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Tumour microenvironment responsive polymeric particles for the delivery of chemotherapy
No full textCancers remain one of the most debilitating diseases and are associated with a high morbidity and mortality. Current chemotherapy treatments are associated with severe adverse events arising from off-target toxicities which can limit the dose given and so reduce the efficacy of treatment. The loading of these cytotoxic drugs into particles < 1000 nm in diameter is an established approach to minimize the off-target toxicity and increase efficacy. These loaded particles are able to limit systemic exposure of the free drug and can accumulate at the tumour site, increasing local concentrations of the drug. However, limited clinical benefit over the free drug has been seen with the current generation of particles, with research into a new generation of polymeric particles with triggerable and targeted behaviour ongoing.
In this thesis block-co-polymers (BCPs) were synthesised using poly(ethylene glycol) (PEG) and responsive hydrophobic monomers. These BCPs were hypothesised to form particles that would be able to encapsulate cytotoxic drugs with minimal leakage until triggered by a tumour specific stimulus. The nature of the responsive units was such that upon triggering, toxic compounds would be generated in the tumour environment via self-immolation adding to the cytotoxicity produced by the encapsulated chemotherapy. The self-assembly of the BCPs was investigated in order to gain control over particle morphology, followed by the evaluation of responsive behaviours. Drug loading was then performed followed by in vitro and in vivo evaluation of these formulations.
The synthesis of the BCPs was optimised using an activators regenerated by electron transfer (ARGET) atom transfer radical polymerisation (ATRP) reaction that avoided degradation of the aryl azide capping group by reducing the copper content and conducting the reaction at room temperature (Chapter 2). This allowed the reaction to proceed without modification between monomers giving a good polydispersity (1.16 – 1.37). The monomer units contained a self-immolative group that was masked by the responsive moiety, either aryl azide or aryl boronate, which was anticipated to give responsive behaviour towards hydrogen sulfide (H2S) and hydrogen peroxide (H2O2) respectively. Linking the self-immolative group to the ethyl methacrylate was either a carbamate or thiocarbamate bond.
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The self-assembly of the BCPs was conducted via nanoprecipitation using different organic solvents (DMF, THF, DMSO) and the anti-solvent PBS, with particle analysis via dynamic light scattering (DLS), cryo-transmission electron microscopy (TEM), cryo- tomography and small angle x-ray scattering (SAXS) (Chapter 3 and 4). In vitro triggering of particles was conducted using the H2S salt, NaSH, for the aryl azide BCPs (Chapter 3) or H2O2 for the aryl boronates (Chapter 4). The outcome of triggering on the particles was dependent upon the relative polarity of the bilayer and the pH of the triggering solution, with the more non-polar BCPs forming cross-linked structures at pH 7.4. The triggering of thiocarbamate containing aryl boronate BCP particles was found to generate H2S in the presence of carbonic anhydrase, a ubiquitous endogenous enzyme.
Loading of the particles with the cytotoxic drugs was performed using passive and active loading techniques. The aryl azide BCP particles were found to be unable to entrap useful amounts of either drug. The aryl boronate BCP particles were able to entrap 10-fold higher amounts of doxorubicin. These particles were evaluated in vitro which revealed an increased IC50 for the thiocarbamate containing particles. In vivo toxicity evaluation with Balb/c mice was piloted. The tested carbamate containing aryl boronate particles was found to be toxic to the mice.
This thesis explored the use of two endogenous triggers with self-immolative responsive groups. It was found that the aryl azide required a polar environment to trigger effectively, which limited loading and as such, alternate polymer structures would be required for use with aryl azide triggering. Aryl boronate particles achieved loading and triggering, although concentration of the formulation was required to reach clinically relevant concentrations of doxorubicin, which led to toxicity. Loading of the aryl- boronate particles therefore needs to be increased or used with a more potent drug. The thiocarbamate containing aryl boronate particles did however lead to the generation of H2S, and with a more potent azide-capped prodrug, polymer toxicity may be avoided. Alternatively, these particles could find use in pathologies characterised by oxidative stress, such as ischemia/reperfusion in cardiac or cerebral tissue, where generation of H2S has been shown to be protective
Characterization of atherosclerotic plaque with MARS imaging
Get PDFThis thesis illustrates the ability of MARS photon counting spectral CT (SPCCT) to identify and quantify intrinsic features of atherosclerotic plaque responsible for its rupture.
Atherosclerosis is a disease in which plaque build-up in the arterial wall that can rupture and cause luminal occlusion leading to vascular insufficiency to the end organ. It is an ongoing degenerative process with grave consequences; necessitating timely identification of rupture prone plaque for risk stratification and mitigation of the disease. An estimated eight carotid endarterectomies are required to prevent one stroke in symptomatic patients with severe carotid artery stenosis whereas 30 carotid endarterectomies are required to prevent one stroke in asymptomatic patients. This limited ability to select patients at risk of stroke and the numbers need to treat with invasive and complex surgery that has an intrinsic risk of iatrogenic stroke has compelled to find more efficient imaging technology. Works presented in this thesis illustrate an effectiveness of MARS SPCCT in characterising different morphological components of atheroma, essential parameters to distinguish rupture prone plaque from stable one.
Intrinsic characteristics of plaques were quantitatively and qualitatively evaluated in MARS images and compared with histopathological findings. Individual experiments explained in this thesis were designed to address research hypotheses while addressing possible sources of biases. Data analysis were done with suitable statistical tests.
This research demonstrates the effectiveness of MARS SPCCT in atherosclerotic plaque imaging. It also shows the traslational potential of MARS SPCCT for clinical application helping clinician to choose appropriate protocol thereby improving patient care
and treatment outcomes
The strategic use of ingroup favouritism as a tool to restore a threatened sense of belonging
Get PDFThe research presented in the following thesis sought to assess the association between ingroup favouritism and belonging. Four studies were conducted. Study 1 revealed that participants reported increased levels of belonging following the display of ingroup favouritism. Study 2 sought to replicate these results, and further examine that idea that threats to belonging could lead to increased levels of ingroup favouritism. Whilst Study 2 provided additional support for the idea that that ingroup favouritism led to increased belonging, no evidence was found for the premise that threats to belonging (manipulated via cyberball ostracism) would lead to increased ingroup favouritism. Studies 3a and 3b were conducted in order to examine the circumstances under which threats to belonging (again manipulated via cyberball ostracism) would lead to increased intergroup discrimination. The findings from Study 3a showed that (a) men who were ostracised and whose evaluations of ingroup and outgroup members were to be made public (i.e., seen by other men) and (b) men who were included and whose evaluations of ingroup and outgroup members were to be kept private, showed increased levels of intergroup discrimination. Contrary to expectations, the findings from Study 3b showed that women, regardless of whether they were included or ostracised and/or whether their responses were to be kept private or made public, showed pronounced levels of ingroup favouritism. In an attempt to further understand how threats to belonging might impact on ingroup favouritism amongst women an additional study was conducted. Study 4 utilised a face-to-face false feedback paradigm whereby women were either fully included, fully excluded or marginalised (i.e., excluded but given a chance to be reincluded). The results revealed that those who were marginalised showed approximately 6 times more ingroup favouritism than did those who were excluded. In overall terms, these findings suggest that ingroup favouritism leads to increased belonging, threats to belonging only lead to increased favouritism in particular circumstances
On the Dynamics of Southern Hemisphere Sudden Stratospheric Warmings
Get PDFAbove both poles harsh temperature gradients fuel strong westerlies. These winds form a vortex, which will breakdown in spring. During sudden stratospheric warmings (SSW), however, the polar vortex is dramatically disrupted earlier than expected. The Arctic experiences one SSW every two years, however, the Antarctic has only had two. The most recent Antarctic SSW occurred in 2019, here, temperatures in the stratosphere rose by 50 K, and the mesospheric winds reversed. The anomalies induced by the SSWs influence the neighbouring atmosphere. The 2019 SSW contributed to the dry spring conditions over Australia, and the ozone hole was extraordinarily small. Currently, SSWs are believed to occur as planetary waves interact with the polar atmospheric flow. Our understanding, however, remains incomplete.
This thesis investigated the dynamics of the 2019 Antarctic SSW, using MERRA-2 reanalysis data, first locally around the pole, then extending towards the equator. Later analysis was expanded to consider the 2002 SH SSW and other years with similar equatorial flow. Using geopotenital height, zonal wind and potential vorticity, we found that the mesospheric vortex was displaced and weakened - well before the SSW onset date. This motivated us to peer into the upper atmosphere, and extend our analysis to the equator. We found an intersection between two equatorial atmospheric modes, the quasi-biennial oscillation (QBO) and the semiannual oscillation (SAO), during the SH winters of 2019 and 2002. In early winter the two modes merge over the equator, during their easterly phases. Together they form a zero-wind line that stretches from the lower stratosphere into the mesosphere. This influences the meridional wave guide, and easterly momentum is deposited in the mesosphere throughout the polar winter, reducing the magnitude of the westerly winds. As the winter progresses these features descend into the stratosphere, until SSW conditions are reached. We find similar behaviour in two other years, 1988 and 2017, which have dynamical disruptions later in the spring. The timing and magnitude of the SAO-QBO intersection, in the years with SH SSW, was unique when compared to the years with a similar QBO phase.
We theorise that this early winter behaviour could be a key physical processes that decelerates the mesospheric winds, which may precondition the Southern Hemisphere for a SSW. Hence, the early winter equatorial upper stratosphere-mesosphere together with the polar mesosphere may provide critical early clues to an imminent SH SSW - potentially extending the current predictability from ∼ 10 days to multiple months
Narrative identity and wellbeing in mid-adolescence: The neglected middle child in narrative identity research
No full textThe way in which we talk about events from our past has implications for our psychological wellbeing. Narratives about past events that are high in narrative coherence may reflect a stronger narrative identity, which could be one pathway through which we can experience better psychological wellbeing. These links have been studied in adults and adolescents, but less attention has been paid empirically to those in the mid-adolescent age group. Additionally, recent research has shown that narrative coherence may be modifiable over long periods of time, but it is unknown whether or not this growth is also linked to psychological wellbeing. The work in this thesis addresses these gaps in the literature by investigating how narrative coherence presents in mid-adolescence and also what its relationship is with psychological wellbeing in this age group, both concurrently and longitudinally. It also extends on a previous longitudinal study investigating an intervention to improve narrative coherence. In the first study, we assessed the relationship between narrative coherence (causal and thematic coherence) and psychological outcomes (depressive symptoms, rumination and life satisfaction) in a sample of middle adolescents (Mage= 16.1 years). Causal coherence was associated with lower depressive symptoms and rumination, and higher life satisfaction concurrently. Causal coherence also predicted higher life satisfaction one year later. This is the first research to suggest that causal coherence may play a causal role in increasing life satisfaction in adolescents. In the second study, using the same sample as in the first study, we compared “repeaters” (those who chose to write about the same event one year later) to “non-repeaters” (those who chose a different event to write about) in terms of their narrative coherence and psychological wellbeing. There was no difference between the groups with their narrative coherence, but repeaters reported higher psychological wellbeing than non-repeaters. These findings suggest that selecting the same event to narrate over time may be beneficial. The final study was an extension of an experimental longitudinal project. The effects of a maternal elaborative reminiscing intervention, delivered to mothers when children were approximately 19 months old, were assessed when the children were 15 years of age. The outcomes of interest were narrative coherence and psychological wellbeing. Those whose mothers were in the intervention group displayed higher levels of causal coherence and reported fewer emotional symptoms than those whose mothers were in the control group. Further analyses showed that the relationship between the intervention and lower emotional symptoms was not mediated by causal coherence. This study shows that the benefits from an elaborative reminiscing intervention early in childhood continue to have benefits well into adolescence, with respect to both narrative coherence and psychological wellbeing. Overall, we found evidence for narrative coherence playing an important role in the psychological wellbeing of mid-adolescents. It may contribute to higher psychological wellbeing over time, and appears to be modifiable via an intervention in early childhood
Obstruction and obfuscation: Regulatory barriers to human embryo research in New Zealand
Get PDFOver the last half-century, significant innovations have occurred in the fields of embryology
and human assisted reproduction as a result of human embryo research. This dynamic and
ethically complex field is generally subject to extensive regulatory oversight. This article
examines New Zealand’s legal framework governing such research. It argues that, despite
the core legislative objective of establishing a robust and flexible framework, the current
legal regime established under the Human Assisted Reproductive Technology Act 2004 is a
classic example of regulatory failure. While not a necessary outcome of the devolved,
principles-based regulatory scheme, this failure is primarily due to the perceived lack of
authority and independence of the statutory policymaking body established under the Act,
as well as the broader regulatory environment in which it operates. It argues that a confluence
of problems, including Ministerial overreach as well as a lack of transparency and
accountability on the part of decision makers, undermine the legitimacy of the current
embryo research policy. This regime not only unjustifiably prevents the conduct of valuable
embryo research, but also hinders simple quality improvement practices undertaken in the
course of ordinary IVF service provision. This article concludes that, given the significance of
embryo research as well as the associated ethical and legal challenges, the issue of embryo
research should be remitted back to Parliament to legislate directly as a matter of urgency
Service user, whānau and peer support workers’ perceptions of advance directives for mental health
Get PDFAdvance directives allow users of mental health services to make statements for their future care. In New Zealand, their use is supported by the Health and Disability Commissioner, and was identified in the Disability Action Plan 2014-2018 as a key mechanism for advancing the human rights of people under the MHA. This study used a qualitative descriptive methodology involving focus groups to explore the perceptions of service users, whānau and peer support workers concerning advance directives. Thematic analysis revealed certain belief patterns about what should or could be included in an advance directive, and about how and with whom one should be created. It revealed generally positive perceptions about how they can uphold service users’ right to have preferences considered, to plan flexibly around dynamic needs, and about their value and utility. We conclude that advance directives can support services users’ expressions of their preferences for care, but they need to be supported by clinicians if they are to realise this potential. Our findings can also inform service provision in New Zealand, and the planned reform of the MHA
The Australasian Approach to the Definition of Mental Disorder in a Mental Health Act
Get PDFHow should the mental element be defined in the legal standards governing a person’s ‘sectioning’ or placement under the Mental Health Act (MHA)? This article considers how this mental element is defined in many MHAs in Australasia: via a statutory list of disorders of mental function said to ‘characterise’ the necessary state of mind. This article assesses the assumptions that lie behind the adoption of this approach. It discusses the views of several English law reform committees that have explored how the mental element should be defined. It examines the philosophy of psychiatry, expounded clearly by Aubrey Lewis, that lies behind the Australasian approach, a philosophy that emphasises the need to identify mental disturbance by reference to disorders of ‘part-function of the mind’, not by reference to behaviour alone. It considers how the Australasian statutes address the question of personality disorder’s cover by the Act. In conclusion, it endorses cautiously the Australasian approach, principally on the ground that it may contribute positively to the conduct of review proceedings for compulsory patients under the Act. It may concentrate the attention of tribunals on particular features of the patient’s mental state, on how those features are linked to the associated dangers or risks, and on how the presence of those features may justify placing decisions about the patient’s treatment in others’ hands. Throughout, comparisons are made with the manner in which the mental element has been defined in mental health legislation for England and Wales
The Self Divided: The problems of contradictory claims to Indigenous peoples’ self-determination in Australia
Get PDFWhen the United Nations General Assembly endorsed the United Nations Declaration on the Rights of Indigenous Peoples (‘UNDRIP’) in 2007, many extolled it for recognising Indigenous peoples’ right of self-determination. Although there is some consensus that all peoples have self-determination, as a legal claim it has routinely inspired criticism that it will lead to contradictory claims, interpretations, and further political contestation. Ten years after UNDRIP's endorsement, some Indigenous claims of self-determination in Australia are contradictory. While contradictory claims may not be inherently problematic, in the context explored in this article, there are problematic effects. This article examines how contradictory self-determination claims arose in response to Australia's recent Native Title Amendment (Indigenous Land Use Agreements) Act 2017 (Cth) (‘2017 Amendments’), which amended and weakened the Native Title Act 1993 (Cth) (‘NTA’). It also evaluates the consequences of those contradictory claims and argues for renewed critical assessment of who legitimately determines the self who claims self-determination
Perinatal and Maternal Mortality in New Zealand 2008: Fourth Report to the Minister of Health - July 2009 to June 2010
Get PDFThe Fourth Report of the Perinatal and Maternal Mortality Review Committee provides an accurate estimate of the absolute numbers and rates of perinatal and maternal deaths in New Zealand for 2008, describes the risk factors for these deaths, and seeks to identify where the attention of maternity and neonatal services might be best focused to prevent perinatal and maternal deaths