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Hyaluronic Acid-Based Nanohydrogel as Effective Carrier for Transdermal Delivery of CBD for Melanoma Cancer Therapy
No full textSignificance of this research: Cutaneous melanoma, located at the junction of the epidermis and dermis, is a prevalent form of skin cancer. Transcutaneous drug delivery offers a promising approach to directly target melanoma cells without the need for undergoing gastrointestinal or liver metabolism. Cannabidiol (CBD) has shown potential as an anti-tumour or anti-cancer agent, either alone or in combination therapy for melanoma. However, improvements are needed in CBD’s bioavailability, stability, efficacy, and sustained delivery. A comprehensive literature review identified a significant research gap in the nano-encapsulation of CBD and its transdermal delivery for melanoma treatment. Methodology: The methodology involved the chemical modification of hyaluronic acid (HA) through grafting a fatty amine (FA) onto its structure. The resulting HA conjugates (MH) with varying degrees of substitution were utilised to nano-encapsulate CBD using the high-energy nano-emulsification method. The properties of the optimised formulation, i.e. size, polydispersity, short- and long-term stability, loading efficiency, and release behaviour, were characterised. The limited in vitro toxicity of the empty nano-formulation and the anti-proliferative, apoptotic-inducing, and migration inhibition abilities of the CBD-loaded nano-formulation were assessed using malignant melanoma cell lines and normal human cell lines. Cellular and subcellular trafficking of the labelled nano-formulation were tracked and quantified by confocal microscopy and flow cytometry techniques. Furthermore, an ex vivo permeation protocol using pig ear skin was utilised to evaluate CBD release and penetration through the skin. Results: The results demonstrated successful conjugation of FA in the HA structure, leading to the development of a carrier that preserved CBD in the oil core and exhibited excellent long-term stability at ambient temperature. The nano-formulation displayed controlled release profiles at physiological and acidic pH, with a stable droplet size (~75 nm) and low polydispersity. The empty nano-formulation exhibited high biocompatibility with both malignant melanoma and normal cell lines. In contrast, the nano-encapsulated CBD demonstrated selective cytotoxicity and apoptotic induction in cancerous cell lines compared to normal cells in 2D and 3D cultures. Moreover, the nano-formulation, with or without CBD, showed penetration beyond the stratum corneum into the deeper layers of the viable epidermis where melanocytes originate. Conclusion: The current project successfully developed a facile and mild method for encapsulating CBD, resulting in nano-carriers with demonstrated efficiency in inhibiting the proliferation of primary and secondary melanoma cancer cell lines. The optimised nano-carriers exhibited a sustained release pattern over a 72-hour period under in vitro conditions. Additionally, these nano-carriers demonstrated pH sensitivity, allowing CBD to detach from the nano-carrier at the target tissue and potentially maintain therapeutic release within the desired range. The outcomes of this research hold promise for introducing a new transdermal nano-carrier that can enhance the efficiency of CBD in treating melanoma cancer, increase skin permeability, and improve CBD’s stability. Key unique aspects: Here are a few key unique aspects: • Technical advantages of optimised formulation include excellent long-term stability at ambient temperature, controlled release profiles at physiological and acidic pH, selective cytotoxicity, a stable droplet size with low polydispersity, and enhanced delivery to deeper layers of the skin. These properties could potentially enhance the therapeutic efficacy of CBD. • Selective Cytotoxicity: The nano-encapsulated CBD demonstrated selective cytotoxicity and apoptotic induction in cancerous cell lines compared to normal cells in 2D and 3D cultures. This selective cytotoxicity is crucial to cancer therapy, as it can potentially minimise damage to healthy cells. • Transdermal Delivery: The nano-formulation, with or without CBD, showed penetration beyond the stratum corneum into the deeper layers of the viable epidermis where melanocytes originate. This suggests that our optimised nano-formulation could potentially be used for transdermal delivery of CBD or similar therapeutic molecules, which could be a less invasive and more convenient method of administration for patients.</p
Myelin Oligodendrocyte Glycoprotein (MOG)35–55 Mannan Conjugate Induces Human T-Cell Tolerance and Can Be Used as a Personalized Therapy for Multiple Sclerosis
No full textWe have previously performed preclinical studies with the oxidized mannan-conjugated peptide MOG35-55 (OM-MOG35-55) in vivo (EAE mouse model) and in vitro (human peripheral blood) and demonstrated that OM-MOG35-55 suppresses antigen-specific T cell responses associated with autoimmune demyelination. Based on these results, we developed different types of dendritic cells (DCs) from the peripheral blood monocytes of patients with multiple sclerosis (MS) or healthy controls presenting OM-MOG35-55 or MOG-35-55 to autologous T cells to investigate the tolerogenic potential of OM-MOG35-55 for its possible use in MS therapy. To this end, monocytes were differentiated into different DC types in the presence of IL-4+GM-CSF ± dexamethasone (DEXA) ± vitamin D3 (VITD3). At the end of their differentiation, the DCs were loaded with peptides and co-cultured with T cells +IL-2 for 4 antigen presentation cycles. The phenotypes of the DC and T cell populations were analyzed using flow cytometry and the secreted cytokines using flow cytometry or ELISA. On day 8, the monocytes had converted into DCs expressing the typical markers of mature or immature phenotypes. Co-culture of T cells with all DC types for 4 antigen presentation cycles resulted in an increase in memory CD4+ T cells compared to memory CD8+ T cells and a suppressive shift in secreted cytokines, mainly due to increased TGF-β1 levels. The best tolerogenic effect was obtained when patient CD4+ T cells were co-cultured with VITD3-DCs presenting OM-MOG35-55, resulting in the highest levels of CD4+PD-1+ T cells and CD4+CD25+Foxp3+ Τ cells. In conclusion, the tolerance induction protocols presented in this work demonstrate that OM-MOG35-55 could form the basis for the development of personalized therapeutic vaccines or immunomodulatory treatments for MS.</p
The rising threat of Ross River virus: Climate change and its implications on public health in Australia
No full textThe escalating impact of alphaviruses, particularly Ross River Virus (RRV), represents a growing public health challenge, especially in Australia and the broader Southern Pacific region. Initially identified in the 1950s in Ross River, Townsville, Queensland, RRV has not only remained the predominant mosquito-borne disease in Australia but has also extended its reach to Papua New Guinea and even as far as Indonesia, Fiji, Samoa, the Moluccas, Vietnam and New Caledonia during a major outbreak in the 1980s. The urgency to intensify efforts against RRV is driven by heightened risks from climate change, urbanization, and global travel, which continue to increase transmission risks beyond the peak season.</p
Conceptualising, Mapping and Analysing the Social-Ecological Value of Informal Green Spaces
No full textThere is a growing understanding of the important role informal green spaces (IGS) play as part of
urban green space networks, providing many ecological and social benefits to urban populations. As
IGS are unplanned in nature, careful consideration is required when determining how land use decision
making may best capitalise on their potential benefits without compromising their existing value.
Current land use decision making often overlooks these spaces and their unique attributes, resulting in
sub-optimal social-ecological outcomes. There is a growing need for research to improve the way we
consider and study these spaces so that we may learn more about them, the ways in which they benefit
urban populations, and what this means for their potential governance and management. This thesis
contributes to the IGS discourse through a three-part process where I develop a framework to identify
IGS conceptually, Map IGS spatially, and analyse the ways they provide value to the urban
environment. I then use the outcomes from this process to recommend ways in which land use decision
making could more actively consider these spaces.
In Chapter 1, I introduce the concept of IGS, detail the approach taken in studying these spaces and
discuss key ontological and epistemological considerations adopted throughout this thesis.
In Chapter 2, I present a conceptual framework that enables more considered identification of IGS. I
undertake a narrative literature review of research pertaining to IGS, and identify key characteristics
used to describe these spaces. I present a framework of 11 key social-ecological characteristics of IGS,
able to be used by researchers looking to study these spaces. This framework helps us better understand
what IGS are and what makes them unique.
In Chapter 3, I develop a novel method for mapping IGS. The method uses characteristics from the
conceptual framework developed in Chapter 2 and open-source data to spatially locate IGS at a high
resolution, in a resource sensitive way. An onsite validation process is undertaken to validate the
mapping method, finding the method to accurately predict the location of IGS. The mapping method
presents opportunities for further research interrogating the value of IGS in the urban landscape.
In Chapter 4 and 5, I apply the mapping method to interrogate the social-ecological value of urban IGS.
Chapter 4 focuses on social elements of the social-ecological value of IGS, with Chapter 5 focusing
more on their ecological value. Firstly, I interrogate the role IGS play in facilitating human-nature
interactions in urban areas. I overlay citizen science data on a map of IGS in Greater Melbourne,
Australia to determine if there is any difference between formal and informal spaces in facilitating these
interactions. I find no statistically significant difference between IGS and formal green spaces in the
density of human-nature interactions they support, with railway and utility easements being particularly
important types of IGS. I also find that, while important, IGS do not replace high quality formal green
spaces like parks, which are the most important spaces for human-nature interactions in cities. Secondly,
I interrogate the role of IGS in supporting biodiversity outcomes. I map IGS in Greater Melbourne,
Australia to determine whether there is a statistically significant difference between IGS and formal
green space in their contribution to native species richness. I find that, relative to their abundance in the
landscape, there is no statistically significant difference between IGS and formal green space in the
number of native species present. Utility easements and brownfield sites were found to be particularly
important for birds and plants respectively with formal parks also being important.
Once I establish the social-ecological value of IGS in Greater Melbourne, I turn my attention to the
ways land use decision making may better consider these spaces to maximise these benefits. In Chapter
6, I provide a synthesis of the literature concerning IGS and how this thesis contributes to the discourse.
I then outline three potential approaches that could be taken by land use decision makers when planning
for IGS. These include a strategic hands-off approach, a formalisation approach, and a temporary use
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approach. No single approach is considered appropriate for all circumstances, and I outline the positives
and limitations of each. I contribute to the IGS literature through furthering our knowledge on the socialecological
values of IGS and what this means in terms of the future governance and management of
these spaces.</p
Self-assembled Lipid Nanoparticles for Targeted Cancer Therapeutics
No full textIn recent decades, lipid nanoparticles (LNPs) have gained significant attention as innovative drug delivery systems due to their therapeutic potential. Among these, non-lamellar LNPs, such as cubosomes and hexosomes, have garnered particular interest. Cubosomes are characterized by bicontinuous lipid bilayers that form two distinct, non-intersecting water channels, resulting in a large internal surface area. Hexosomes, on the other hand, possess an internal mesophase compartmentalized by lipid bilayers arranged parallel to the plane of a hexagonal lattice. The unique structures of cubosomes and hexosomes offer several advantages, including enhanced drug encapsulation, controlled release, and improved cell fusion, all of which contribute to greater pharmaceutical efficacy. Their substantial internal surface areas allow for higher payload loading, making them ideal carriers for a wide range of therapeutic compounds, including cancer drugs, proteins, peptides, and RNA.
In aqueous environments, amphiphilic lipids and stabilizers are the primary structural components of non-lamellar LNPs. Monoolein (MO) and phytantriol (PT) are the most extensively studied lipids in this context. While amphiphilic lipids can self-assemble into bulk mesophases, their exposure to the external aqueous environment often leads to lipid particle aggregation due to the presence of hydrophobic domains. Stabilizers play a crucial role in preventing this by providing electrostatic or steric barriers that enhance particle stability. Among the various stabilizers available, Pluronic® block copolymers, particularly F127, have been widely used over the past few decades. However, despite its effectiveness in stabilizing these structures, Pluronic® F127 does not impart MO/PT-based LNPs with responsiveness to biological stimuli, limiting its applicability in dynamic biological environments.
Increasing efforts are being made to develop stimuli-responsive LNPs that exploit physiological differences between healthy and cancerous tissues to reduce side effects on healthy cells. For example, the pH of normal cells and tissues is around 7.4, while the pH of cancerous sites typically ranges from 5.5 to 6.5. Additionally, the concentration of hydrogen peroxide (H2O2) in cancer cells is about 100 times higher than in normal cells.
This thesis focuses on the design and synthesis of amphiphilic block copolymers using Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization. These copolymers offer dual functionality: they stabilize MO/PT-based cubosomes and introduce additional properties, such as structural responsiveness to pH and H2O2. The copolymers include pH-responsive groups like 2-(dimethylamino)ethyl methacrylate (DMAEMA) and diethylaminoethyl methacrylate (DEAEMA), H2O2-responsive groups like 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate (TBA), and a fluorescent probe, tetraphenylethylene (TPE). Additionally, they feature a hydrophilic segment with 113 PEG units. The hydrophobic blocks interact with lipid bilayers, while the hydrophilic PEG block extends into the aqueous environment to prevent particle aggregation through steric hindrance. By engineering the surface of LNPs with these multifunctional stabilizers, this work aims to enhance controlled drug release, cell targeting, and bioimaging capabilities.
To investigate the internal mesophases of LNPs stabilized by newly developed polymers, high-throughput synchrotron SAXS was employed. The SAXS results reveal that the internal mesophases of these LNPs are influenced by the copolymer structure, the concentration of the added polymer, and the types of lipids used (Chapter 2 and Chapter 5). Notably, the pH responsiveness of the MO/PT-based LNP systems shows a transition from cubic (Q2) to hexagonal (H2) mesophases as the pH increases. This behavior is attributed to the pH-sensitive nature of DMAEMA and DEAEMA functional blocks, whose solubility changes due to the protonation or deprotonation of their amine groups at different pH values (Chapter 2). These findings underscore the potential of these LNPs in the development of stimuli-responsive drug delivery systems for various biomedical applications.
In terms of controlled drug release, encapsulation studies of anticancer drugs were conducted using developed responsive LNPs. Chapter 3 details the encapsulation of the highly hydrophobic drug Paclitaxel (PTX), while Chapter 4 covers Temozolomide (TMZ) and the hydrophilic drug Cisplatin (CDDP). The LNPs demonstrated high encapsulation efficiency for both hydrophilic and hydrophobic drugs. Notably, LNPs functionalized with DMAEMA and TBA groups effectively controlled drug release rates in response to pH and H2O2 variations. Specifically, PTX was released more rapidly under acidic conditions (pH 5.5) and/or in the presence of 50 mM H2O2, compared to physiological pH 7.4. The release behavior conformed well to the Higuchi model (Chapter 3).
For cell targeting, Chapter 4 describes the development of Angiopep-2 (Ang2)-functionalized cubosomes designed to cross the blood-brain barrier (BBB) and target glioblastoma therapy. In vitro models, including the BBB hCMEC/D3 cell monolayer, 3D BBB cell spheroids, and microfluidic BBB/GBM-on-a-chip models, were used to assess the efficiency of these cubosomes. Results indicated that Ang2-functionalized cubosomes penetrated the BBB more effectively than unfunctionalized particles. In vivo biodistribution studies showed a threefold increase in brain accumulation of Ang2-functionalized cubosomes compared to their unfunctionalized counterparts. Additionally, these cubosomes exhibited significantly higher uptake by U87 glioblastoma cells in both the BBB/GBM-on-a-chip model and 3D U87 cell spheroids.
In Chapter 5, the polymeric surface stabilizer of LNP was modified to provide bioimaging capability to the system. This was done through the introduction of TPE groups into amphiphilic block and random copolymers with varying lengths of DMAEMA segments. The TPE groups in the LNPs showed aggregation-induced emission (AIE) property, which were significantly influenced by copolymer concentration and pH value. Enhanced TPE fluorescence observed at higher copolymer concentrations and elevated pH levels. Cellular uptake studies confirmed that TPE-functionalized LNPs are effectively tracked in vitro, with endocytosis identified as the primary internalization pathway.
This thesis presents the development of multifunctional amphiphilic block copolymers incorporating pH- and H2O2-responsive groups and bioimaging functionalities. These innovative stabilizers enable controlled drug release, precise cancer targeting, and real-time tracking, advancing the design of next-generation LNP systems for biomedical applications.</p
Effects of specimen characteristics, fibre and mix constituents on the acoustic performance of rubberised concrete for traffic noise walls
No full textRecycling end-of-life tires (EOLT) presents a sustainable solution for addressing a major waste issue in many countries. This study focuses on the reuse of EOLT as construction materials, particularly in the form of EOLT-based rubberised concrete. However, several research gaps hinder the understanding of this construction material for implementation into practice. This study delves into key parameters, including admixture composition, aging, thickness, rubber distribution, and surface roughness, which play pivotal roles in designing and implementing rubberised concrete noise barriers. The paper presents the results of investigations into the performance of fibre-reinforced rubberised concrete when entrained with air, shedding light on flexural toughness and post-crack behaviour. The effects of incorporating fly ash and ground granulated blast furnace slag (GGBFS) as cement replacements are also examined. The acoustic performance of fibre-reinforced rubber concrete is studied, including the impact of sample conditioning (surface saturated dry or dry). The results indicate that air-entraining admixtures, the replacement of coarse sand with tire-derived rubber shreds, and the inclusion of recycled polypropylene fibre significantly enhance the mechanical and acoustic properties of the concrete. For instance, compressive strength improves by 43%, flexural strength by 120% and acoustic performance nearly twice, while water absorption and volume of permeable voids remain relatively unaffected. This study suggests an optimized sustainable mix design with rubber replacing more than 75% of the aggregate volume. It underscores the potential of EOLT-based rubberised concrete as an environmentally responsible construction material, offering enhanced performance across multiple domains, including noise attenuation barriers.</p
Spontaneous Liquefaction of Solid Metal–Liquid Metal Interfaces in Colloidal Binary Alloys
No full textCrystallization of alloys from a molten state is a fundamental process underpinning metallurgy. Here the direct imaging of an intermetallic precipitation reaction at equilibrium in a liquid-metal environment is demonstrated. It is shown that the outer layers of a solidified intermetallic are surprisingly unstable to the depths of several nanometers, fluctuating between a crystalline and a liquid state. This effect, referred to herein as crystal interface liquefaction, is observed at remarkably low temperatures and results in highly unstable crystal interfaces at temperatures exceeding 200 K below the bulk melting point of the solid. In general, any liquefaction process would occur at or close to the formal melting point of a solid, thus differentiating the observed liquefaction phenomenon from other processes such as surface pre-melting or conventional bulk melting. Crystal interface liquefaction is observed in a variety of binary alloy systems and as such, the findings may impact the understanding of crystallization and solidification processes in metallic systems and alloys more generally.</p
An Integrated Model of the Sustainable Consumer
No full textThe term ‘sustainable consumer’ (SC) is used across various knowledge domains, from sustainable consumption, green marketing, sustainability, and social change to social marketing for sustainability issues. However, the term SC lacks a precise definition, which leads to the inaccurate evaluation and measurement of the impact of green marketing or social marketing campaigns on consumption—sustainable or otherwise. This paper develops a framework to clarify the term ‘sustainable consumer’ to assist both scholars and practitioners. The application of systems thinking was applied to the extant literature to theorise the SC. This conceptual paper provides a new framework for theorising SCs: the integrated model of the sustainable consumer (ISMC). This framework emphasises the interconnected relationships of influences within the SC profile to assist scholars in examining SCs within these systems with precision. We contend that, to promote and maintain the desired sustainable consumption for long-term effects, researchers and practitioners should consider the impact not only of the socio-psycho-demographic characteristics but also the connection of the person to the environment and their community, in addition to their worldviews. The framework presented here challenges linear models by proposing a nested, dynamic structure that recognizes the interconnected influences within the sustainable consumer’s ecosystem. The framework also enables a targeted intervention design according to the layer and element and permits more precise evaluations of behaviour change campaigns’ effectiveness.</p
A review of emerging sustainable fashion business models: triple bottom line perspective
No full textThis paper explores and review the emerging sustainable fashion business models as a potential solution to the current catastrophic impact of the Global Fashion Industry on the Ecosystem. There has been emergence of several new innovative fashion business models recently namely circular fashion business, renting and sharing, slow fashion, durability, upcycling and recycling, waste management, ecofriendly materials, subscription models, modular design, additive manufacturing and zero waste fashion. There is a research gap to evaluate the effectiveness of some these models in the perspective of triple bottom line, especially in developing countries. This study has investigated the status of some of these new business models such as durable products, modular design, advanced communication technologies, waste management and additive manufacturing in Vietnam. An exploratory study approach involving six fashion enterprises was used to know the status of these techniques in Vietnamese fashion sector. It was found that some of the concepts such as additive manufacturing and waste management are quite new in Vietnamese fashion sector. However, some sustainable models such as waste management and durable products are well understood by the fashion enterprises.</p
To what extent are students fulfilling their values and thriving in mathematics education?—The case for Victoria, Australia
No full textMathematical wellbeing (MWB) is the experience of positive feelings and functioning linked to the fulfillment of seven ultimate values (accomplishment, cognitions, engagement, meaning, perseverance, positive emotions, and relationships) in the mathematics classroom. The study in this chapter psychometrically tests and then measures Australian Year 8 students’ (n = 488) valuing, experiences, and fulfillment of these seven ultimate values. Findings demonstrate that Year 8 students value relationships as the most important and engagement the least important ultimate values; and that they experience the ultimate values cognitions the most and positive emotions the least in the mathematics classroom. We then examine students’ success in fulfilling their own values, finding that students are the most successful in fulfilling their valuing of perseverance and the least successful in fulfilling their valuing of positive emotions. Whilst female students report lower overall value fulfillment than males, females also experience lower MWB than males. Our psychometrically valid and reliable survey can be used to assess and track students MWB, whilst providing target areas for teachers to help improve students’ experiences and engagement in the mathematics classroom.</p