Stephen G. Boyes

Polymer-Modified Gadolinium Metal-Organic Framework Nanoparticles Used as Multifunctional Nanomedicines for the Targeted Imaging and Treatment of Cancer

Novel nanoscale theragnostic devices were successfully prepared through attachment of well defined, multifunctional polymer chains to gadolinium (Gd) metal-organic framework (MOF) nanoparticles. Copolymers of poly(N-isopropylacrylamide)-co-poly(N-acryloxysuccinimide)-co-poly(fluorescein O-methacrylate) were prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization. The succinimide functionality was utilized as a scaffold for attachment of both a therapeutic agent, such as methotrexate, and a targeting ligand, such as H-glycine-arginine-glycine-aspartate-serine-NH(2) peptide. Employment of a trithiocarbonate RAFT agent allowed for reduction of the polymer end groups to thiolates providing a means of copolymer attachment through vacant orbitals on the Gd(3+) ions at the surface of the Gd MOF nanoparticles. These versatile, nanoscale scaffolds were shown to be biocompatible and have cancer cell targeting, bimodal imaging, and disease treatment capabilities. This unique method provided a simple yet versatile route of producing polymer-nanoparticle theragnostic materials with an unprecedented degree of flexibility in the construct, potentially allowing for tunable loading capacities and spatial loading of targeting/treatment agents, while incorporating bimodal imaging capabilities through both magnetic resonance and fluorescence microscopy.

Tuning the Magnetic Resonance Imaging Properties of Positive Contrast Agent Nanoparticles by Surface Modification with RAFT Polymers

A novel surface modification technique was employed to produce a polymer modified positive contrast agent nanoparticle through attachment of well-defined homopolymers synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. A range of RAFT homopolymers including poly[N-(2-hydroxypropyl)methacrylamide], poly(N-isopropylacrylamide), polystyrene, poly(2-(dimethylamino)ethyl acrylate), poly(((poly)ethylene glycol) methyl ether acrylate), and poly(acrylic acid) were synthesized and subsequently used to modify the surface of gadolinium (Gd) metal-organic framework (MOF) nanoparticles. Employment of a trithiocarbonate RAFT agent allowed for reduction of the polymer end groups under basic conditions to thiolates, providing a means of homopolymer attachment through vacant orbitals on the Gd3+ ions at the surface of the Gd MOF nanoparticles. Magnetic resonance imaging (MRI) confirmed the relaxivity rates of these novel polymer modified structures were easily tuned by changes in the molecular weight and chemical structures of the polymers. When a hydrophilic polymer was used for modification of the Gd MOF nanoparticles, an increase in molecular weight of the polymer provided a respective increase in the longitudinal relaxivity. These relaxivity values were significantly higher than both the unmodified Gd MOF nanoparticles and the clinically employed contrast agents, Magnevist and Multihance, which confirmed the constructs ability to be utilized as a positive contrast nanoparticle agent in MRI. Further characterization confirmed that increased hydrophobicity of the polymer coating on the Gd MOF nanoparticles yielded minimal changes in the longitudinal relaxivity properties but large increases in the transverse relaxivity properties in the MRI.

Synthesis of gadolinium nanoscale metal-organic framework with hydrotropes: manipulation of particle size and magnetic resonance imaging capability.

Gadolinium metal-organic framework (Gd MOF) nanoparticles are an interesting and novel class of nanomaterials that are being studied as a potential replacement for small molecule positive contrast agents in magnetic resonance imaging (MRI). Despite the tremendous interest in these nanoscale imaging constructs, there are limitations, particularly with respect to controlling the particle size, which need to be overcome before these nanoparticles can be integrated into in vivo applications. In an effort to control the size, shape, and size distribution of Gd MOF nanoparticles, hydrotropes were incorporated into the reverse microemulsion synthesis used to produce these nanoparticles. A study of how hydrotropes influenced the mechanism of formation of reverse micelles offered a great deal of information with respect to the physical properties of the Gd MOF nanoparticles formed. Specifically, this study incorporated the hydrotropes, sodium salicylate (NaSal), 5-methyl salicylic acid, and salicylic acid into the reverse microemulsion. Results demonstrated that addition of each of the hydrotropes into the synthesis of Gd MOFs provided a simple route to control the nanoparticle size as a function of hydrotrope concentration. Specifically, Gd MOF nanoparticles synthesized with NaSal showed the best reduction in size distributions in both length and width with percent relative standard deviations being nearly 50% less than nanoparticles produced via the standard route from the literature. Finally, the effect of the size of the Gd MOF nanoparticles with respect to their MRI relaxation properties was evaluated. Initial results indicated a positive correlation between the surface areas of the Gd MOF nanoparticles with the longitudinal relaxivity in MRI. In particular, Gd MOF nanoparticles with an average size of 82 nm with the addition of NaSal, yielded a longitudinal relaxivity value of 83.9 mM⁻¹ [Gd³⁺] sec⁻¹, one of the highest reported values compared to other Gd-based nanoparticles in the literature to date.

Poly(acrylic acid) Bridged Gadolinium Metal–Organic Framework–Gold Nanoparticle Composites as Contrast Agents for Computed Tomography and Magnetic Resonance Bimodal Imaging

Imaging contrast agents for magnetic resonance imaging (MRI) and computed tomography (CT) have received significant attention in the development of techniques for early stage cancer diagnosis. Gadolinium (Gd)(III), which has seven unpaired electrons and a large magnetic moment, can dramatically influence the water proton relaxation and hence exhibits excellent MRI contrast. On the other hand, gold (Au), which has a high atomic number and high X-ray attenuation coefficient, is an ideal contrast agent candidate for X-ray-based CT imaging. Gd metal-organic framework (MOF) nanoparticles with tunable size, high Gd(III) loading and multivalency can potentially overcome the limitations of clinically utilized Gd chelate contrast agents. In this work, we report for the first time the integration of GdMOF nanoparticles with gold nanoparticles (AuNPs) for the preparation of a MRI/CT bimodal imaging agent. Highly stable hybrid GdMOF/AuNPs composites have been prepared by using poly(acrylic acid) as a bridge between the GdMOF nanoparticles and AuNPs. The hybrid nanocomposites were then evaluated in MRI and CT imaging. The results revealed high longitudinal relaxivity in MRI and excellent CT imaging performance. Therefore, these GdMOF/AuNPs hybrid nanocomposites potentially provide a new platform for the development of multimodal imaging probes.

Polymer-Modified Nanoparticles as Targeted MR Imaging Agents

A novel surface modification technique was employed to produce a polymer-modified, positive contrast agent nanoparticle for targeted magnetic resonance imaging (MRI). A range of both hydrophilic and hydrophobic homopolymers, along with novel multifunctional copolymers of poly(N-(2-hydroxypropyl) methacrylamide)-co-poly(N-methacryloxysuccinimide)-co-poly(fluorescein O-methacrylate), were synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization. These polymers were subsequently used to modify the surface of gadolinium (Gd) metal-organic framework (MOF) nanoparticles. The succinimide functionality of the copolymer was utilized as a scaffold for attachment of the targeting ligands, H-glycine-arginine-glycine-aspartate-serine-NH2 peptide or the antibody for epidermal growth factor. Reduction of the trithiocarbonate RAFT polymer end groups to thiolates provided a means of polymer attachment through vacant orbitals on the Gd3+ ions at the surface of the Gd MOF nanoparticles. MRI confirmed that the relaxivity rates of these novel polymer-modified structures were easily tuned by changes in size and shape of the nanoparticles or by modifying the molecular weight and chemical structure of the polymers attached to the surface of the nanoparticles. In most cases, the relaxivity values were significantly higher than both the unmodified Gd MOF nanoparticles and the clinically employed contrast agents, Magnevist® and MultiHance®. These versatile, polymer-modified nanoscale scaffolds were shown to provide biocompatibility, cancer cell targeting, and diagnostic imaging through positive contrast in MRI and fluorescence microscopy. This unique method provided a simple yet versatile route of producing polymer-modified nanoparticles for targeted MRI of cancer with an unprecedented degree of flexibility in the construct, potentially allowing for tunable loading capacities and spatial loading of targeting agents while incorporating bimodal imaging capabilities.

POLYMER-MODIFIED GADOLINIUM NANOPARTICLES FOR TARGETED MAGNETIC RESONANCE IMAGING AND THERAPY

Functional imaging is a novel area in radiological sciences and allows for the non-invasive assessment and visualization of specific targets such as gene and protein expression, metabolic rates, and drug delivery in intact living subjects. As such, the field of molecular imaging has been defined as the non-invasive, quantitative, and repetitive imaging of biomolecules and biological processes in living organisms. For example, cancer cells may be genetically altered to attract molecules that alter the magnetic susceptibility, thereby permitting their identification by magnetic resonance imaging. These contrast agents and/or molecular reporters are seen as essential to the task of molecular medicine to increase both sensitivity and specificity of imaging. Therefore, there are five general principles which need to be fulfilled in order to conduct a successful in vivo molecular imaging study: (1) selection of appropriate cellular and subcellular targets; (2) development of suitable in vivo affinity ligands (molecular probes); (3) delivery of these probes to the target organ; (4) amplification strategies able to detect minimal target concentrations; and (5) development of imaging systems with high resolution. Although there has been a wide range of routes taken to incorporate both imaging agents and a disease-targeting moiety into diagnostic devices, arguably the most interesting of these routes employs the use of nanoparticles. Nanoscale diagnostic systems that incorporate molecular targeting agents and diagnostic imaging capabilities are emerging as the next-generation imaging agents and have the potential to dramatically improve the outcome of the imaging, diagnosis, and treatment of a wide range of diseases. The present review addresses chemical aspects in development of molecular probes based upon gadolinium nanoparticles and their potential role in translational clinical imaging and therapy.

Direct esterification of a hydroxyl functional polyester resin with p-hydroxybenzoic acid: Part A: investigation of the direct esterification reaction scheme and characterisation of products

Direct esterification of a hydroxyl functional polyester resin with p-hydroxybenzoic acid (PHBA) was carried out at 200-230 degreesC in the presence of p-toluene sulphonic acid and xylene. Acid value, molecular weight distribution, differential scanning calorimetry and both H-1 and C-13 NMR analysis were used to monitor the reaction. The optical texture of the final products were examined using a polarising optical microscope. The products from the reaction were the polyester with approximately 1 PHBA molecule per polymer chain end and unreacted PHBA. The dominant reaction in the system appears to be transesterification, resulting in a decrease of the molecular weight during the reaction. A liquid crystalline phase was not formed as multiple grafts of PHBA were not formed

Direct esterification of a hydroxyl functional polyester resin with p-hydroxybenzoic acid: Part B: coating preparation and evaluation

Comparison of the physical properties of direct esterified, both purified and unpurified, and standard polyester coatings was undertaken. Clear and pigmented baked enamels, both non-cross-linked and cross-linked, were produced. Results indicate that coating binders containing the unpurified direct esterified resin are potentially superior to conventional binders as they exhibit the outstanding feature of being both hard and flexible. This improvement is due to the presence of unreacted p-hydroxybenzoic acid in the resin and is not due to a liquid crystal phase. The improvement in physical properties is dependent upon the bake conditions used, with temperatures of 232°C causing a marked decrease in coating performance.