Nanoparticle theranostics for applications in cancer diagnostics and cancer therapy

Traditionally, medicine has been conducted using a diagnostic procedure followed by an appropriate therapy and monitored were possible. On the whole, these steps have happened independently of each other. In recent years however many have started to question this independent approach and have asked whether technologies that seek to combine diagnostics and therapies would be more beneficial at treating diseases. This new medical discipline has been termed theranostics. The aim of this project was to design and synthesise a novel theranostic nanoparticle, using a micelle forming amphiphilic carbohydrate, with the overall hypothesis of determining whether using a nanomedicine that can simultaneously image and treat would improve the effectiveness of a cancer treatment. Super paramagnetic iron oxide nanoparticles (IONPs) have gained considerable attention as an MRI contrast agent due to their unique magnetic properties and relatively inoffensive toxicity profile. Before IONPs may be used in a biological environment they must overcome several challenges, including being stable to aggregation and organ targeting. In this project a modified chitosan amphiphilic polymer was used to successfully formulate IONPs into colloidal stable aqueous dispersions using two different methods which produced blackberry nanoparticles and raspberry nanoparticles. The raspberry nanoparticles were extensively characterised in vitro and in vivo and were found to be highly effective as an MRI imaging probe for the liver and spleen. Following this, they were tested for their cancer imaging properties in an in vivo mouse tumour model. The drug loading capacity of the raspberry nanoparticles was investigated using lomustine, paclitaxel and methotrexate, however no effective drug encapsulation was determined in this project. Overall, a highly effective MRI probe was engineered and characterised, although its future success will be determined by its activity towards a disease target

The Milky Way: Paediatric milk-based dispersible tablets prepared by direct compression - a proof-of-concept study

Objectives: Dispersible tabletsare proposed by the World Health Organisation as the preferred paediatric formulation. It was hypothesised that tablets made from a powdered milk-base that disperse in water to form suspensions resembling milk might be a useful platform to improve acceptability in children. Methods: Milk-based dispersible tablets containing various types of powdered milk and infant formulae were formulated. The influence of milk type and content on placebo tablet properties was investigated using a design-of-experiments approach. Responses measured included friability, crushing strength, and disintegration time. Additionally, the influence of compression force on the tablet properties of a model formulation was studied by compaction simulation. Key findings: Disintegration times increased as milk content increased. Compaction simulation studies showed that compression force influenced disintegration time. These results suggest that the milk content, rather than type, and compression force were the most important determinants of disintegration. Conclusion: Up to 30% milk could be incorporated to produce 200 mg 10 mm flat-faced placebo tablets by direct compression disintegrating within 3 minutes in 5-10 ml of water, which is a realistic administration volume in children. The platform could accommodate 30% of a model API (caffeine citrate)

Facile aqueous, room temperature preparation of high transverse relaxivity clustered iron oxide nanoparticles

Clustering superparamagnetic iron oxide nanoparticles (SPIONs) is one method of providing the biomedical benefits of larger SPIONs [e.g. superior T2 weighted magnetic resonance imaging (MRI) contrast] without increasing particle size. The work presented herein, describes the facile synthesis of clustered SPIONs that are suitable for MRI applications, by using a chitosan based polymer: N-palmitoyl-N-monomethyl-N-N-dimethyl-N-N-N-trimethyl-6-O-glycolchitosan (GCPQ) and aqueous nanoprecipitation followed by probe sonication, in the absence of organic solvents or elevated temperatures. The resulting clustered SPIONs consist of individual 8 nm iron oxide nanoparticles clustered into a 150 nm particle with a positive zeta potential (+23 mV) at neutral pH. X-ray diffraction confirms the presence of crystalline magnetic iron oxide, while magnetometer experiments show the clustered SPIONs are superparamagnetic giving an overall M s of 63.5 ± 1.3 emu g −1 . Relaxometry analyses revealed that the clustered SPIONs (inclusive of coatings) had a high r 2 value of 294.8 mM −1 s −1 and an r 2 /r 1 of 21.1 making the clustered SPIONs suitable for T2 weighted (negative) MRI contrast imaging applications. The resulting clustered SPIONs demonstrate that highly sensitive T2 contrast agents may be produced in mild room temperature conditions, without the need for organic solvents or low molecular weight surfactants

Clustering superparamagnetic iron oxide nanoparticles produces organ-targeted high-contrast magnetic resonance images

AIM: Superparamagnetic iron oxide nanoparticles (SPIONs) have been used as magnetic resonance imaging (MRI) contrast agents; however, a number of T2-weighted imaging SPIONs have been withdrawn due to their poor clinical contrast performance. Our aim was to significantly improve SPION T2-weighted MRI contrast by clustering SPIONs within novel chitosan amphiphiles. METHODS: Clustering SPIONs was achieved by encapsulation of hydrophobic-coated SPIONs with an amphiphilic chitosan polymer (GCPQ). RESULTS: Clustering increases the spin-spin (r2) to spin-lattice (r1) relaxation ratio (r2/r1) from 3.0 to 79.1, resulting in superior contrast. Intravenously administered clustered SPIONs accumulated only in the liver and spleen; with the reduction in T2 relaxation confined, in the liver, to the extravascular space, giving clear MRI images of the liver vasculature

Recognition memory, self-other source memory, and theory-of-mind in children with autism spectrum disorder.

This study investigated semantic and episodic memory in autism spectrum disorder (ASD), using a task which assessed recognition and self-other source memory. Children with ASD showed undiminished recognition memory but significantly diminished source memory, relative to age- and verbal ability-matched comparison children. Both children with and without ASD showed an “enactment effect”, demonstrating significantly better recognition and source memory for self-performed actions than other-person-performed actions. Within the comparison group, theory-of-mind (ToM) task performance was significantly correlated with source memory, specifically for other-person-performed actions (after statistically controlling for verbal ability). Within the ASD group, ToM task performance was not significantly correlated with source memory (after controlling for verbal ability). Possible explanations for these relations between source memory and ToM are considered

An Expert Discussion on Autism and Empathy

Autism in Adulthood strives to be a home for constructive interprofessional dialogue on pressing issues that affect the lives of autistic adults. We do this in a number of ways. One is to hold roundtable discussions with experts in the field. Our first roundtable discussion concerns the topic of autism and empathy, a hotly debated construct within and outside academia.1 As early as 1962, psychologists described children with “autistic psychopathy” as being “unable to achieve empathy.”2 An empathy deficit has since become a core feature in many conceptualizations of autism, including the theory of mind (or mind-blindness) model and the empathizing-systematizing model.3 Researchers have distinguished between cognitive empathy (or theory of mind; the capacity to understand another person's perspective or mental state) and emotional or affective empathy (the capacity to experience affective reactions to the observed experiences of others), asserting that autistic individuals have deficits in the former, but not in the latter.4,5 Even this position, however, has been widely criticized by autistic individuals in online forums. For example, purported deficits in cognitive empathy may be a problem of experiencing too much emotional empathy or of needing more time to process empathy's cognitive aspects.6 Or they may be due to a breakdown in mutual understanding between people who experience the world differently (and may apply just as much to neurotypical people failing to empathize with autistic people as it does in the opposite direction).7 Autistic adults often argue that the notion that autistic individuals lack empathy or theory of mind is dehumanizing and perpetuates dangerous stereotypes and oversimplifications.6 Following is a transcript of our roundtable discussion, with minor edits for clarity

Dominance relationships and coalitionary aggression against conspecifics in female carrion crows

Funding: European Research Council (ERCStG-336536 FuncSpecGen to J.W.), the Swedish Research Council Vetenskapsrådet (621-2013-4510 to J.W.), Knut and Alice Wallenberg Foundation (to J.W.) and Tovetorp fieldstation through Stockholm University.Cooperation is a prevailing feature of many animal systems. Coalitionary aggression, where a group of individuals engages in coordinated behaviour to the detriment of conspecific targets, is a form of cooperation involving complex social interactions. To date, evidence has been dominated by studies in humans and other primates with a clear bias towards studies of male-male coalitions. We here characterize coalitionary aggression behaviour in a group of female carrion crows consisting of recruitment, coordinated chase, and attack. The individual of highest social rank liaised with the second most dominant individual to engage in coordinated chase and attack of a lower ranked crow on several occasions. Despite active intervention by the third most highly ranked individual opposing the offenders, the attack finally resulted in the death of the victim. All individuals were unrelated, of the same sex, and naive to the behaviour excluding kinship, reproduction, and social learning as possible drivers. Instead, the coalition may reflect a strategy of the dominant individual to secure long-term social benefits. Overall, the study provides evidence that members of the crow family engage in coordinated alliances directed against conspecifics as a possible means to manipulate their social environment.Publisher PDFPeer reviewe

Abstract Reasoning and Friendship in High Functioning Preadolescents with Autism Spectrum Disorders

To investigate the relationship between cognitive and social functioning, 20 Israeli individuals with HFASD aged 8–12 and 22 age, maternal education, and receptive vocabulary–matched preadolescents with typical development (TYP) came to the lab with a close friend. Measures of abstract reasoning, friendship quality, and dyadic interaction during a play session were obtained. As hypothesized, individuals with HFASD were significantly impaired in abstract reasoning, and there were significant group differences in friend and observer reports of friendship quality. There also was consistency in reports between friends. Two factors—“relationship appearance” and “relationship quality” described positive aspects of the relationships. Disability status and age related to relationship appearance. Proband abstract reasoning was related to relationship quality

Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study

A decrease in interaction between brain regions is observed in individuals with autism spectrum disorder (ASD), which is believed to be related to restricted neural network access in ASD. Propranolol, a beta-adrenergic antagonist, has revealed benefit during performance of tasks involving flexibility of access to networks, a benefit also seen in ASD. Our goal was to determine the effect of propranolol on functional connectivity in ASD during a verbal decision making task as compared to nadolol, thereby accounting for the potential spurious fMRI effects due to peripheral hemodynamic effects of propranolol. Ten ASD subjects underwent fMRI scans after administration of placebo, propranolol or nadolol, while performing a phonological decision making task. Comparison of functional connectivity between pre-defined ROI-pairs revealed a significant increase with propranolol compared to nadolol, suggesting a potential imaging marker for the cognitive effects of propranolol in ASD

Migratory Pathways and Connectivity in Asian Houbara Bustards: Evidence from 15 Years of Satellite Tracking

Information on migratory pathways and connectivity is essential to understanding population dynamics and structure of migrant species. Our manuscript uses a unique dataset, the fruit of 103 individual Asian houbara bustards captured on their breeding grounds in Central Asia over 15 years and equipped with satellite transmitters, to provide a better understanding of migratory pathways and connectivity; such information is critical to the implementation of biologically sound conservation measures in migrant species. At the scale of the distribution range we find substantial migratory connectivity, with a clear separation of migration pathways and wintering areas between western and eastern migrants. Within eastern migrants, we also describe a pattern of segregation on the wintering grounds. But at the local level connectivity is weak: birds breeding within the limits of our study areas were often found several hundreds of kilometres apart during winter. Although houbara wintering in Arabia are known to originate from Central Asia, out of all the birds captured and tracked here not one wintered on the Arabian Peninsula. This is very likely the result of decades of unregulated off-take and severe habitat degradation in this area. At a time when conservation measures are being implemented to safeguard the long-term future of this species, this study provides critical data on the spatial structuring of populations