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.
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 construct's 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.
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.
The synthesis of diblock copolymer brushes, including poly(styrene) (PSty)-b-PSty, PSty-bpoly(acrylic acid), PSty-b-poly(N-isopropylacrylamide), and poly(methyl acrylate)-b-poly(N,N-(dimethylamino)ethyl acrylate), was achieved utilizing a combination of surface-mediated atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization techniques. Conversion of bromine end groups of homopolymer brushes formed by ATRP via a modified atom transfer addition reaction to a RAFT agent and diblock extension via RAFT polymerization allowed the direct formation of well-defined stimuliresponsive diblock copolymer brushes. The addition of sacrificial initiator and/or chain transfer agent permitted formation of well-defined diblock copolymer brushes and free polymer chains in solution. The free polymer chains were isolated and used to estimate the molecular weights and polydispersity index of chains attached to the surface. Ellipsometry, contact angle measurements, grazing angle attenuated total reflectance-Fourier transform infrared spectroscopy, and wide-scan X-ray photoelectron spectroscopy (XPS) were used to characterize initiator deposition, homopolymer brush formation via ATRP, conversion to macro-RAFT agent, and diblock copolymer brush formation via RAFT polymerization. Selective solvent treatment demonstrated the stimuli-responsive nature of the diblock copolymer brushes via changes in the water contact angles and wide-scan XPS atomic percentages.
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