Layered rare-earth hydroxide nanoparticles for theranostic applications and targeted drug delivery

Abstract

This thesis centres around the synthesis of a family of structurally related nanoparticulate systems, based on layered rare-earth hydroxides, with a combination of properties that make them suitable for theranostic applications. These materials have the ability to carry drug cargo, provide contrast in magnetic resonance and luminescence imaging, and the possibility to incorporate photosensitizers to facilitate photothermal and photodynamic therapy. The use of these systems in the context of targeted cancer treatment will be explored. The possibility to deliver image-guided therapy directly to tumours is of particular interest in this field, as it has the potential to obviate issues with off target toxicity which very commonly arise with traditional chemotherapies. Chapter 1 begins with a discussion of current chemotherapeutic treatments and their limitations. The concept of theranostic medicines is introduced, and the modalities of drug delivery, photo-responsive therapies, and imaging contrast are covered. The various material types employed in theranostic research are described, with a particular focus on inorganic materials. Finally, the layered double hydroxides and layered rare-earth hydroxides are discussed, along with a detailed overview of their intercalation chemistry and use in the literature in recent years. The rationale behind focusing on layered rare-earth hydroxides along with the aims of this project are laid out. Chapter 2 concerns the synthesis and characterisation of layered terbium hydroxide Tb2(OH)5]Cl·1.5H2O (LTbH-Cl). Intercalation compounds of LTbH-Cl and several non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, and naproxen) were prepared and their functional performance in terms of drug release, cytotoxicity, and luminescence was assessed. It was found that LTbH-Cl and its drug intercalates had high biocompatibility, exhibited luminescence properties potentially suitable for imaging applications, and released at least 60% of their drug cargo within 5 hours (in phosphate buffered saline, at 37 °C). Chapter 3 considers the optimisation of a hydrothermal synthesis route to LTbH-Cl. It details a further series of experiments conducted to explore the relationship between the synthetic parameters and the resulting particle size of LTbH-Cl. An optimised method was thus developed and shown to consistently produce particles with a much narrower size distribution and smaller average size (152 ± 59 nm) than those produced by the method described in Chapter 2 (670 ± 564 nm), which are better suited to exploit the enhanced permeation and retention effect for passive tumour targeting. In Chapter 4, the optimised synthetic method derived in Chapter 3 was used to produce a range of layered rare-earth hydroxide systems with alternative compositions, including the elements praseodymium, neodymium, gadolinium, erbium, and ytterbium. Based on the subsequent characterisation data of these systems, further LRH materials combining the elements gadolinium and terbium in varying ratios were synthesised in order to exploit their respective magnetic and luminescent properties to create a theranostic platform capable of bi-modal imaging contrast. A lead formulation (LGd1.41Tb0.59H-Cl) was selected for further study, based on having the highest relative luminesce intensity as well as relatively strong magnetic relaxivity for magnetic resonance imaging contrast. Chapter 5 explores the potential photodynamic and photothermal response of the lead LRH formulation and several intercalate systems. First, the selection, design, assembly, and testing of a laser apparatus for this series of experiments is discussed. The lead LRH formulation, LGd1.41Tb0.59H, was loaded with the known photothermal/photodynamic sensitiser indocyanine green, and isophthalic acid, which has recently been reported to act as an efficient photodynamic therapy agent when intercalated into a structurally similar LDH system.1 The resultant materials were characterised, and tested in terms of their performance as photodynamic agents by utilising a colorimetric approach, and as photothermal agents using thermometry. Though the photothermal response measurement of the generated materials was not successful, the LRH-indocyanine green composite showed promising photodynamic activity, with enhanced efficiency relative to free indocyanine green. Chapter 6 is the concluding section of this report, which summarises the key findings and challenges encountered in the work herein and explores some future avenues for research that should be considered