Iron oxide nanocubes for magnetic hyperthermia
- Autores: Dina Niculaes
- Directores de la Tesis: Miquel Angel Pericàs (dir. tes.), Teresa Pellegrino (codir. tes.)
- Lectura: En la Universitat Rovira i Virgili ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Davide Comoretto (presid.), Pablo Jose Ballester Balaguer (secret.), Oliver Reiser (voc.)
- Programa de doctorado: Programa de Doctorado en Ciencia y Tecnología Química por la Universidad Rovira i Virgili
- Materias:
- Enlaces
- Tesis en acceso abierto en: hdl.handle.net TDX
- Resumen
During the three year doctoral course (XXIX cycle, 2014–2016), in the Nanochemistry department at the Italian Institute of Technology (Genoa, Italy), my research was focused on the development of new nanosystems based on iron oxide cubic-shaped nanoparticles for magnetic hyperthermia application in cancer treatment. Three main projects were conducted under the supervision of Dr. Teresa Pellegrino. The goals of each project and the main results obtained are summarized below.
The novel use of magnetic hyperthermia set-up for the mild oxidization of Fe1-xO/Fe3-δO4 core-shell nanocubes to single Fe3O4 phase was demonstrated. The wüstite/magnetite core-shell nanocubes after synthesis via decomposition of iron pentacarbonyl Fe(CO)5, resulting in non-interacting particles with moderate magnetization, were easily transferred into water by exchanging the short organic surfactant with a poly(ethylene glycol) based water soluble polymer. The water transferred samples had their specific absorption rate (SAR) values determined. Given that these values were lower compared to fully magnetite iron oxide nanocubes of similar cube edge length, the unstable FeO core was oxidized in two different ways: a “harsh” one, after which the SAR values increased alongside the loss of stability and a “mild” one that preserved sample stability. The latter was called magnetic hyperthermia (MH) stimulation. After a handful of MH treatments, the SAR values increased up to two times, while colloidal stability, size distribution and shape remained unaffected. The magnetically stimulated iron oxide nanocubes (IONCs) showed a significantly higher saturation magnetization MS than the initial core-shell ones, reflecting structural and compositional changes as confirmed by high resolution transmission electron microscopy/scanning transmission electron microscopy and superconductive quantum interference device studies. The MH treatment also opened up the possibility of attaching biologically relevant molecules to the surface of core-shell nanocubes and preserving their activity while improving the IONCs heat performance. On biotin-tagged nanoparticles, the affinity of biotin towards streptavidin ligands was preserved even after 25 hours of magnetic oxidation treatment. The method here described enabled a mild magnetic transformation of nanocubes resulting in more efficient heat mediators while preserving both the colloidal stability and molecular targeting of the heating nano-probes. These are all crucial features for optimal preparation of heat mediators for in vivo hyperthermia.
In continuity with the previous work, the SAR values of core-shell iron oxide nanocubes could be enhanced not only by oxidizing the FeO core, but by controlled clustering of nanocubes in chain like structures driven by anisotropic interactions. Initially the controlled clustering of the IONCs during their water transfer was developed, enabling the formation of soft colloidal clusters with average hydrodynamic sizes that could be tuned between ca. 30 and 100 nm. The size tuning could be achieved both by varying the ratio of the amphiphilic random copolymer, poly(styrene-co-maleic anhydride), cumene terminated (Mn = 1 600 g/mol), to the particle surface or by varying the initial iron concentration. With this versatile method, magnetic nanoparticles of different shapes—spherical, cubic, cubic with rounded edges—and sizes—in the range 15 to 22 nm— alongside gold nanoparticles, could be clustered in a controlled manner. By increasing the ratio of amphiphilic polymer per nm2 of particle surface or the Fe concentration bigger nanoclusters were obtained.
The hyperthermia response of individually coated nanocubes vs. soft colloidal nanoclusters of different sizes, with hydrodynamic diameters below 100 nm was evaluated. These results were correlated with their magnetic properties as determined by various magnetic characterization techniques. The so called “dimers” and “trimers”, 1D and 2D structures formed with two and respectively three iron oxide nanocubes, showed higher SAR values compared both to individual IONCs or more-centro symmetrical clusters with the number of cubes per cluster higher than 4. Lastly, by implementing previous findings, the clusters could be formed with freshly synthesized core-shell nanocubes, followed by their annealing in aqueous solutions at 80 °C, that resulted in stable nanosystems with higher specific absorption rate values.
Drug loading on two nanosystems designed for heat-triggered chemotherapeutic drug release was achieved. Both systems were based on magnetite 19 nm iron oxide nanocubes coated with thermo-responsive polymers grown from the surface of the IONCs by living radical polymerization, one being reversible addition-fragmentation chain transfer (RAFT) polymerization. Doxorubicin hydrochloride (doxo) loading conditions as a function of initial doxo concentration, incubation time, cleaning method, and loading volume were studied. The two thermo-responsive polymers of choice were poly(N-isopropylacrylamide)-co-poly(ethylene glycol) methyl ether acrylate (PNIPAM-co-PEGA) and poly(diethylene glycol methyl ether methacrylate-co-oligo ethylene glycol methyl ether methacrylate) (P(DEGMEMA-co-OEGMEMA)) due to their biocompatibility and ease of lower critical solution temperatures (LCST) tuning in the range from 39 to 41 °C, by varying the polymer composition. The goal was to have stable nanocarriers at body temperature that would release the cargo (the chemotherapeEcole Nationale Superieure de Chimie,de Biologie et de Physiqutic drug) exclusively upon the application of an alternating magnetic field, generating an increase in temperature that would be accompanied by the shrinking of the polymeric shell and release of the entrapped drug. Once individually thermo-responsive polymer coated iron oxide nanocubes with high specific absorption values were obtained, solutions of these IONCs were characterized in terms of specific absorption rate and maximum temperature reached during 3 cycles of 30 minutes of hyperthermia treatment, carried out in small volumes of 50 µL at Fe concentrations ranging from 2.5 to 4 g/L in preparation for in vivo studies. The heat-triggered doxorubicin release under alternating magnetic field, at biologically relevant frequency (105 kHz) and field amplitude (25 mT), was qualitatively, but not quantitatively proven.
During my ten-month mobility stay (2015–2016), in the group of Professor Miquel A. Pericàs at the Institute of Chemical Research of Catalonia (Tarragona, Spain), the selective oxidation of benzyl alcohol into benzaldehyde under mild reaction conditions, using caffeic acid coated iron oxide nanoparticles (spherical and cubic) as catalysts was investigated. The oxidation process was studied as a function of reaction time, amount, and type of catalyst. Recyclability studies were carried out once the best reaction conditions had been identified.
