Superparamagnetic Iron Oxide Nanoparticles For Drug Delivery

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1 Superparamagnetic Iron Oxide Nanoparticles For Drug Delivery Yana Petri C150 Special Topic SPION ferrofluid

Background and Motivation Most promising magnetic iron oxide nanoparticles for biomedical applications: Magnetite (Fe 3 O 4 ) and maghemite (y-fe 2 O 3 ) Valued for tunable size-dependent magnetic

2 Background and Motivation Most promising magnetic iron oxide nanoparticles for biomedical applications: Magnetite (Fe 3 O 4 ) and maghemite (y-fe 2 O 3 ) Valued for tunable size-dependent magnetic properties, nontoxicity, biodegradability On-command drug delivery and release minimal off-target effects Potential for more efficient cancer treatments Numerous in vitro and in vivo applications Figuerola, A.; Di Corato, R.; Manna, L.; Pellegrino, T. Pharmacol. Res. 2010, 62,

3 Magnetite Structure and Ferrimagnetism Octahedral B sublattice Fe 3+ Fe 2+ Tetrahedral A sublattice Fe 3+ Magnetite (Fe 2+ F 3+ 2O 4 ) has a cubic spinel crystal structure. O atoms have a close-packed FCC structure and Fe atoms occupy interstitial positions. A sublattice contains Fe 3+ ions, B sublattice contains Fe 3+ and Fe 2+ ions. Net moments in B-site are aligned ferromagnetically via double exchange. Fe 3+ ions in A and B sites are coupled antiferromagnetically via superexchange. Upon cancellation, a ferrimagnet with a net moment of 4u B results. Zhang, Z.; Satpathy, S. Phys. Rev. B. 1991, 44,

Iron Oxide Nanoparticles: Size-Dependent Properties Bulk magnetite: ferrimagnetic, Curie T of 858 K, multi domain, hysteresis loop present Coercivity is maximized at 100 nm Particles < 20 nm become

4 Iron Oxide Nanoparticles: Size-Dependent Properties Bulk magnetite: ferrimagnetic, Curie T of 858 K, multi domain, hysteresis loop present Coercivity is maximized at 100 nm Particles < 20 nm become superparamagnetic in zero magnetic field, magnetization is zero; no hysteresis loop; large magnetic susceptibility in applied magnetic field Ling, D.; Lee, N.; Hyeon, T. Acc. Chem. Res. 2015, 48,

5 Iron Oxide Nanoparticles: Superparamagnetism A B A) Blocked state: t between spin flips is larger than the measurement t well-defined state is observed (below blocking T) B) Superparamagnetic state: t between spin flips is smaller than the measurement t time-averaged net moment of 0 is observed (above blocking T) * Compared to paramagnets, have much larger magnetic susceptibility Pankhurst, Q. A.; Connolly, J.; Jones, S. K.; Dobson, J. J. Phys. D. Appl. Phys. 2003, 36, R167.

6 Iron Oxide Nanoparticles: Synthetic Methods Wu, W.; Wu, Z.; Yu, T.; Jiang, C.; Kim, W. S. Sci. Technol. Adv. Mater. 2015, 16,

7 Iron Oxide Nanoparticles: Microemulsion Synthesis Control nanoparticle size by modulating the size of the aqueous micellar core Dhand, C.; Dwivedi, N.; Loh, X. J.; Ying, A. N. J.; Verma, N. K., Beuerman; Ramakrishna, S. RSC Adv. 2015, 5,

using solvents with different BPs Size variation < 5%, inexpensive, non-toxic 40 g scale, > 95% yield Larger solvent BP larger NPs, since

8 Iron Oxide Nanoparticles: Heat-up Synthesis 1) Nucleation at 200 o C, one oleate ligand dissociation by CO 2 elimination Fe(oleate) 3 2) Nucleation at 300 o C, dissociation of the remaining oleate ligands from Fe(oleate) 2 SPIONs Principle: separation of nucleation and growth Control NP size by using solvents with different BPs Size variation < 5%, inexpensive, non-toxic 40 g scale, > 95% yield Larger solvent BP larger NPs, since iron-oleate complex is more reactive in high BP solvents Park, J.; An, K.; Hwang, Y.; Park, J. G.; Noh, H. J.; Kim, J. Y.; Hyeon, T. Nat. Mater. 2004, 3, 891.

9 Iron Oxide Nanoparticles: Surface Functionalization Most popular method: ligand exchange Benefits: Agglomeration prevention, biocompatibility, long-term stability in aqueous media Oleic acid-coated NPs (synthesized via the heat-up process) are rendered hydrophilic via ligand exchange and condensation. PEGylated nanoparticles result. Fang, C.; Bhattarai, N.; Sun, C., & Zhang, M. Small 2009, 5,

10 Iron Oxide Nanoparticles: ph-dependent Drug Release ph 7.4 (extracellular) min release ph 5.5 (intracellular) max release Basis: acid-labile hydrazone bonds Drug: O6-BG for cancer treatment (DNA repair interruption) Stephen, Z. R.; Gebhart, R. N.; Jeon, M.; Blair, A. A.; Ellenbogen, R. G.; Silber, J. R.; Zhang, M. Bioconjug. Chem ,

Biomedical Applications and Current Research 1) Cell labelling and magnetic separation Pass by a permanent magnet or magnetic field for selective removal 2) Tissue repair Heating or soldering with

11 Biomedical Applications and Current Research 1) Cell labelling and magnetic separation Pass by a permanent magnet or magnetic field for selective removal 2) Tissue repair Heating or soldering with protein-coated NPs for enhanced tissue joining 3) Magnetic resonance imaging (MRI) NPs act as contrast agents that alter the relaxation rates of nearby water protons 4) Targeted delivery Radionuclides, genes, proteins, small-molecule drugs, etc. Translational movement generated by magnetic field gradient 5) Hyperthermia Selectively heat malignant tissue via alternating magnetic field Lee, N.; Yoo, D.; Ling, D.; Cho, M. H.; Hyeon, T.; Cheon, J. Chem. Rev. 2015, 115, Gupta, A. K.; Gupta, M. Biomater. 2005, 26,

In Vivo Delivery of Magnetic SPION Aerosol Droplets Theory Force acting on a magnetizable NP in external magnetic field: Depends on magnetic moment of the droplet and magnetic flux gradient.

12 In Vivo Delivery of Magnetic SPION Aerosol Droplets Theory Force acting on a magnetizable NP in external magnetic field: Depends on magnetic moment of the droplet and magnetic flux gradient. An inhomogeneous field is required. NPs move in the direction of the steepest ascent of the E density scalar field. Dames, P.; Gleich, B.; Flemmer, A.; Hajek, K., Seidl; N., Wiekhorst, F.; Trahms, L. Nat. Nanotech. 2007, 2, 495.

13 In Vivo Delivery of Magnetic SPION Aerosol Droplets Theory Force acting on a magnetizable NP in external magnetic field: Depends on magnetic moment of the droplet and magnetic flux gradient. An inhomogeneous field is required. NPs move in the direction of the steepest ascent of the E density scalar field. Computer model of mouse bronchi Dames, P.; Gleich, B.; Flemmer, A.; Hajek, K., Seidl; N., Wiekhorst, F.; Trahms, L. Nat. Nanotech. 2007, 2, 495.

14 Challenge: Extending Technology to Patients Research problem: Nonlinear fall of magnetic force with distance Nacev, A.; Komaee, A.; Sarwar, A.; Probst, R.; Kim, S. H.; Emmert-Buck, M.; Shapiro, B. IEEE Cont. Sys. 2012, 32,

Hyperthermia AC magnetic field required Cancer cells destroyed above 43 o C, but normal cells survive Ferrimagnetic NPs: heat generated due to magnetic hysteresis loss

15 Hyperthermia AC magnetic field required Cancer cells destroyed above 43 o C, but normal cells survive Ferrimagnetic NPs: heat generated due to magnetic hysteresis loss Superparamagnetic NPs (ferrofluids): changes in M lag behind changes in H Bae, K. H.; Park, M.; Do, M. J.; Lee, N.; Ryu, J. H.; Kim, G. W.; Hyeon, T. ACS Nano 2012, 6,

16 Thank you! Questions?

Chapter 2 Magnetic Properties

Chapter 2 Magnetic Properties Abstract The magnetic properties of a material are the basis of their applications. Specifically, the contrast agents that will be developed in Chaps. 4 and 5 use their magnetic