Definicion de Uso en Salud

This thesis presents research pertaining to the vision of developing a toolkit of nanoparticle building blocks, which may be assembled in a predictable and controlled way, governed by relatively simple and easily optimised abiotic molecular systems. The interesting and often unique properties defined by nanoparticle chemical composition, size and shape, also crucially depend on assembly structure when several nanoparticles are brought together. Simple, nonbiomolecular assembly strategies have so far failed to deliver a precise level of control over nanoparticle assembly. This thesis develops the use of simple, small organic molecules for the control of nanoparticle functionalisation and assembly.

Using gold nanoparticles as a prototypical monolayer-stabilised nanoparticle systems, the synthesis of functionalised nanoparticles has been explored through the use of a single-phase method. This operationally simple approach has been applied to the synthesis of a range of functionalised nanoparticles, offering access to both organic and water-soluble nanoparticles with a narrow size distribution. Furthermore, control over nanoparticle size has been demonstrated in a ligand-nonspecific manner, whereby a slower rate of addition of the reducing agent results in a larger nanoparticle size, crucially, with no detrimental effect on the nanoparticle size distribution. Previously, identically functionalised nanoparticles of different sizes could only be accessed through ligand exchange procedures. The slow addition approach for tuning nanoparticle size developed here offers a general approach to the size- controlled synthesis of functionalised nanoparticles, resulting in easy access to nanoparticle building blocks in a range of sizes.

The reversibly dynamic covalent properties of boronic ester formation presents a highly desirable route to the functionalisation and assembly of nanoparticles. Boronic acid functionalised gold nanoparticles have been synthesised and fully

characterised. Detailed molecular-level characterisation revealed the peroxide- induced oxidation of boronic acids to the corresponding phenol during the synthesis. This phenomenon was suppressed by the addition of an antioxidant, establishing a robust route to boronic acid functionalised nanoparticles in high purity and with control of nanoparticle size. The oxidation of nanoparticle-bound boronic acids has significant implications for a variety of other functionalised nanoparticle systems that seek to exploit boronic acid chemistry but for which molecular-level characterisation has not to this point been achieved.

Boronic ester formation has been investigated, and catechol, salicylic acid and salicylamide have been established as a range of isostructural binding partners for boronic acids, exhibiting a range of association constants across an order of magnitude for the molecular processes in freely-dissolved solution. Direct molecular evidence from 19_{F NMR spectroscopy of nanoparticle-bound boronic}

ester formation has been demonstrated for the first time. Dynamic boronic ester exchange has been demonstrated in a reversible manner, confirming the equilibrium control of the process on nanoparticle-bound monolayers. 19_{F NMR}

spectroscopy has further allowed the characterisation of nanoparticle-bound boronic ester formation in a quantitative manner, allowing association constants to be measured for the process within the nanoparticle-bound monolayer. The association constants for boronic ester formation on nanoparticle-bound boronic acids are lower than for corresponding isostructural freely soluble model compounds. This is attributed to a negative cooperativity on nanoparticle-bound boronic ester formation due to steric crowding. Initial experiments indicate that even minor structural changes of the binding partner can strongly influence the extent of this steric effect.

Having established the thermodynamic control of nanoparticle-bound boronic ester formation, boronic ester-mediated assembly of nanoparticles was investigated. A bis-catechol linker was shown to induce nanoparticle assembly by covalently linking nanoparticles. Covalently linked nanoparticles precipitated as large aggregates. Remarkably, these covalently linked aggregates could be entirely disassembled and re-suspended by addition of a molecular stimulus to break the inter-nanoparticle covalent boronic ester linkages. Varying the

nanoparticle/linker ratio resulted in a quantifiable change in assembly morphology. Chemical changes in the linker structure demonstrated the link between molecular input and assembly morphology further, demonstrating in turn, for the first time, molecular control over dynamic covalently-linked nanoparticle assemblies. This establishes the presence of fundamental links between the molecular details of nanoparticle-bound dynamic covalent processes with the resulting assembly structure upon formation of dynamic covalently-linked assemblies.

Boronic ester mediated nanoparticle assembly offers a combination of kinetic lability and covalent bond strength. Much weaker noncovalent interactions which also present kinetic lability offer the prospect for sufficient bond strength are employed in a highly multivalent fashion. An unanticipated observation of assembly between 1,2-diol-functionalised nanoparticle and citrate-stabilised nanoparticles to form planet–satellite nanoparticle architectures presented an alternative assembly strategy based on highly multivalent hydrogen bonding. The resulting assemblies were shown to be both highly structurally and colloidally stable, with the colloidal stability properties of the 1,2-diol satellite nanoparticles transferred to the assembly as a whole. The rapid, operationally simple one-step assembly procedure – which, unlike existing methods, does not require careful control of environmental conditions and eliminates the need for complex biological, supramolecular or macromolecular nanoparticle ligands – is readily scalable. The shape, size and material of the planet nanoparticle were varied, resulting in predictable isotropic coverage of the planet nanoparticle. The resulting nanoparticle assemblies have shown SERS enhancement of a small-molecule probe, simply by mixing the preassembled planet–satellites with the receptor, which contrasts existing methods which require assembly of the planet–satellite structure around the probe.

In this thesis, the development of a general strategy for the assembly of dynamic molecularly controlled building blocks has been pursued. Further investigations to better understand the implications of molecular confinement within a nanoparticle-bound monolayer are certainly key to developing molecular control over nanoparticle assembly. The influence of features such as

nanoparticle size, shape, ligand length and reactive ligand surface concentration is not well understood. As demonstrated by the boronic ester- mediated nanoparticle assembly, the molecular detail of binding strength determines the nanoparticle assembly structure. Many of the fundamental principles of reactivity of nanoparticle-bound boronic acids should apply to a range of dynamic covalent reactions (for example, hydrazones, imines and acetals), further emphasising the urgent need for a better understanding of these processes at the molecular level.

Despite the inherent challenges of studying nanoparticle-bound systems, the links between molecular structure and assembly properties demonstrated in this thesis highlight the importance of future work in this field. A better understanding of the reactivity of nanoparticle-bound molecular species will pave the way for accessing the full potential for the rational design of predictable, reconfigurable dynamic nanoparticle assembly systems, and therefore allow access to new nanomaterials and nanodevices.

Experimental and synthetic