (055663/Z/98/Z) for funding to the Electron Microscopy Facility, School of Life Sciences, University of Warwick