Applied synthesis and characterisation of nanoparticles

This thesis covers three areas of development of nanomaterials synthesis; namely the synthesis of superhydrophobic polymer-nanoparticle composites (chapter 3), the synthesis of doped quantum dots for catalysis and photoluminescence enhancement (chapter 4) and the synthesis of magnetic iron oxide nanoparticles from inexpensive, readily available reagents (chapter 5). Details of characterisation and analytical techniques and synthetic methods used are given in chapter 2, and the thesis summarised in chapter 6. Superhydrophobic polymer-nanoparticle composites represent a class of material which combine the superhydrophobicity of the polymer with the functionality of incorporated nanoparticles. Reactive oxygen species generated by photocatalytic nanoparticles degrade organic matter, and thus degrade the polymer, resulting in a loss of superhydrophobicity. In this chapter, a general method for the incorporation of hydrophobically ligated nanoparticles into a superhydrophobic poly(dimethylsiloxane) polymer matrix via AACVD is demonstrated. This resulted in a highly effective, robust titania nanoparticle-poly(dimethylsiloxane) composite for photocatalysis, along with, to the best of the author's knowledge, the first superparamagnetic-superhydrophobic polymer composite. Chapter 4 deals with the synthesis and characterisation of a quantum dot based photoactivated catalyst vector which releases Cu+ via UV irradiation, the first of its kind. The catalytic activity was evaluated using “click” chemistry under UV irradiation, with quantum dots being recoverable and able to undergo several catalytic cycles. A mechanism for the photoluminescence and copper release is also postulated. The copper is incorporated into the shells of quantum dots via the decomposition of single source metal-dithiocarbamates. Chapter 5 details a method for the synthesis of iron oxide nanoparticles for magnetic hyperthermia, but from reagents obtained from the high street. A low cost synthesis was developed and the resulting nanoparticles functionalised with an amphiphilic polymer and tested for magnetic hyperthermia

The in situ synthesis of PbS nanocrystals from lead(II) n-octylxanthate within a 1,3-diisopropenylbenzene-bisphenol A dimethacrylate sulfur copolymer

The synthesis of lead sulfide nanocrystals within a solution processable sulfur ‘inverse vulcanization’ polymer thin film matrix was achieved from the in situ thermal decomposition of lead(II) n-octylxanthate, [Pb(S2COOct)2]. The growth of nanocrystals within polymer thin films from single-source precursors offers a faster route to networks of nanocrystals within polymers when compared with ex situ routes. The ‘inverse vulcanization’ sulfur polymer described herein contains a hybrid linker system which demonstrates high solubility in organic solvents, allowing solution processing of the sulfur-based polymer, ideal for the formation of thin films. The process of nanocrystal synthesis within sulfur films was optimized by observing nanocrystal formation by X-ray photoelectron spectroscopy and X-ray diffraction. Examination of the film morphology by scanning electron microscopy showed that beyond a certain precursor concentration the nanocrystals formed were not only within the film but also on the surface suggesting a loading limit within the polymer. We envisage this material could be used as the basis of a new generation of materials where solution processed sulfur polymers act as an alternative to traditional polymers

Porous carbons from inverse vulcanised polymers

Elemental sulfur is an underutilised industrial by-product. It has been recently shown that it can be simply and scalably co-polymerised, by “inverse vulcanisation” with organic crosslinkers. The properties of porous carbons, which have extensive uses in science and industry, are influenced by the materials from which they are generated. Reported here are the first examples of porous carbons produced from high-sulfur inverse vulcanised polymers. The materials produced show micro-porosity, gas selectivity, and are doped with sulfur. The simplicity of the technique, and wide range of other potential inverse vulcanised feedstocks, gives scope for transferability and control of properties

pH-responsive nanocomposite fibres allowing MRI monitoring of drug release

Magnetic resonance imaging (MRI) is one of the most widely-used non-invasive clinical imaging tools, producing detailed anatomical images whilst avoiding side effects such as trauma or X-ray radiation exposure. In this article, a new approach to non-invasive monitoring of drug release from a drug delivery vehicle via MRI was developed, using pH-responsive Eudragit L100 and S100 fibres encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) and carmofur (a drug used in the treatment of colon cancer). Fibres were prepared by electrospinning, and found to be smooth and cylindrical with diameters of 645 ± 225 nm for L100 and 454 ± 133 nm for S100. The fibres exhibited pH responsive dissolution behaviour. Around the physiological pH range, clear pH-responsive proton relaxation rate changes due to matrix swelling/dissolution can be observed: r2 values of L100 fibres increase from 29.3 ± 8.3 to 69.8 ± 2.5 mM-1s-1 over 3 h immersion in a pH 7.4 medium, and from 13.5 ± 2.0 mM-1 s-1 to 42.1 ± 3.0 mM-1 s-1 at pH 6.5. The r2 values of S100 fibres grow from 30.4 ± 4.4 to 64.7 ± 1.0 mM-1 s-1 at pH 7.4, but at pH 6.5, where the S100 fibres are not soluble, r2 remains very low ( 0.94) between the two. Mathematical equations were developed to predict carmofur release in vitro, with very similar experimental and predicted release profiles obtained. Therefore, the formulations developed herein have the potential to be used for non-invasive monitoring of drug release in vivo, and could ultimately result in dramatic reductions to off-target side effects from interventions such as chemotherapy

Exploring precision polymers to fine-tune magnetic resonance imaging properties of iron oxide nanoparticles

The use of bio-polymers as stabilising agents for iron oxide-based negative magnetic resonance imaging (MRI) contrast agents has become popular in recent years, however the wide polydispersity of biologically-derived and commercially available polymers limits the ability to produce truly tuneable and reproducible behaviour, a major challenge in this area. In this work, stable colloids of iron oxide nanoparticles were prepared utilising precision-engineered bio-polymer mimics, poly(2-acrylamido-2-methylpropane sodium sulfonate) (P(AMPS)) polymers, with controlled narrow polydispersity molecular weights, as templating stabilisers. In addition to producing magnetic colloids with excellent MRI contrast capabilities (r2 values reaching 434.2 mM−1 s−1 at 25 °C and 23 MHz, several times higher than similar commercial analogues), variable field relaxometry provided unexpected important insights into the dynamic environment of the hydrated materials, and hence their exceptional MRI behaviour. Thanks to the polymer’s templating backbone and flexible conformation in aqueous suspension, nanocomposites appear to behave as “multi-core” clustered species, enhancing interparticle interactions whilst retaining water diffusion, boosting relaxation properties at low frequency. This clustering behaviour, evidenced by small-angle X-ray scattering, and strong relaxometric response, was fine-tuned using the well-defined molecular weight polymer species with precise iron to polymer ratios. By also showing negligible haemolytic activity, these nanocomposites exhibit considerable potential for MRI diagnostics

SiO₂-coated layered gadolinium hydroxides for simultaneous drug delivery and magnetic resonance imaging

Layered gadolinium hydroxides (LGdH) have significant potential in simultaneous drug delivery and magnetic resonance imaging (MRI). In this work, we synthesized LGdH nanocomposites surface functionalised with SiO₂ nanodots (LGdH@SiO₂). We find these to have good dispersibility in cell culture medium, and a reduced tendency to aggregate compared to their uncoated analogue. Under the optimal reaction conditions, SiO₂ nanodots were evenly spread across the surface of the LGdH particles. We further intercalated ibuprofen (Ibu) and 5-fluorouracil (5FU) into LGdH@SiO₂, and explored the use of the resultant composites for drug delivery in vitro. While the SiO₂ coating could effectively reduce aggregation of the Ibu intercalate prepared by ion exchange from the parent LGdH, it was noted to increase aggregation in the case of the 5FU-loaded systems produced by coprecipitation. With a SiO₂ coating, 5FU release from the composite was almost zero-order at pH 7.4. The LGdH-5FU@SiO₂ composites can effectively inhibit the growth of A549 cells (a human adenocarcinoma cell line). In contrast, the Ibu-loaded materials are highly biocompatible. After SiO₂ modification, LGdH-5FU@SiO₂ retains the same proton relaxivity properties as LGdH-5FU, while LGdH-Ibu@SiO₂ ecomes suitable for use as a negative contrast agent in MRI. Overall, we find the LGdH@SiO₂ nanocomposites are promising materials for theranostic applications

Radio-metal cross-linking of alginate hydrogels for non-invasive in vivo imaging

Alginate hydrogels are cross-linked polymers with high water content, tuneable chemical and material properties, and a range of biomedical applications including drug delivery, tissue engineering, and cell therapy. However, their similarity to soft tissue often renders them undetectable within the body using conventional bio-medical imaging techniques. This leaves much unknown about their behaviour in vivo, posing a challenge to therapy development and validation. To address this, we report a novel, fast, and simple method of incorporating the nuclear imaging radio-metal 111In into the structure of alginate hydrogels by utilising its previously-undescribed capacity as an ionic cross-linking agent. This enabled non-invasive in vivo nuclear imaging of hydrogel delivery and retention across the whole body, over time, and across a range of model therapies including: nasal and oral drug delivery, stem cell transplantation, and cardiac tissue engineering. This information will facilitate the development of novel therapeutic hydrogel formulations, encompassing alginate, across disease categories

Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone.

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water. X-ray crystallography is used to rationalize site preference in terms of the discontinuity in conjugation in the DMBBQ system. Quinone formation occurs by increasing in situ halogen generation and water. Conversely, radical trifluoromethylation occurs at the quinone of the DMBBQ

SWCNT photocathodes sensitised with InP/ZnS core-shell nanocrystals

Increasing the light harvesting efficiency of photocathodes is an integral part of optimising the future efficiencies of solar technologies. In contrast to the more extensively studied photoanode systems, current state-of-the-art photocathodes are less efficient and are commonly replaced with rare and expensive materials such as platinum group metals. The significance of photocathodes is in the development of tandem electrodes, enhancing the performance of existing devices. Carbon nanotubes are promising candidates for photocathodes, which, in addition to their p-type conductivity and catalytic properties, possess a suite of unique optical and electrical attributes. This work describes the fabrication of single walled carbon nanotube (SWCNT) photocathodes sensitised with indium phosphide/zinc sulfide (InP/ZnS) core–shell nanocrystals (NCs). Under air mass (AM) 1.5 conditions, the sensitisation of SWCNT photocathodes with InP/ZnS NCs increased the photocurrent density by 350% of the unsensitised output. This significant enhancement of current density demonstrates the potential of InP/ZnS NCs as effective sensitisers to improve the performance of carbon-based photocathode thin films

A multicentre, randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of early nutritional support via the parenteral versus the enteral route in critically ill patients (CALORIES)

BACKGROUND: Malnutrition is a common problem in critically ill patients in UK NHS critical care units. Early nutritional support is therefore recommended to address deficiencies in nutritional state and related disorders in metabolism. However, evidence is conflicting regarding the optimum route (parenteral or enteral) of delivery. OBJECTIVES: To estimate the effect of early nutritional support via the parenteral route compared with the enteral route on mortality at 30 days and on incremental cost-effectiveness at 1 year. Secondary objectives were to compare the route of early nutritional support on duration of organ support; infectious and non-infectious complications; critical care unit and acute hospital length of stay; all-cause mortality at critical care unit and acute hospital discharge, at 90 days and 1 year; survival to 90 days and 1 year; nutritional and health-related quality of life, resource use and costs at 90 days and 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Adult general critical care units in 33 NHS hospitals in England. PARTICIPANTS: 2400 eligible patients. INTERVENTIONS: Five days of early nutritional support delivered via the parenteral (n = 1200) and enteral (n = 1200) route. MAIN OUTCOME MEASURES: All-cause mortality at 30 days after randomisation and incremental net benefit (INB) (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: By 30 days, 393 of 1188 (33.1%) patients assigned to receive early nutritional support via the parenteral route and 409 of 1195 (34.2%) assigned to the enteral route had died [p = 0.57; absolute risk reduction 1.15%, 95% confidence interval (CI) -2.65 to 4.94; relative risk 0.97 (0.86 to 1.08)]. At 1 year, INB for the parenteral route compared with the enteral route was negative at -£1320 (95% CI -£3709 to £1069). The probability that early nutritional support via the parenteral route is more cost-effective - given the data - is < 20%. The proportion of patients in the parenteral group who experienced episodes of hypoglycaemia (p = 0.006) and of vomiting (p < 0.001) was significantly lower than in the enteral group. There were no significant differences in the 15 other secondary outcomes and no significant interactions with pre-specified subgroups. LIMITATIONS: Blinding of nutritional support was deemed to be impractical and, although the primary outcome was objective, some secondary outcomes, although defined and objectively assessed, may have been more vulnerable to observer bias. CONCLUSIONS: There was no significant difference in all-cause mortality at 30 days for early nutritional support via the parenteral route compared with the enteral route among adults admitted to critical care units in England. On average, costs were higher for the parenteral route, which, combined with similar survival and quality of life, resulted in negative INBs at 1 year. FUTURE WORK: Nutritional support is a complex combination of timing, dose, duration, delivery and type, all of which may affect outcomes and costs. Conflicting evidence remains regarding optimum provision to critically ill patients. There is a need to utilise rigorous consensus methods to establish future priorities for basic and clinical research in this area. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17386141. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 28. See the NIHR Journals Library website for further project information