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Many anti-cancer drugs are hydrophobic, and this requires the use of organic solvents for their clinical administration, resulting in inefficient therapies and side effects including cardiotoxicity, nephrotoxicity, neurotoxicity and hypersensitivity when injected into the bloodstream. To tackle these issues, there has been tremendous research on a variety of carrier-based nanoparticles (NPs), but such strategies often fail to encapsulate drugs efficiently and require significant amounts of inorganic and/or organic nanocarriers with potential toxicity in the long term. The preparation of nanoformulations without using carriers for the delivery of anti-cancer drugs with poor water solubility is thus desired, requiring elegantly designed strategies for nanoproducts with high performance and stability. These strategies include direct physical self-assembly or chemical modifications where drug molecules are coupled or conjugated together via various functional molecules. Facile tuning of hydrophobic drug molecule properties by combining them with different chemotherapeutics, immunotherapeutic agents and functional molecules enables the preparation of nanodrugs with improved functional performance. This thesis presents three different novel approaches for the preparation of carrier-free therapeutic anti-cancer agents as nanodrugs. Initial work focussed on the direct physical self-assembly of two anti-cancer agents, paclitaxel (PTX) and curcumin (CUR). While PTX fails to form stable NPs on its own, the addition of CUR into the drug molecule enabled NP formation. An investigative study on the preparation of carrier-free PTX-CUR NPs was performed to understand the stability of the resulting NPs. It was found that different variables, such as PTX:CUR weight ratio and the purity of CUR, which can be obtained as curcuma longa (turmeric) extract (>65% curcumin) or as high purity (>98%) powders, have significant effects on the self-assembly process. The latter observation was further investigated using both experimental and computational methods and it was discovered that the naturally existing curcuminoids inside the turmeric extract help with the selfassembly process and are essential for the formation of monodisperse, spherical nanodrugs. Later stages of the work focussed on preparing conjugate drugs to form multifunctional nanosystems. First, NLG919, an immunotherapy agent which inhibits the over-expressed indoleamine dioxygenase (IDO) in many types of cancer, was covalently bonded with PTX to form PTX-NLG919 conjugates linked by an esterase-sensitive chemical bond. The conjugates were then nanoprecipitated to form carrier-free NPs in a single step to achieve potential chemo-immunotherapy agents. This strategy directly tackled the issues associated with the poor water solubility of both PTX and NLG919, where two drug molecules incapable of forming stable NPs on their own in the absence of excipient carrier molecules were able to do so when they were conjugated. This was attributed to the folding properties of the linker bridge as investigated in literature previously. Finally, another novel prodrug molecule was prepared by conjugating DOX, another FDA-approved chemotherapy drug with dehydroepiandrosterone (DHEA), an inhibitor of glucose-6 phosphate dehydrogenase (G6PD) which causes energy loss which is required for cell proliferation. Given that both DOX and DHEA affect the cell replication cycle, their combinational use may improve their respective anti-cancer properties. The molecules were conjugated via different chemical linkages - ester and thioether bonds. While the prodrug synthesis was successful, the preparation of stable NPs was challenging using the nanoprecipitation method. The anti-cancer efficacies of all the reported formulations were investigated in vitro. PTX-CUR NPs demonstrated comparable cell viabilities to free drug PTX, whereas PTX-NLG919 NPs and DOX-DHEA prodrug exhibited relatively milder cytotoxicity due to the presence of the linker bridge, prolonging the release of the anti-cancer agents. It must be noted that similar observations were also made with different prodrug conjugates in vitro, but such systems' cytotoxicities improved drastically in in vivo studies due to the tumour redox environment and the presence of over-expressed enzymes as well as the improved delivery enabled the nanodrugs. The results described in this thesis demonstrate the strong potential of the prepared NPs for in vivo and clinical studies as well as the versatility of the carrier-free nanodrug systems for cancer therapy. With more synthetic approaches for the preparation of carrier-free nanodrugs than ever, we expect a range of new carrier-free formulations to be developed and employed in safe and effective cancer therapy in the future.

The question of the nature of speakers' linguistic representations has been explained by accounts that fall into two different theoretical camps: generativist (i.e., formalist or Universal Grammar) and constructivist (i.e., semantics-based or usage-based). While generativist accounts propose that speakers possess innate knowledge that governs and constrains formal syntactic rules in language acquisition and use (e.g., Chomsky, 1981; Newmeyer. 2003), constructivist accounts emphasize accumulative experience of input that forms language structures (e.g., Croft & Cruse, 2004; Langacker, 2008). The overall aim of this thesis is to test the predictions of these competing accounts with respect to the passive construction, across two languages: English and Balinese. Chapter 1 sets out the general properties of different individual accounts that fall under the generativist and constructivist approaches, and presents some evidence with respect to these accounts in relation to language representation (including some studies with children). Chapter 2 sets out the detailed proposals from generativist and constructivist approaches with reference to the passive construction in particular. Although the focus is again on the nature of adults' representations, child studies are also included, since they bear on the question on the formation of these representations. Study 1 in Chapter 3 test these accounts by replicating Messenger, Branigan, McLean & Sorace's (2012) Study 2 – a passive priming study – in a sufficiently powered sample of adults (N=240). This study is replicated to test both generativist and constructivist claims with regard to the passive. The original study, while underpowered, found that theme-experiencer (e.g., frighten) and experiencer-theme verbs (e.g., ignore) appear to be equally effective at priming agent-patient passives (e.g., The witch was hugged by the cat). That is "the magnitude of priming was unaffected by verb type" (Messenger et al, 2012) – no semantic effect was found. This previous study therefore constitutes evidence against constructivist accounts, which assume the passive construction has its own meaning ("affectedness"). In (partial) contrast, the present study found only weak semantic effects in priming; though (in a Bayesian analysis) it certainly did not find positive evidence against semantic effects. Study 2 in Chapter 4 reports a grammatical acceptability judgment conducted in Balinese, following other crosslinguistic studies of the passive in Indonesian (Aryawibawa & Ambridge, 2018) and Mandarin (Liu & Ambridge, 2020). This study found a significant effect of semantics (i.e., affectedness), and extends previous crosslinguistic investigations across the four different passive types found in Balinese. Thus, this study provides support for the prediction of the constructivist approach with regard to construction semantics. Study 3 in Chapter 5 tests for construction-semantic effects in a new way, by manipulating affectedness not by changing the verb but by changing the context (high and low affectedness) while holding the verb (and indeed the whole sentence) constant. The result showed that although relatively small (due to the use of only grammatically acceptable sentences), the context effect is statistically significant, again providing support for the constructivist account. Chapter 6 summarizes all the findings from Study 1-3 and their theoretical and practical implication, as well as providing some suggestions of possible future studies. Even though the findings of this thesis broadly support the constructivist view, it does not of course provide a resolution to the long-running debate between generativist and constructivist claims. It does, however, demonstrate evidence of both semantic and (to some extent) non-linguistic contextual factors; findings that will hopefully prove informative to the ongoing theoretical debate between these approaches.