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The acute toxicity and inherent low water solubility of many chemotherapeutics often prevent such drugs from achieving the optimal therapeutic effect in a clinical setting. Branched vinyl copolymer nanoparticles have been investigated as potential drug delivery vehicles for the controlled release of docetaxel, a commercially available hydrophobic anti-cancer drug. Branched vinyl copolymer nanoparticles were produced via co-nanoprecipitation; this relatively new nanoformulation technique involved the simultaneous nanoprecipitation of high molecular weight, hydrophobic branched copolymers with their corresponding amphiphilic AB block copolymers, through a rapid manipulation of their solvent environment. This approach was used to entrap docetaxel molecules within the hydrophobic cores of branched vinyl copolymer nanoparticles during the co-nanoprecipitation process. A comprehensive study was undertaken to expand the scope of branching vinyl copolymer nanoparticles that can be produced via co-nanoprecipitation, beyond the limited number of nanomaterials that have been reported to date. This involved co-nanoprecipitation of a large number of hydrophobic and amphiphilic polymers which possessed a wide range of different chemical and physical properties. This required the development of an unlikely synthetic approach, copper-catalysed reversible-deactivation radical polymerisation in anhydrous alcoholic media, for the development of novel hydrophobic polymeric materials. Fundamental studies were conducted to understand the experimental factors which influence nanoparticle formation during co-nanoprecipitation and, where possible, these factors were used as leavers to influence nanoparticle characteristics. Promising branched vinyl copolymer nanoparticle candidates were taken forward to drug encapsulation and release studies. This involved the use of radiometric techniques to quantify the encapsulation and release of docetaxel from branched vinyl copolymer nanoparticles. Docetaxel loadings of up to 25 weight % of the total nanoparticle mass and encapsulation efficiencies of up to 97 % were achieved during co-nanoprecipitation. The properties of the polymers used to construct branched vinyl copolymer nanoparticles also had a significant impact on docetaxel release. The impact of nanoparticle properties, including core polarity and viscosity, on the levels of docetaxel entrapment during co-nanoprecipitation and the rate of docetaxel release will be presented. The suitability of leading nanoparticle candidates as prospective drug nanocarriers in vivo will be discussed.

Modulation of network state is a ubiquitous feature of nervous systems. A major challenge in understanding the physiological flexibility of neural circuits is linking molecules that regulate behaviour to changes in the properties of individual neurons. Here, we use a defined neural circuit in C. elegans to frame this universal problem. By genetic dissection of the behavioural state that sustains escape of 21% O2, we identify novel neuronal functions for several highly conserved genes, including a caspase-like molecule, a calcium-sensitive transcription factor, and two translation initiation factors. These molecules have been implicated in diverse forms of human disease, but their role in the nervous system is either unexplored or poorly understood. Using in vivo Ca2+ imaging techniques to investigate neuron physiology in immobilized and behaving animals, we demonstrate their effect on the properties of individual neurons. The activity of RMG hub neurons is associated with the switch in behavioural state induced by 21% O2. Recently it has been shown that the input-output relationship of RMG is controlled by cytokine signaling, an increasingly appreciated form of neuromodulation. Here I present biochemical and genetic evidence that characterize a novel signaling component downstream of IL-17 receptors in RMG. Our data suggest that, reminiscent of its role in the immune system, it performs both scaffolding and enzymatic functions in neurons. Additionally, we show that RMG responsiveness is controlled by widely expressed, putative regulators of gene expression. Our analyses of these proteins elucidate their function within the URX-RMG circuit, but also raise hypotheses that can be tested more generally in the nervous system. We propose that a calmodulin-binding protein regulates adaptation to ambient O2 conditions, which may reflect a widespread requirement for controlling homeostatic plasticity. Two translation factors that have been shown to be dispensable for general translation are important for regulation of the response to stress. Our study raises the possibility that their role in promoting the activity of all, or some subset of, neurons might underlie this contextual requirement. Together, our findings provide mechanistic insight into the regulation of a behavioural state associated with a specific environmental context.