WO2015077775A1 - Nanoparticules magnétiques revêtues - Google Patents

Nanoparticules magnétiques revêtues Download PDF

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Publication number
WO2015077775A1
WO2015077775A1 PCT/US2014/067410 US2014067410W WO2015077775A1 WO 2015077775 A1 WO2015077775 A1 WO 2015077775A1 US 2014067410 W US2014067410 W US 2014067410W WO 2015077775 A1 WO2015077775 A1 WO 2015077775A1
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Prior art keywords
nanoparticles
peg
magnetic
nanoparticle
pmao
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PCT/US2014/067410
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English (en)
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Amit P. KHNADHAR
Kannan M. Krishnan
R. Matthew FERGUSON
Scott Kemp
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Khnadhar Amit P
Krishnan Kannan M
Ferguson R Matthew
Scott Kemp
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Publication of WO2015077775A1 publication Critical patent/WO2015077775A1/fr
Priority to US15/043,313 priority Critical patent/US9555136B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1857—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
    • A61K49/186—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA the organic macromolecular compound being polyethyleneglycol [PEG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1854—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly(meth)acrylate, polyacrylamide, polyvinylpyrrolidone, polyvinylalcohol

Definitions

  • SPIONs Superparamagnetic iron oxide nanoparticles
  • magnetite Fe 3 0 4
  • maghemite Fe 2 0 3
  • CKD chronic kidney disease
  • SPIONs of various compositions have been used for biomedical applications such as cell labeling and separation, drug delivery, magnetic gene transfection (magnetofection), tissue repair and hyperthermia [Gupta et al, Biomaterials 2005; 26:3995-4021, Krishnan, IEEE Trans. Mag. 46, 2523-2558 (2010) ].
  • the unique nonlinear magnetic response of SPIONs can be exploited in alternating magnetic fields to induce a detectable signal that is proportional to the ac- susceptibility (m'(H)).
  • Applications such as magnetic particle imaging (MPI) [Gleich and Weizenecker, Nature 2005;435: 1214-7], magnetic sentinel lymph node biopsy (SLNB) [M. Douek et al, Ann. Surg. Oncol., 21, 1237 (2013)]and magnetic fluid hyperthermia (MFH) [R. K. Gilchrist et al, Ann. Surgery 146, 596 (1957); U. Gneveckow et al, Med. Phys.
  • the first generation of SPIONs designed for either in vivo MPI or MFH therapy must be biocompatible and demonstrate appropriate circulation times to enable vascular imaging or site-specific heating, respectively.
  • a circulation time of approximately 1 hour should provide clinicians sufficient time; for instance, Ablavar® (Lantheus Medical Imaging) - a gadolinium-based MRI blood pool agent remains in circulation for up to 1 hour [www.ablavar.com].
  • Ablavar® Long Surgical Imaging
  • a gadolinium-based MRI blood pool agent remains in circulation for up to 1 hour [www.ablavar.com].
  • even shorter circulation times may be sufficient.
  • each nanoparticle includes:
  • a core comprising iron oxide, wherein the core has a diameter of 15 nm to 30 nm;
  • Rl is a hydrophobic moiety
  • the method comprises applying a magnetic field to a plurality of nanoparticles according to the disclosed embodiments.
  • the magnetic field is applied to a subject into which the nanoparticles have been dispersed.
  • FIGURE 1 schematically illustrates a representative magnetic nanoparticle in accordance with the disclosed embodiments.
  • FIGURES 2A-2C graphically illustrate hydrodynamic size data from three samples of PMAO-PEG nanoparticles (>20 nm) in RPMI+10% FBS cell culture medium:
  • FIGURES 2A and 2B are comparative samples with 5k Da PEG at a loading of 9% and 13%, respectively;
  • FIGURE 2C is an exemplary embodiment having 20k Da PEG at a loading of 13%.
  • FIGURES 3A-3C graphically illustrate magnetic particle spectrometry data from three samples of PMAO-PEG nanoparticles in DI water and serum-rich cell culture medium:
  • FIGURE 3A is a comparative sample of 25 nm core diameter coated with 5k Da PEG at a loading of 9%;
  • FIGURE 3B is a comparative sample of 23 nm core diameter coated with 5k Da PEG at a loading of 13%;
  • FIGURE 3C is an exemplary embodiment of 25 nm core diameter coated with 20k Da PEG at a loading of 13%.
  • FIGURE 4A graphically illustrates the effect of centrifugation on the hydrodynamic diameter of PMAO-PEG nanoparticles.
  • FIGURE 4B graphically illustrates the mass (top) and intensity (bottom) of the PMAO-PEG nanoparticles evaluated in FIGURE 4A by magnetic particle spectrometry.
  • FIGURES 5A and 5B graphically illustrate the magnetic particle spectrometry response to magnetic nanoparticle core diameter based on intensity (FIGURE 5A) and mass (FIGURE 5B).
  • FIGURES 6A and 6B graphically illustrate the magnetic response linearity of magnetic nanoparticles according to the disclosed embodiments in blood.
  • FIGURE 7 graphically illustrates magnetic signal stability in blood of exemplary nanoparticles in vivo (mice).
  • R j is a hydrophobic moiety.
  • the molecular weights of the PMAR and PEG portions of the copolymer, as well as the core diameter of the nanoparticles are selected in order to produce optimal performance for specific applications.
  • Representative applications of the nanoparticles include magnetic particle imaging (MPI), magnetic sentinel lymph node biopsy (SLNB), and magnetic fluid hyperthermia (MFH).
  • MPI magnetic particle imaging
  • SLNB magnetic sentinel lymph node biopsy
  • MFH magnetic fluid hyperthermia
  • the disclosed nanoparticles are tools for these methods that provide previously unachieved levels of stability and customi
  • NP nanoparticles
  • MNP magnetic nanoparticles
  • SPIONs superparamagnetic iron oxide nanoparticles
  • each nanoparticle includes:
  • a core comprising iron oxide, wherein the core has a diameter of 15 nm to 30 nm;
  • Rl is a hydrophobic moiety.
  • the combination of the specific size range of the core, coupled with the specific composition of the coating, provides the nanoparticles with unexpectedly superior properties compared to known nanoparticles. These benefits include, but are not limited to, improving dispersal in water, preventing aggregation, and preserving the nonlinear magnetic response or AC-susceptibility in aqueous media and serum-containing in vivo environments, such as circulating blood.
  • the molecular weight and surface density of PEG chains conjugated to the PMAR can be tailored to tune the in vivo blood half-life of nanoparticles injected intravenously or through a catheter in order to provide sustained nonlinear magnetic signal for first-pass and steady-state imaging or detection.
  • FIGURE 1 schematically illustrates an exemplary magnetic nanoparticle in accordance with the disclosed embodiments.
  • the nanoparticle includes PMAO-PEG coating on oleic acid coated nanoparticles.
  • the hydrophobic alkyl chains (CI 6) in PMAO intercalate with oleic acid chains and are bound by hydrophobic van der Waals forces.
  • the core of the nanoparticles is iron oxide. Any iron oxide can be used in the nanoparticles.
  • the iron oxide is selected from the group consisting of wustite, magnetite, maghemite, and combinations thereof.
  • the iron oxide is wustite.
  • the iron oxide is magnetite.
  • the iron oxide is maghemite.
  • Iron oxide cores are generally known to those of skill in the art but their size, distribution and phase purity must be carefully selected to have appropriate magnetic relaxation characteristics.
  • the size or diameter of the iron oxide nanoparticle cores can be determined, for example, by transmisstion electron microscopy (TEM).
  • the core has a diameter ("size") of 15 nm to 30 nm. It has been determined that this core size range is valuable for applications such as MPI.
  • Example 3 illustrates the inferiority of cores smaller than 15 nm in diameter. The optimal core size range for the system of Example 3 is 23-27 nm.
  • the core has a diameter of 18 nm to 30 nm.
  • the core has a diameter of 23 nm to 30 nm.
  • the core has a diameter of 23 nm to 27 nm.
  • the cores are monodisperse, as defined by their having a diameter distribution with geometric standard deviation of equal to or less than 1.35 when a log-normal distribution function is used. In another embodiment, the cores are monodisperse, as defined by their having a diameter distribution with geometric standard deviation of equal to or less than 1.11 when a log-normal distribution function is used.
  • the geometric standard deviation of a plurality of nanoparticles is defined as relating to how spread out are the particle diameters in the sample, with 68% of the samples falling between the lower bound set by do/exp ( ⁇ ) and the upper bound do*exp ( ⁇ ), where do is the median diameter of the distribution and exp ( ⁇ ) is the geometric standard deviation.
  • An exemplary calculation of the geometric standard deviation is included in the Examples below.
  • a log-normal distribution may be applied to the data even if the data do not perfectly fit the log-normal distribution.
  • the distribution function may obey other relationships besides a log-normal distribution, including a normal distribution, a bimodal distribution, and any other relationship known to those of skill in the art.
  • the monodispersity of the nanoparticles is important because it provides uniform characteristics that translate to optimized, reproducible and predictable magnetic performance and stability in aqueous, in vitro and in vivo environments. Many physical properties of nanoparticles vary exponentially with particle size, with some sizes being well-suited to a particular application and other sizes being ill-suited. Monodisperse samples can be optimized for an application by making all particles very nearly the optimum size. Polydisperse samples cannot be optimized, since they contain both desirable and undesirable sizes. Monodiserse magnetic nanoparticles provide more intense signals, whereas polydisperse magnetic nanoparticles often give broad and lower intensity signal response.
  • the plurality of nanoparticles is 100 or more nanoparticles. In one embodiment, the plurality of nanoparticles is 1,000 or more nanoparticles. In one embodiment, the plurality of nanoparticles is 1,000,000 or more nanoparticles.
  • the primary factor is the amount of iron oxide, which is defined by the size and number of nanoparticles. As an example, for a mouse circulation time study using MPI a typical injection is about 0.1 mg of iron oxide, which contains about 3.3 xlO 12 nanoparticles with a 25 nm core diameter.
  • the coating is attached to the core by a mechanism selected from the group consisting of covalent bonding, ionic bonding, van der Waals forces, and hydrophobic/hydrophobic interactions .
  • the core comprises an attachment layer on its surface that provides functionality such that the coating adheres to the core.
  • An exemplary attachment layer is oleic acid, which provides hydrophobic moieties extending from the core surface, which can facilitate hydrophobic -hydrophobic bonding.
  • a coating surrounds the core in order to decrease aggregation between nanoparticles and preserve magnetic characteristics of the core.
  • the term "surrounds" includes both complete surface coverage, as well as partial surface coverage.
  • the coating completely surrounds the core.
  • the coating partially surrounds the core.
  • at least a portion of the plurality of nanoparticles comprises a single core surrounded with the coating.
  • the coating provides both physical and magnetic isolation between adjacent nanoparticles. Specifically, the coating minimizes magnetic dipole-dipole interactions between individual nanoparticles, minimizing clustering and aggregation and preserving their nonlinear magnetic response in alternating magnetic fields used in inductive measurement techniques. As a result, the induced signal is quantitative (linear with concentration) and remains unchanged after administration in in vivo environments (e.g. intravenous injection), thus enabling high quality imaging or detection, and quantitation.
  • the nanoparticle relaxation or magnetic moment reversal of each core is independent of an adjacent nanoparticle.
  • the coating includes an amphiphilic polymer.
  • a hydrophobic moiety is any chemical moiety that provides hydrophobic character. Representative hydrophobic moieties include alkyl and alkenyl groups, both substituted and unsubstituted.
  • Rl is a C6 to C18 hydrocarbon.
  • the PMAR-PEG polymer is of the type typically embodied by poly(maleic anhydride alt-octadecene)-PEG, referred to as "PMAO-PEG.” Accordingly, in one embodiment, the PMAR portion is PMAO and thus the PMAR-PEG polymer is PMAO- PEG.
  • the PMAR-PEG polymer is configured as a pendant-type copolymer, with the PMAR portion forming the backbone and the PEG portions pendant off of the PMAR portion.
  • PMAR provides functional binding sites such that up to two PEG portions can be bound to each PMAR monomer.
  • PEGs are grafted onto the PMAR portion by reacting carboxylates on the PMAR portion with terminal hydroxyl or primary amines on the PEG portions to form ester or amide bonds, respectively.
  • the amount of PEG bound to the PMAR is referred to herein as the PEG "loading.”
  • the loading is a percentage based on the number of PEG portions attached to the available number of carboxylates of the PMAR portion, given the presence of 2 carboxylates per maleate in the PMAR portion.
  • the PMAR-PEG copolymer has 1% to 50% PEG loading. In one embodiment, the PMAR-PEG copolymer has 12.5% to 25% PEG loading.
  • MW molecular weights
  • Mn number average molar mass
  • Rl hydrophobic moieties
  • the PMAR portion has a molecular weight (Mn) of 1,000 Da to 100,000 Da. In one embodiment, the PMAR portion has a molecular weight (Mn) of 10,000 Da to 70,000 Da. In a further embodiment, the PMAR portion has a molecular weight (Mn) of 30,000 Da to 50,000 Da. This size range for the PMAR portion provides hydrophobic moieties sufficient to attach the PMAR-PEG polymer to the core. The PMAR portion additionally provides a structure onto which PEG portions are attached.
  • the molecular weight of the PEG portions strongly defines the character of the nanoparticle properties.
  • a plurality of the PEG portions each have a molecular weight (Mn) of 10,000 Da or greater.
  • PEG portions with a molecular weight greater than 10,000 Da were found to reduce aggregation while preserving magnetic properties of the cores, as illustrated in Examples 1, 2, and 7.
  • all of the PEG portions have a MW of 10,000 Da or greater. However, in other embodiments, less than all of the PEG portions have a MW of 10,000 Da or greater.
  • the PEG portions have a molecular weight (Mn) of 15,000 Da or greater. In certain embodiments, the PEG portions have a molecular weight (Mn) of 20,000 Da or greater.
  • PEG MW provides strong anti-aggregation effects and improved nanoparticle properties
  • PEG MW is too high deleterious effects can occur.
  • relatively high MW PEG e.g., greater than 40k Da
  • the reaction dynamics when synthesizing the PMAR-PEG are adversely affected by the increased PEG MW and coupling to the PMAR is negatively impacted.
  • high MW PEG is not typically commercially available or, if available, expensive.
  • increasing PEG MW leads to increased hydrodynamic diameter of the nanoparticles, which affects in vivo performance due to filtering by the body (e.g., spleen).
  • the PEG portions have a molecular weight (Mn) of 30,000 Da or less. In a further embodiment, the PEG portions have a molecular weight (Mn) of 40,000 Da or less. In yet a further embodiment, the PEG portions have a molecular weight (Mn) of 50,000 Da or less. It is anticipated that PEG MW greater than 50,000 Da will be incompatible with the disclosed embodiments, or will not provide additional benefit beyond what is described herein.
  • the PEG portions have a molecular weight (Mn) of 10,000 Da to 50,000 Da. In one embodiment the PEG portions have a molecular weight (Mn) of 15,000 Da to 40,000 Da. In one embodiment the PEG portions have a molecular weight (Mn) of 15,000 Da to 30,000 Da. In one embodiment the PEG portions have a molecular weight (Mn) of 10,000 Da to 20,000 Da. In one embodiment the PEG portions have a molecular weight (Mn) of 15,000 Da to 25,000 Da.
  • the coating consists essentially of the PMAR-PEG copolymer.
  • the molecular weight and surface density of PEG portions can be modified to optimize colloidal stability of the nanoparticles, with negligible inter-particle dipolar interactions, preserve their nonlinear magnetic response in alternating magnetic fields, and also tune their blood half-life after intravenous injection.
  • Example 4 demonstrates signal linearity in blood
  • Example 5 demonstrates signal stability in vivo
  • Example 6 demonstrates the tunability of blood half-life based on alteration of the PEG molecular weight and/or PEG loading.
  • the blood half-life can be modified to enable first-pass cardiovascular MPI imaging, such as coronary angiography after intracatheter administration in coronary artery, and steady state imaging of the vascular system after intravenous or intracatheter administration.
  • first-pass cardiovascular MPI imaging such as coronary angiography after intracatheter administration in coronary artery
  • steady state imaging of the vascular system after intravenous or intracatheter administration.
  • the nanoparticles can be formed using any methods known to those of skill in the art.
  • the core is synthesized in organic solvents and then transferred from the organic to aqueous phase using the amphiphilic polymer. Hydrophobic-hydrophilic interactions attach the polymer to the cores in the aqueous phase.
  • the polymer coating is a polymer:
  • R j is a hydrophobic moiety (e.g., an alkyl of C6-C18 length).
  • R2 comprises from 2% to 100% of -NH-R4 or -O-R4 and the remaining percentage of R 2 is selected from one or more of the following: -OH (or -0 ), -NH2, - NHCH 2 CH 2 CH 2 N(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHR 5 , -OR 5 or other hydrophilic moiety.
  • R 3 is selected from one or more of the following: -OH (or -0 ), -NH 2 , - NHCH 2 CH 2 CH 2 N(CH 3 ) 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHR 5 -OR 5 or other hydrophilic moiety.
  • R4 is a polyethyleneglycol chain with a molecular weight (Mn) of 10,000 Da or more.
  • R5 is a polyethyleneglycol chain with a molecular weight (Mn) of 5,000 Da of less.
  • R4 is a polyethyleneglycol chain with a molecular weight
  • R 4 is a polyethyleneglycol chain with a molecular weight (Mn) of 15,000 Da to 30,000 Da. In one embodiment R4 is a polyethyleneglycol chain with a molecular weight (Mn) of 10,000 Da to 20,000 Da. In one embodiment R4 is a polyethyleneglycol chain with a molecular weight (Mn) of 15,000 Da to 25,000 Da.
  • nanoparticle size depends on several variables, including core diameter and PEG molecular weight. As used herein, nanoparticle size is defined as measured by Z-average dynamic light scattering (DLS) (defined in ISO 22412:2008).
  • DLS Z-average dynamic light scattering
  • the diameter of the core is 18 nm or greater and a Z-average hydrodynamic diameter of less than 150 nm.
  • the diameter of the core is 23 nm or greater and the molecular weight (Mn) of the PEG portions is 20,000 Da or greater.
  • the nanoparticles have a Z-average hydrodynamic diameter of less than 250 nm. This size relates to a relatively large core diameter and PEG molecular weight.
  • the provided nanoparticles can be used for any applications currently known or developed in the future that utilize magnetic particles.
  • Exemplary methods include MPI, SLNB, and MFH.
  • the nanoparticles are magnetic tracers configured to be introduced into a subject.
  • the subject is a human.
  • the subject is a non-human animal.
  • the nanoparticles are of sufficient number to possess the required magnetic properties and suspended in a medium compatible with introduction into the subject (e.g., into the subject's bloodstream).
  • the nanoparticles have a magnetic moment reversal in serum- containing media (including examples such as fetal bovine serum (FBS), Roswell Park Memorial Institute cell culture+10% fetal bovine serum, whole blood, etc.) that is similar to that in water and other aqueous systems.
  • serum- containing media including examples such as fetal bovine serum (FBS), Roswell Park Memorial Institute cell culture+10% fetal bovine serum, whole blood, etc.
  • the nanoparticles have a magnetic moment reversal preserved in AC fields with frequency from 1 kHz to 500 kHz.
  • the nanoparticles are administered in vivo and their magnetic moment reversal is preserved.
  • the inductive signal is preserved in vivo. . In one embodiment, the inductive signal is linear with concentration.
  • the method comprises applying a magnetic field to a plurality of nanoparticles according to the disclosed embodiments.
  • the magnetic field is applied to a subject into which the nanoparticles have been dispersed.
  • the method is a magnetic particle imaging method and the magnetic field comprises a spatially varying magnetic field with a field-free region and a time varying magnetic field.
  • Representative MPI methods with which the nanoparticles are compatible include those disclosed in U.S. Patent No. 7,778,681 and U.S. Patent Application Publication No. 2011/0089942, the disclosures of which are both incorporated herein by reference in their entirety.
  • the method is a magnetic hyperthermia method and the magnetic field is an alternating magnetic field configured to heat the plurality of nanoparticles.
  • the method is a magnetic sentinel lymph node biopsy method, the method further comprising a step of detecting a magnetic response to the magnetic field.
  • TEM Transmission electron microscopy
  • d is the core diameter measured by TEM
  • do is the median core diameter
  • ⁇ ( ⁇ ) is the geometric standard deviation.
  • the geometric standard deviation is used to establish the bounds of confidence intervals for log-normally distributed variables; e.g. the 68% confidence interval has upper bound do*exp ( ⁇ ) and lower bound ⁇ 3 ⁇ 4)/exp ( ⁇ ).
  • Dynamic light scattering measures the hydrodynamic diameter of nanoparticles. Hydrodynamic diameter includes the core diameter, any surfactants or polymers attached to the core and any hydration or counter-ion layer (if surface is charged) surrounding the outer surface. Hydrodynamic size increases if nanoparticles aggregate, or additional molecules, such as antibodies or other targeting moieties, are intentionally or unintentionally (non-specific adsorption of serum proteins) attached to the surface.
  • Vibrating sample magnetometer measures the magnetization response of nanoparticles as a function of applied field (dc field). Saturation magnetization (Ms) and the core diameter - obtained from fitting the magnetization curve - are included. The magnetic core diameter is determined from magnetization data by fitting to the equation
  • L (a) Coth(a) — 1/a
  • a ⁇ ⁇ ⁇ 0 ⁇ /k b T '
  • v the volume of the magnetic core
  • M the saturation magnetization of the particle in A/m
  • T the sample temperature in Kelvin
  • ⁇ 4 ⁇ 10 ⁇ H/m
  • ⁇ the applied field (in Tesla)
  • k b the Boltzmann constant
  • 1.38xl0 ⁇ 23 g (d) is a log-normal size distribution function
  • the magnetic core diameter is often, though not always, similar to the iron oxide core diameter measured by TEM.
  • MPS Magnetic particle spectrometry
  • All MPS measurements were performed with a sinusoidal excitation magnetic field at 25 kHz and 20 mT/ ⁇ amplitude.
  • MPS measures the induced signal, which is proportional to the derivative of the total magnetic moment - m'(H(t), where m [Am ] is the magnetic moment of the nanoparticles in the test sample.
  • the m'(H(t) curves are presented in two ways: (1) intensity normalized - to compare the full width at half maximum (FEHM), and (2) mass normalized - to compare the magnetic signal per unit mass of iron.
  • FEHM full width at half maximum
  • MPS also provides the harmonic spectrum of nanoparticles, which is the magnetization response of nanoparticles in the frequency domain.
  • FIGURES 2A-2C graphically illustrate hydrodynamic size data from three samples (see Table 1) of PMAO-PEG nanoparticles (>20 nm) in RPMI+10% FBS cell culture medium:
  • FIGURES 2A and 2B are comparative samples with 5k Da PEG at a loading of 9% and 13%, respectively;
  • FIGURE 2C is an exemplary embodiment having 20k Da PEG at a loading of 13%.
  • FIGURES 3A-3C graphically illustrate magnetic particle spectrometry data from three samples of PMAO-PEG nanoparticles in DI water and serum-rich cell culture medium:
  • FIGURE 3A is a comparative sample of 25 nm core diameter coated with 5k Da PEG at a loading of 9%;
  • FIGURE 3B is a comparative sample of 23 nm core diameter coated with 5k Da PEG at a loading of 13%;
  • FIGURE 3C is an exemplary embodiment of 25 nm core diameter coated with 20k Da PEG at a loading of 13%.
  • the insets of FIGURES 3A-3C show intensity-normalized MPS data.
  • FIGURES 3A-3C The SPION samples of FIGURES 3A-3C are within the optimum size range for MPI (23-27 nm, core dia.) and were coated with either one of three different PMAO-PEG polymers: PMAO-PEG(5KDa), with -9% or -13% PEG loading and PMAO- PEG(20KDa) with -13% PEG loading.
  • PMAO-PEG(5KDa) PMAO-PEG(5KDa)
  • PMAO- PEG(20KDa) PMAO- PEG(20KDa) with -13% PEG loading.
  • MPS data provides insight into the relaxation behavior of SPIONs in the biological environment - together the two methods enable us to probe the physical changes in SPIONs that can affect MPS performance.
  • both forward and reverse scans are shown in FIGURES 3A-3C.
  • SPIONs coated with PMAO-PEG(5kDa) @ 9% PEG loading showed immediate degradation in m'(H) after dispersing in RPMI+10%FBS medium; the appearance of peaks at -10 mT/ ⁇ and +10 mT/ ⁇ suggest a high coercive field required for magnetization reversal, which occurs when SPIONs are interacting due to potential agglomeration.
  • the colloidal stability data for the same sample presented in FIGURE 3A confirms that SPIONs are indeed agglomerating.
  • FIGURE 4A graphically illustrates the effect of centrifugation on the hydrodynamic diameter of PMAO-PEG nanoparticles.
  • FIGURE 4B graphically illustrates the mass (top) and intensity (bottom) of the PMAO-PEG nanoparticles evaluated in FIGURE 4A by magnetic particle spectrometry.
  • FIGURES 5A and 5B graphically illustrate the magnetic particle spectrometry response to magnetic nanoparticle core diameter based on intensity (FIGURE 5A) and mass (FIGURE 5B).
  • the core diameter varies as noted; the coating is PMAO-PEG (5k MW).
  • Data shows that nanoparticles smaller than 15 nm in core diameter have MPS performance worse than Resovist® - signal is nearly equivalent but FWHM is significantly broader/worse.
  • nanoparticles smaller than 15 nm core diameter are inferior for MPI and other AC inductive measurement techniques.
  • nanoparticles with core diameter between 23-27 nm are excellent for AC inductive measurements; example of 25.1 nm particles shown.
  • FIGURES 6A and 6B graphically illustrate the magnetic response linearity of magnetic nanoparticles according to the disclosed embodiments in blood. Analyzed samples are described in Table 2.
  • Nanoparticles coated with PMAO-PEG(20kDa) demonstrate signal stability and signal linearity in blood.
  • Iron concentration of PMAO-PEG coated samples was determined using ICP and dilution series in DI water and blood were prepared. After 24 hours of incubation in blood, magnetic signal induced in ac magnetic field (25 kHz and 20 mT/ ⁇ ) from both samples was linear with concentration and changed minimally compared to signal in DI water and Oh incubation time-point in blood.
  • Results demonstrate the ability to stabilize large core diameter nanoparticles (>25 nm) in water and biological media, while preventing long-term aggregation and preserving nanoparticle relaxation dynamics that are critical for ac magnetic field detection and imaging applications.
  • FIGURE 7 graphically illustrates magnetic signal stability in blood of exemplary nanoparticles in vivo (mice).
  • Nanoparticles were injected in the tail-vein of mice and allowed to circulate. Blood was drawn after 60 and 90 minutes of circulation and the nanoparticle- containing blood samples were placed in 25 kHz (20 mT/ ⁇ amplitude) ac magnetic field. The induced magnetic signal from nanoparticles in blood after 60 and 90 minutes of circulation showed little change, as characterized by the signal full-width at half maximum (FWHM).
  • FWHM full-width at half maximum
  • Table 3 summarizes blood half-life data for comparative and exemplary nanoparticles.
  • Nanoparticles coated with 20 kDa PEG at 12.5% PEG loading showed a 2-fold increase in blood half- life compared to nanoparticles coated with 5 kDa PEG at a similar PEG loading of 13% (sample B).
  • Table 4 summarizes the composition of comparative and exemplary nanoparticles disclosed herein.
  • Table 5 summarizes the characteristics of the nanoparticles of Table 4. The synthesis of the polymers, cores, and coated nanoparticles of Tables 4 and 5 are disclosed in detail below.
  • MPS Magnetic Particle Spectroscopy
  • VSM Vibrating Sample Magnetometry
  • Poly(maleic anhydride-alt- 1-octadecene) (average Mn 30,000-50,000 Da) was obtained from Sigma-Aldrich.
  • Benzyltriethylammonium chloride (>98%) p-toluenesulfonyl chloride (>99%) was obtain from Tokyo Chemical Industry CO, LTD.
  • Sodium hydroxide, magnesium sulfate (anhydrous), sodium sulfate (anhydrous) and methylene chloride (HPLC grade) were obtained from Fisher Scientific.
  • mPEG-NH2 of various MWs were either purchased from JenKem or produced from the appropriate mPEG-OH by formation of the tosylate, displacement with sodium azide and reduction of the azide to the amine with triphenylphosphine.
  • Dialysis of the polymer solution using 50 kDa mw cut off dialysis tubes was performed against water for 24 hours with 8 water changes.
  • the polymer solution was lyophilized to give 100% mPEG(5 kDa)-NH-PMAO (3.468 g).
  • the resulting residue was dissolved with water (90 mL) and 30% aqueous sodium hydroxide (0.5 mL) and stirred for 1 hour. Dialysis using 50 kDa mw cut off dialysis tubes was performed against water for 24 hours with 8 water changes. The polymer solution was lyophilized to give 25% (5 kDa) and 25% (10 kDa) mPEG-NH-PMAO (1.401 g).
  • Dialysis using 50 kDa mw cut off dialysis tubes was performed against water for 24 hours with 8 water changes.
  • the polymer solution was lyophilized to give 12.5% (20 k) and 25% (5 kDa) mPEG-NH-PMAO (1.425 g).
  • the resulting residue was dissolved with water (125 mL) and 30% aqueous sodium hydroxide (0.5 mL) and stirred for 18 hours. Dialysis using 50 kDa mw cut off dialysis tubes was performed against water for 24 hours with 8 water changes. The polymer solution was lyophilized to give 37.5% N,N-dimethyl-l,3-propane diamine and 12.5% (20 k) mPEG-NH-PMAO (1.035 g).
  • the resulting polymer solution was divided into four portions for batch dialysis using 50 kDa mw cut off dialysis tubes was performed against water for 24 hours with 8 water changes.
  • the polymer solution was lyophilized to give 25% (20 k) mPEG- NH-PMAO (15.875 g).
  • Nanoparticle washing procedure Iron oxide nanoparticle cores were synthesized according to U.S. Patent Application Publication No. 2013/0149539, the disclosure of which is hereby incorporated by reference in its entirety. Nanoparticles from crude synthesis batch were washed with a mixture of hexanes, acetone and ethyl acetate. After separating iron oxide cores with a magnet, supernatant containing excess oleic acid and octadecene was decanted. To iron oxide core pellet, hexane was added and sonicated in water-bath sonicator for 10 minutes.
  • 40 mg of polymer batch ak051313 (PMAO loaded with 13% 20 kDa mPEG-OH; Mn ⁇ 6.37E5 g/mol) was dissolved in 3 mL chloroform and mixed with 1 mL of washed iron oxide nanoparticles (batch 5-87) dispersed in chloroform.
  • the final polymer and nanoparticle concentrations were 10 mg/mL and 2.5 mg/mL, respectively, dispersed in a total of 4 mL chloroform in a 20 mL glass vial (approximately 187 PMAO-PEG polymer units per iron oxide nanoparticle, assuming 26.3 nm core diameter).
  • the mixture was sonicated for 60 minutes, followed by rotary evaporation to dryness.
  • the solid nanoparticle and polymer mixture was further dried under high vacuum for 60 minutes.
  • 10 mL of lx TAE buffer was added, and nanoparticle and polymer solid mixture was dispersed by sonication for 60 minutes. The solution was checked for any visible aggregates and sonicated for additional time if necessary.
  • the PMAO-PEG coated nanoparticles dispersed in lx TAE buffer were stirred for 24 hours using magnetic stir bar, then filtered with 200 nm nylon syringe filter. To remove excess polymer and salt, filtered PMAO-PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre-rinsed with DI water.
  • nanoparticle core 5-87 phase transferred with 5-153 230 mg of polymer batch 5-153 (PMAO loaded with 50% 5 kDa mPEG-NH2; Mn ⁇ 6.10E5 g/mol) was dissolved in 11.5 mL chloroform (20 mg/mL concentration). 10 mg of washed iron oxide nanoparticles (batch 5-87) were dispersed in 1 mL chloroform (10 mg/mL concentration) using a water-bath sonicator. To a 20 mL glass vial containing 0.75 mL of 20 mg/mL polymer solution dissolved in chloroform, was added 1 mL of iron oxide nanoparticles dispersed in chloroform.
  • nanoparticle core 5-206 phase transferred with 9-3 155.2 mg of polymer batch 9-3 (PMAO loaded with 25% lOkDa mPEG-NH2; Mn ⁇ 6.10E5 g/mol) was dissolved in 9.1 mL chloroform (17 mg/mL concentration). 10 mg of washed iron oxide nanoparticles (batch 5-206) were dispersed in 1 mL chloroform (10 mg/mL concentration) using a water-bath sonicator. To a 20 mL glass vial containing 2.79 mL of 17 mg/mL polymer solution dissolved in chloroform, was added 1 mL of iron oxide nanoparticles dispersed in chloroform.
  • nanoparticle and polymer solid mixture was dispersed by sonication for 60 minutes. After sonication, the solution was checked for any visible aggregates and sonicated for additional time if necessary.
  • the PMAO-PEG coated nanoparticles dispersed in lx TAE buffer were stirred for 24 hours using magnetic stir bar, then filtered with 200 nm nylon syringe filter. To remove excess polymer and salt, filtered PMAO-PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre- rinsed with DI water. To remove aggregates, nanoparticles were centrifuged at 5,000 rcf for 15 minutes and supernatant containing aggregate-free nanoparticles was carefully collected.
  • nanoparticle and polymer solid mixture was dispersed by sonication for 60 minutes. After sonication, the solution was checked for any visible aggregates and sonicated for additional time if necessary.
  • the PMAO-PEG coated nanoparticles dispersed in lx TAE buffer were stirred for 24 hours using magnetic stir bar, then filtered with 200 nm nylon syringe filter. To remove excess polymer and salt, filtered PMAO-PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre-rinsed with DI water. To remove aggregates, nanoparticles were centrifuged at 5,000 rcf for 15 minutes and supernatant containing aggregate-free nanoparticles was carefully collected.
  • nanoparticle core 5-87 phase transferred with 9-2 190 mg of polymer batch 9-2 (PMAO loaded with 25% 10 kDa mPEG-NH2 and 25% 5 kDa mPEG- NH2; Mn ⁇ 8.95E5 g/mol) was dissolved in 5.4 mL chloroform (35 mg/mL concentration). 10 mg of washed iron oxide nanoparticles (batch 5-87) were dispersed in 1 mL chloroform (10 mg/mL concentration) using a water-bath sonicator.
  • filtered PMAO- PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre-rinsed with DI water. To remove aggregates, nanoparticles were centrifuged at 5,000 rcf for 15 minutes and supernatant containing aggregate-free nanoparticles was carefully collected.
  • nanoparticle core 5-87 phase transferred with 9-3 152.2 mg of polymer batch 9-3 (PMAO loaded with 25% 10 kDa mPEG-NH2; Mn ⁇ 6.10E5 g/mol) was dissolved in 9.1 mL chloroform (17 mg/mL concentration). 10 mg of washed iron oxide nanoparticles (batch 5-87) were dispersed in 1 mL chloroform (10 mg/mL concentration) using a water-bath sonicator. To a 20 mL glass vial containing 2.79 mL of 17 mg/mL polymer solution dissolved in chloroform, was added 1 mL of iron oxide nanoparticles dispersed in chloroform.
  • nanoparticle and polymer solid mixture was dispersed by sonication for 60 minutes. After sonication, the solution was checked for any visible aggregates and sonicated for additional time if necessary.
  • the PMAO-PEG coated nanoparticles dispersed in lx TAE buffer were stirred for 24 hours using magnetic stir bar, then filtered with 200 nm nylon syringe filter. To remove excess polymer and salt, filtered PMAO-PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre-rinsed with DI water. To remove aggregates, nanoparticles were centrifuged at 5,000 rcf for 15 minutes and supernatant containing aggregate-free nanoparticles was carefully collected.
  • 111 mg of polymer batch 9-4 (PMAO loaded with 12.5% 20 kDa mPEG-NH2; Mn ⁇ 6.10E5 g/mol) was dissolved in 14.8 mL chloroform (7.5 mg/mL concentration).
  • 10 mg of washed iron oxide nanoparticles (batch 5-87) were dispersed in 1 mL chloroform (10 mg/mL concentration) using a water-bath sonicator.
  • filtered PMAO-PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre-rinsed with DI water. To remove aggregates, nanoparticles were centrifuged at 5,000 rcf for 15 minutes and supernatant containing aggregate-free nanoparticles was carefully collected.
  • the final polymer concentration was 9.25 mg/mL and iron oxide nanoparticle concentration to 1 mg/mL (approximately 234 PMAO-PEG polymer units per iron oxide nanoparticle, assuming 26.3 nm core diameter).
  • the nanoparticle and polymer mixture in chloroform was sonicated for 60 minutes and then stirred using a magnetic stir bar. After 24 hours of stirring, chloroform was evaporated using rotary evaporation, giving a nanoparticle and polymer solid mixture that was dried overnight under high vacuum.
  • nanoparticle and polymer solid mixture was dispersed by sonication for 60 minutes. After sonication, the solution was checked for any visible aggregates and sonicated for additional time if necessary.
  • the PM AO-PEG coated nanoparticles dispersed in lx TAE buffer were stirred for 24 hours using magnetic stir bar, then filtered with 200 nm nylon syringe filter. To remove excess polymer and salt, filtered PM AO- PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre-rinsed with DI water. To remove aggregates, nanoparticles were centrifuged at 5,000 rcf for 15 minutes and supernatant containing aggregate-free nanoparticles was carefully collected.
  • the final polymer concentration was 6.80 mg/mL and iron oxide nanoparticle concentration to 0.94 mg/mL (approximately 351 PMAO-PEG polymer units per iron oxide nanoparticle, assuming 26.3 nm core diameter).
  • the nanoparticle and polymer mixture in chloroform was sonicated for 60 minutes and then stirred using a magnetic stir bar. After 24 hours of stirring, chloroform was evaporated using rotary evaporation, giving a nanoparticle and polymer solid mixture that was dried overnight under high vacuum.
  • nanoparticle core 5-87 phase transferred with 9-19 75 mg of polymer batch 9-19 (PMAO loaded with 12.5% 20 kDa mPEG-NH2 and 25% 5 kDa mPEG- NH2; Mn ⁇ 8.95E5 g/mol) was dissolved in 7.5 mL chloroform (10 mg/mL concentration). 6 mg of washed iron oxide nanoparticles (batch 5-87) were dispersed in 0.6 mL chloroform (10 mg/mL concentration) using a water-bath sonicator.
  • filtered PMAO- PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre-rinsed with DI water. To remove aggregates, nanoparticles were centrifuged at 5,000 rcf for 15 minutes and supernatant containing aggregate-free nanoparticles was carefully collected.
  • nanoparticle core 5-87 phase transferred with 9-20 56 mg of polymer batch 9-20 (PMAO loaded with 12.5% 20 kDa mPEG-NH2 and 37.5% N,N- dimethyl-l,3-propanediamine; Mn ⁇ 6.19E5 g/mol) was dissolved in 7.5 mL chloroform (10 mg/mL concentration). 6 mg of washed iron oxide nanoparticles (batch 5- 87) were dispersed in 0.6 mL chloroform (10 mg/mL concentration) using a water-bath sonicator.
  • filtered PM AO- PEG coated nanoparticles were passed through S-200 sephacryl gel column (GE Healthcare) pre-rinsed with DI water. To remove aggregates, nanoparticles were centrifuged at 5,000 rcf for 15 minutes and supernatant containing aggregate-free nanoparticles was carefully collected.
  • nanoparticle core 9-71 phase transferred with 9-55 936 mg of polymer batch 9-55 (PMAO loaded with 25% 20 kDa mPEG-NH2; Mn ⁇ 1.18E6 g/mol) was dissolved in 46.8 mL chloroform (20 mg/mL concentration). 93.6 mg of washed iron oxide nanoparticles (batch 9-71) were dispersed in 9.36 chloroform (10 mg/mL concentration) using a water-bath sonicator. To a 250 mL round bottom flask containing 46.8 mL of 20 mg/mL polymer solution dissolved in chloroform, was added 9.36 mL of iron oxide nanoparticles dispersed in chloroform.

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Abstract

L'invention concerne des nanoparticules magnétiques d'oxyde de fer revêtues de polymère, et leurs procédés de fabrication et d'utilisation. Les nanoparticules sont revêtues avec un copolymère poly(maléique anhydride alt-H2C=CH-R1)-polyéthylène glycol (PMAR-PEG), où R1 est un fragment hydrophobe. Les poids moléculaires des parties PMAR et PEG du copolymère, ainsi que le diamètre central des nanoparticules, sont choisis de façon à produire une performance optimale pour des applications spécifiques. Des applications représentatives des nanoparticules comprennent l'imagerie à particules magnétiques, la biopsie de ganglion sentinelle magnétique et l'hyperthermie de fluide magnétique. Les nanoparticules sont des outils pour ces procédés qui fournissent des niveaux précédemment inachevés de stabilité (par exemple, par l'intermédiaire d'une agglomération réduite) et de personnalisation (par exemple, demi-vie de circulation sanguine ajustée in vivo).
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Citations (2)

* Cited by examiner, † Cited by third party
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US20030085703A1 (en) * 2001-10-19 2003-05-08 Bernhard Gleich Method of determining the spatial distribution of magnetic particles
US20130149539A1 (en) * 2010-06-21 2013-06-13 University Of Washington Through Its Center For Commercialization Tuned multifunctional magnetic nanoparticles for biomedicine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030085703A1 (en) * 2001-10-19 2003-05-08 Bernhard Gleich Method of determining the spatial distribution of magnetic particles
US20130149539A1 (en) * 2010-06-21 2013-06-13 University Of Washington Through Its Center For Commercialization Tuned multifunctional magnetic nanoparticles for biomedicine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHIOZAWA ET AL.: "Sentinel lymph node biopsy in patients with breast cancer using superparamagnetic iron oxide and a magnetometer.", BREAST CANCER, vol. 20, no. 3, July 2013 (2013-07-01), pages 223 - 229, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/22240965> [retrieved on 20150116] *

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