WO2018053460A1

WO2018053460A1 - Paramagnetic polymers

Info

Publication number: WO2018053460A1
Application number: PCT/US2017/052141
Authority: WO
Inventors: Gabriel E. SANOJYA; Rachel A. Segalman; Samir S. Mitragotri
Original assignee: The Regents Of The University Of California
Priority date: 2016-09-19
Filing date: 2017-09-19
Publication date: 2018-03-22

Abstract

Embodiments of the present disclosure describe a paramagnetic polymer composition comprising a polymer backbone, an ion covalently tethered to the polymer backbone, and a counter-ion, wherein at least one of the ion and counter-ion include one or more of a transition metal and rare-earth metal, wherein the counter-ion electrostatically associates with the tethered ion to form a paramagnetic polymer. Embodiments of the present disclosure further describe a method of forming a paramagnetic polymer comprising associating an ion covalently tethered to a polymer backbone with a counter-ion, wherein at least one of the tethered ion and counter-ion include one or more of a transition metal and rare-earth metal. Embodiments also describe contrast agents based on the paramagnetic polymers.

Description

PARAMAGNETIC POLYMERS

BACKGROUND

[0001] Magnetic resonance imaging is a noninvasive diagnostic tool for visualizing the internal structure and function of a body. Generally it utilizes a powerful magnetic field, radio waves, and field gradients to obtain images of organs, tissues, and joints, among other things. The images are generally derived from proton nuclear magnetic resonance (¹H- MR) peaks of water and fat molecules present in the subject being imaged. Two important parameters to consider in generating images relate to proton relaxation times. Spin-lattice relaxation time (Ti) refers to a measure of the rate at which the longitudinal magnetization vector of spinning nuclei recovers towards the equilibrium direction after a resonant radio frequency pulse. The spin-spin relaxation time (T₂) refers to a time constant describing the dephasing of the transverse nuclear magnetization. T₁ and T₂ depend on the chemical and physical environment of protons in various organs and tissues, for example.

[0002] The diagnostic power of magnetic resonance imaging can be enhanced with the use of a contrast agent. Contrast agents generally shorten the relaxation times to enhance contrast and generate a better resolved image. Generally, MRI contrast agents are categorized as T₁ and T₂ agents. T₁ agents include paramagnetic metal ions with unpaired valence electrons that predominantly shorten the T₁ relaxation time of water nuclei in close proximity via electron-nuclear spin-spin coupling. T₂ agents also include paramagnetic metal ions that disrupt the homogeneity of the magnetic field to predominantly shorten T₂ relaxation times. While ferromagnetic materials are suitable for Ti and T₂ MRI contrast agents, such materials are extremely unstable and/or toxic in biological conditions.

[0003] The only intravenous magnetic resonance imaging contrast agents currently approved for general use by the Food and Drug Administration are gadolinium -based (Gd-based) contrast agents. Gd-based contrast agents are generally chelates (e.g., diethylene triamine pentaacetic acid) containing gadolinium. However, low molecular weight chelates that do not bind to plasma proteins are rapidly filtered out in the kidneys or liver, often yielding concentrations of paramagnetic agents insufficient for contrast enhancement and/or imaging. Gd-based contrast agents present a toxicity risk, with a correlation existing between the use of Gd-based contrast agents and nephrogenic systemic fibrosis.

[0004] Accordingly, it would be desirable to provide tunable and improved contrast agents for medical imaging applications.

SUMMARY

[0005] In general, embodiments of the present disclosure describe paramagnetic polymers and applications thereof, as well as methods of forming paramagnetic polymers.

[0006] Accordingly, embodiments of the present disclosure describe a paramagnetic polymer composition comprising a polymer backbone, an ion covalently tethered to the polymer backbone, and a counter-ion electrostatically associated with the tethered ion, wherein at least one of the ion and counter-ion include one or more of a transition metal and rare-earth metal.

[0007] Embodiments of the present disclosure further describe a method of forming a paramagnetic polymer comprising associating an ion covalently tethered to a polymer backbone with a counter-ion, wherein at least one of the tethered ion and counter-ion include one or more of a transition metal and rare-earth metal.

[0008] Embodiments of the present disclosure also describe a contrast agent for magnetic resonance imaging (MRI) applications comprising a paramagnetic polymer based on a polymerized ionic liquid, comprising: a polymer backbone; an ion covalently tethered to the polymer backbone; and a counter-ion electrostatically associated with the tethered ion; wherein at least one of the ion and counter-ion includes one or more of a transition metal and rare-earth metal.

[0009] The details of one or more examples are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

[0010] This written disclosure describes illustrative embodiments that are non- limiting and non-exhaustive. In the drawings, which are not necessarily drawn to scale, like numerals describe substantially similar components throughout the several views. Like numerals having different letter suffixes represent different instances of substantially similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

[0011] Reference is made to illustrative embodiments that are depicted in the figures, in which:

[0012] FIG. 1 is a schematic diagram of a paramagnetic polymer with cation- anion pairs tethered to a polymer backbone, according to one or more embodiments of the present disclosure.

[0013] FIG. 2 is a schematic diagram of a functional polymerized ionic liquid based on a magnetic ionic liquid and a biocompatible polyethylene glycol, according to one or more embodiments of the present disclosure.

[0014] FIG. 3 is a flowchart of a method of forming a paramagnetic polymer, according to one or more embodiments of the present disclosure.

[0015] FIG. 4 is a schematic diagram of a paramagnetic polymer formed via epoxide ring opening anionic polymerization, thiol-ene click chemistry, nucleophilic substitution, and Lewis acid-base chemistry, according to one or more embodiments of the present disclosure.

[0016] FIG. 5 is a graphical view of cell viability at different concentrations, according to one or more embodiments of the present disclosure.

[0017] FIG. 6 is a graphical view of cell hemolysis at different concentrations, according to one or more embodiments of the present disclosure.

[0018] FIG. 7 is a graphical view illustrating linear reversible magnetization generated in response to an external magnetic field, according to one or more embodiments of the present disclosure.

[0019] FIG. 8 is a graphical view of a longitudinal relaxation curve, according to one or more embodiments of the present disclosure.

[0020] FIG. 9 is a graphical view of relaxation rate (1/Ti) as a function of molar concentration of iron, according to one or more embodiments of the present disclosure. DETAILED DESCRIPTION

[0021] The invention of the present disclosure relates to paramagnetic polymers and methods of forming paramagnetic polymers. The paramagnetic polymers of the present disclosure may be based on magnetic and/or biocompatible polymerized ionic liquids in which a cation and/or anion is tethered to a polymer backbone and electrostatically associated with a counter-ion sufficient to form a paramagnetic polymer. The paramagnetic polymers exhibit a paramagnetic response under the influence of an external magnetic field. The paramagnetic polymers of the present disclosure advantageously and synergistically combine the processability and properties of polymers (e.g., mesostructure) with the versatile chemical functionality of ionic liquids, providing structural hierarchy, a modular synthetic route, and facile incorporation of different functional groups. The paramagnetic polymers of the present disclosure may be optimized by tuning the concentration and chemistry of the ion pair (e.g., cation-anion pair), as well as the size and chemistry of the polymer backbone, to meet the requirements of a particular application. In this way, the transition- or rare- earth metal-containing ions may convey the magnetic properties to the polymer, provide paramagnetic functionality, and/or promote 1H relaxation.

[0022] In many embodiments, the paramagnetic polymers of the present disclosure may be applied as contrast agents and other applications relying on magnetism. For example, the paramagnetic polymers may be applied as contrast agents for magnetic resonance imaging (MRI) applications. The incorporation of transition and/or rare-earth metals with partially filled outer-shell orbitals provides, for example, the spin necessary to affect the magnetic environment experienced by the 1H nuclei of water and generate/improve contrast for MRI. The paramagnetic polymers of the present disclosure may decrease relaxation times by an order of magnitude and enhance contrast. In addition, the selection of the polymer backbone, tethered ion, and counter- ion provide exceptional control over one or more of relaxivity, specific in vivo distribution, magnetic functionality, magnetic response, chemical stability, processability, excretability, and toxicity. In other embodiments, the paramagnetic polymers may be utilized as, among other things, theranostic agents, ion-conducting electrolytes for electrochemical devices, gas separation membranes, and sensors in medical implants to aid in localizing them. Definitions

[0023] The terms recited below have been defined as described below. All other terms and phrases in this disclosure shall be construed according to their ordinary meaning as understood by one of skill in the art.

[0024] As used herein, "associating," "associate," and "associated" refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo. Accordingly, contacting, treating, tumbling, vibrating, shaking, mixing, and applying are forms of associating to bring two or more components together.

[0025] As used herein, "halide" refers to any halogen, as either a compound or ion, including, but not limited to, fluoride, chlorine, bromide, iodide, and astatide.

[0026] As used herein, "paramagnetic ion" may refer to any ion, atom, molecule, moiety, etc. including a transition metal and/or rare-earth metal. The paramagnetic ion may provide the paramagnetic properties. The paramagnetic ion may be one or more of a tethered ion, counter-ion, anion, and cation. In many embodiments, the paramagnetic ion is one or more of a tethered cation, tethered anion, counter-cation, and counter- anion.

[0027] Also, as used herein, "non-paramagnetic ion" may refer to any ion, atom, molecule, moiety, etc. that does not include a transition metal and/or rare-earth metal. The non-paramagnetic ion may include one or more of tethered ion, counter-ion, anion, and cation. In many embodiments, the non-paramagnetic ion is one or more of a tethered cation, tethered anion, counter-cation, and counter-anion.

[0028] As used herein, "rare-earth metal" refers to one or more of seventeen chemical elements, including, but not limited to, cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), gadolinium (Gd), holmium (Ho), lanthanum (La), lutetium (Lu) neodymium (Nd), praseodymium (Pr), promethium (Pm), samarium (Sm), scandium (Sc), terbium (Tb), thulium (Tm), ytterbium (Yb), and yttrium (Y).

[0029] As used herein, "transition metal" refers to one or more of any of the elements in the d-block of the periodic table, including, but not limited to, Groups 3 to 12. As used herein, "transition metal" also refers to any of the elements in the f-block of the periodic table, such as lanthanoids and actinoids. For example, "transition metal" includes, but is not limited to, one or more of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dubnium, seaborgium, bhoriu, hassium, meitnerium, darmstadtium, roentgenium, and copernicium. In addition or in the alternative, "transition metal" includes, but is not limited to, one or more of lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, actinium, thorium, protactinium, uranium, neptunium, plutonium, americium, curium, berkelium, californium, einsteinium, fermium, mendelevium, nobelium, and lawrencium.

[0030] Embodiments of the present disclosure describe a paramagnetic polymer composition comprising a polymer backbone, an ion covalently tethered to the polymer backbone, and a counter-ion electrostatically associated with the ion, wherein at least one of the ion and counter-ion include one or more of a transition metal and rare-earth metal. See, for example, FIG. 1, which is a schematic diagram of a paramagnetic polymer with cation-anion pairs tethered to a polymer backbone, according to an embodiment of the present disclosure.

[0031] The paramagnetic polymers of the present disclosure may be based on a polymerized ionic liquid in which an ion is covalently tethered to a polymer backbone (e.g., the tethered ion) and electrostatically associated with a counter-ion. The paramagnetic properties of the polymers may be due to the incorporation of ions containing transition and/or rare-earth metals with unpaired outer-shell electrons. As used herein, "paramagnetic ion" generally refers to any ion including a transition metal and/or rare-earth metal. The paramagnetic ion may convey paramagnetic properties to the polymer. Either the tethered ion and/or counter-ion may include a paramagnetic ion. In many embodiments, at least one of the tethered ion or counter-ion is a paramagnetic ion. In some embodiments, only one of the tethered ion or counter-ion is a paramagnetic ion and the other ion is non-paramagnetic - that is, an ion that does not include a transition metal and/or rare-earth metal. In other embodiments, the tethered ion and counter-ion are both paramagnetic ionic pairs.

[0032] The paramagnetic ion may include any transition metal and/or rare-earth metal. The transition metals may include any of the elements from the d-block of the periodic table and/or any of the elements from the f-block of the periodic table. For example, the transition metals may include one or more of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dubnium, seaborgium, bhoriu, hassium, meitnerium, darmstadtium, roentgenium, and copernicium. In addition or in the alternative, the transition metals may include one or more of lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, actinium, thorium, protactinium, uranium, neptunium, plutonium, americium, curium, berkelium, californium, einsteinium, fermium, mendelevium, nobelium, and lawrencium.

[0033] The rare-earth metals may include one or more of cerium, dysprosium, erbium, europium, gadolinium, holmium, lanthanum, lutetium, neodymium, praseodymium, promethium, samarium, scandium, terbium, thulium, ytterbium, and yttrium.

[0034] While the tethered ion and counter-ion must generally form a cation-anion pair, either the tethered ion or counter-ion may be the cation and either may be the anion. In addition, either the tethered ion or counter-ion, or both, may be the paramagnetic ion and either may be the non-paramagnetic ion. In other words, the tethered ion and/or counter-ion may be one or more of a paramagnetic ion, non- paramagnetic ion, cation, and anion. For example, the tethered ion may include one or more of a paramagnetic anion, a paramagnetic cation, a non-paramagnetic anion, and a non-paramagnetic cation. The counter-ion may include one or more of a paramagnetic anion, a paramagnetic cation, a non-paramagnetic anion, and a non-paramagnetic cation. The paramagnetic polymer compositions may generally include any combination of tethered ion and counter-ion so long as the tethered ion and counter-ion form an ionic pair. An ionic pair may be formed where at least one of the ions is a cation and at least one of the ions is an anion.

[0035] In many embodiments, the paramagnetic ion (e.g., cation and/or anion), as the tethered ion and/or counter-ion may include a coordination complex including one or more of a transition metal, rare-earth metal, and ligand. The non-paramagnetic ion (e.g., cation and/or anion), as the tethered ion and/or counter-ion may include any ion capable of forming an ionic pair with the paramagnetic ion. Non-limiting examples of paramagnetic ions and non-paramagnetic ions are discussed more fully herein and below.

[0036] In some embodiments, the tethered ion is a non-paramagnetic ion and the counter-ion is a paramagnetic ion. Accordingly, embodiments describe a paramagnetic polymer composition comprising a polymer backbone, a non-paramagnetic ion covalently tethered to the polymer backbone, and a paramagnetic counter-ion electrostatically associated with the non-paramagnetic ion, wherein the paramagnetic ion includes one or more of a transition metal and rare-earth metal.

[0037] In an embodiment, the tethered ion may be a non-paramagnetic cation and the counter-ion may be a paramagnetic anion. The non-paramagnetic cation may include any ion capable of forming an ionic pair with the paramagnetic anion. The non- paramagnetic cation (e.g., tethered ion) generally needs to be chemically stable as in aromatic heterocycles. For example, aromatic heterocycles may include one or more of imidazole, triazole, and tetrazole. Other suitable moieties include trialkylamines, cyclopropenium, and trialkylphosphines. In some embodiments, the aromatic heterocycles may be quaternized to form large ions and anisotropic ions. The paramagnetic anion (e.g., counter-ion) may be a coordination complex including one or more of a transition metal, rare-earth metal, and ligand. For example, the transition and/or rare-earth metal may include one or more of Gd (e.g., Gd(III)), Mn (e.g., Mn(II)), and Fe (e.g., Fe(III)). These shall not be limiting as any of the transition metals and/or rare-earth metals described herein may be used. The ligand may include one or more of chloride, bromide, iodide, fluoride, water, diethylene triamine pentaacetic acid (DTP A), 4,7,10-tetraazacyclododecane-l,4,7, 10-tetraacetic acid (DOPA), and astatide. In many embodiments, the transition metal of the paramagnetic anion may be iron. For example, the anion may include one or more of FeCl₄ ^", FeiCl?^", Fe₃Clio^", FeBr₄ ^", FeBr₃Cl^", and FeBrCl₃ ^". In other embodiments, the rare-earth metal of the paramagnetic anion may gadolinium. For example, the anion may include one or more of GdDTPA^2" and GdDOTA^". In other embodiments, the paramagnetic anion is characterized by the formula MX_n where M is a transition metal and/or rare-earth metal, X is a CI, Br, or I, and n is equal to or greater than one.

[0038] In an embodiment, the tethered ion may be a non-paramagnetic anion and the counter-ion may be a paramagnetic cation. The non-paramagnetic anion (e.g., tethered ion) may include any ion capable of forming an ionic pair with the paramagnetic cation. In many embodiments, the non-paramagnetic anion may include one or more of C0₂ ^" and HPO3^". The paramagnetic cation (e.g., counter-ion) may be a coordination complex that includes one or more of a transition metal, rare-earth metal, and ligand. Any of the transition metals, rare-earth metals, and ligands described herein may be used. In many embodiments, the paramagnetic cation includes one or more of Fe(DOPA)⁺, Mn(bipy)₃ ²⁺, and Gd(DTPA)Lys₂ ⁴⁺.

[0039] In some embodiments, the tethered ion is a paramagnetic ion and the counter-ion is a non-paramagnetic ion. Accordingly, embodiments describe a paramagnetic polymer composition comprising a polymer backbone, a paramagnetic ion covalently tethered to the polymer backbone, wherein the paramagnetic ion includes one or more of a transition metal and rare-earth metal, and a non-paramagnetic counter-ion electrostatically associated with the paramagnetic ion.

[0040] In an embodiment, the tethered ion may be a paramagnetic cation and the counter-ion may be a non-paramagnetic anion. The paramagnetic cation (e.g., tethered ion) may be a coordination complex that includes one or more of a transition metal, rare-earth metal, and ligand. Any of the transition metals, rare-earth metals, and ligands described herein may be used. In many embodiments, the paramagnetic cation includes Mn(py)₆ ²⁺ and Fe(DOPA)⁺. The non-paramagnetic anion (e.g., counter-ion) may include any ion capable of forming an ionic pair with the paramagnetic cation. In many embodiments, the non-paramagnetic anion may include one or more of CI^", HC0₃ ^", and H₂P0₄-.

[0041] In an embodiment, the tethered ion may be a paramagnetic anion and the counter-ion may be a non-paramagnetic cation. The paramagnetic anion (e.g., tethered ion) may be a coordination complex that includes one or more of a transition metal, rare-earth metal, and ligand. Any of the transition metals, rare-earth metals, and ligands described herein may be used. In many embodiments, the paramagnetic anion includes one or more of Fe(DOPA)₃ ^3" and Gd(DTPA)^2". The non-paramagnetic cation (e.g., counter-ion) may include any ion capable of forming an ionic pair with the paramagnetic anion. In many embodiments, the non-paramagnetic cation includes one or more of Na⁺, K⁺, and Ca²⁺.

[0042] In some embodiments, the tethered ion is a paramagnetic ion and the counter-ion is a paramagnetic ion. Accordingly, embodiments describe a paramagnetic polymer composition comprising a polymer backbone, a paramagnetic ion covalently tethered to the polymer backbone, and a paramagnetic counter-ion electrostatically associated with the paramagnetic ion, wherein each of the tethered paramagnetic ion and paramagnetic counter-ion includes one or more of a transition metal and rare-earth metal. In some embodiments, the paramagnetic tethered ion is a cation and the paramagnetic counter-ion is an anion. In other embodiments, the paramagnetic tethered ion is an anion and the paramagnetic counter-ion is a cation.

[0043] In an embodiment, the tethered ion may be a paramagnetic cation and the counter-ion may be a paramagnetic anion. The paramagnetic cation (e.g., tethered ion) may be a coordination complex that includes one or more of a transition metal, rare- earth metal, and ligand. Any of the transition metals, rare-earth metals, and ligands described herein may be used. In many embodiments, the paramagnetic cation includes Mn(py)₆ ²⁺ and Fe(DOPA)⁺. In other embodiments, the paramagnetic cation includes one or more of Mn(py)₆ ²⁺, Fe(DOPA)⁺, Mn(bipy)₃ ²⁺, and Gd(DTPA)Lys₂ ⁴⁺. The paramagnetic anion (e.g., counter-ion) may be a coordination complex including one or more of a transition metal, rare-earth metal, and ligand. For example, the transition and/or rare-earth metal may include one or more of Gd (e.g., Gd(III)), Mn (e.g., Mn(II)), and Fe (e.g., Fe(III)). These shall not be limiting as any of the transition metals and/or rare-earth metals described herein may be used. The ligand may include one or more of chloride, bromide, iodide, fluoride, water, diethylene triamine pentaacetic acid (DTP A), 4,7,10-tetraazacyclododecane-l,4,7, 10-tetraacetic acid (DOPA), and astatide. In many embodiments, the transition metal of the paramagnetic anion may be iron. For example, the anion may include one or more of FeCl₄ ^", Fe₂Cl₇ ^", Fe₃Cli₀ ^", FeBr₄ ^", FeBr₃Cl^", and FeBrCl₃ ^". In other embodiments, the rare-earth metal of the paramagnetic anion may gadolinium. For example, the anion may include one or more of GdDTPA^2" and GdDOTA^". In other embodiments, the paramagnetic anion may include one or more of Fe(DOPA)₃ ³- and Gd(DTPA)^2"

[0044] In an embodiment, the tethered ion may be a paramagnetic anion and the counter-ion may be a paramagnetic cation. The paramagnetic anion (e.g., tethered ion) may be a coordination complex that includes one or more of a transition metal, rare- earth metal, and ligand. Any of the transition metals, rare-earth metals, and ligands described herein may be used. In many embodiments, the paramagnetic anion includes one or more of Fe(DOPA)₃ ^3" and Gd(DTPA)^2". In other embodiments, the metal may include one or more of Gd (e.g., Gd(III)), Mn (e.g., Mn(II)), and Fe (e.g., Fe(III)). The ligand may include one or more of chloride, bromide, iodide, fluoride, water, diethylene triamine pentaacetic acid (DTP A), 4,7, 10-tetraazacyclododecane-l,4,7, 10-tetraacetic acid (DOPA), and astatide. In many embodiments, the transition metal of the paramagnetic anion may be iron. For example, the anion may include one or more of FeCl₄ ^", Fe₂Clv^", Fe₃Clio^", FeBr₄ ^", FeBr₃Cl^", and FeBrCl₃ ^". In other embodiments, the rare- earth metal of the paramagnetic anion may gadolinium. For example, the anion may include one or more of GdDTPA^2" and GdDOTA^". In other embodiments, the paramagnetic ion may include one or more of Fe(DOPA)₃ ^3" and Gd(DTPA)^2" The paramagnetic cation (e.g., counter-ion) may be a coordination complex that includes one or more of a transition metal, rare-earth metal, and ligand. Any of the transition metals, rare-earth metals, and ligands described herein may be used. In many embodiments, the paramagnetic cation includes one or more of Fe(DOPA)⁺, Mn(bipy)₃ ²⁺, and Gd(DTPA)Lys₂ ⁴⁺.

[0045] The polymer backbone may include any monomer unit resulting from a polymerizable group at, for example, an anionic or cationic site. In many embodiments, the polymer backbone includes biologically inert compounds and/or biocompatible polymers. The polymer backbone may include poly(ethylene glycol), polylactic and polyglutaric acid, polyoxazoline, polyglutamic acid, polysialic acid, hyaluronic acid, and hydroxyethyl starch. A person of skill in the art would understand the various polymers that may be utilized for the polymer backbone.

[0046] In an embodiment, the paramagnetic polymer may include a polyethylene glycol as polymer backbone, imidazolium as cation, and trichlorobromoferrate(III) as anion. See FIG. 2, for example, which is a schematic diagram of a reaction mechanism for a functional polymerized ionic liquid based on a magnetic ionic liquid and a biocompatible polyethylene glycol, according to an embodiment of the present disclosure. As shown in FIG. 2, the magnetic polymerized ionic liquid is based on imidazolium and trichlorobromoferrate(III).

[0047] The resulting paramagnetic polymer may include an anion that electrostatically associates with the cationic moiety to form a cation-anion pair. The paramagnetic polymer may be characterized by weak electrostatic interactions due to the size and molecular anisotropy of the cations (e.g., imidazolium cations) and anions (e.g., metal halide anions). The weak electrostatic interactions and anisotropic molecular structure of the cation-anion pairs tethered to these polymers may resemble that of ionic liquids, which are salts that melt at low temperatures.

[0048] A synthetic strategy based on a combination of epoxide ring-opening anionic polymerization, thiol-ene click chemistry, nucleophilic substitution, and Lewis acid-base chemistry may be used to prepare the paramagnetic polymer. Synthetic routes with respect to magnetic polymerized ionic liquids include, but are not limited to, one or more of living polymerizations (e.g., anionic polymerization, cationic polymerization, and radical polymerization), and polymer functionalization reactions (e.g., click chemistry, N-hydroxysuccinimide-ester hydrolysis). In one embodiment, an imidazole functionalized copolymer can be synthesized via ionic copolymerization of ethylene oxide and allyl glycidyl ether, followed by UV activated thiol-ene click chemistry of N- (3-(lH-Imidazol-l-yl)propyl)4-mercaptobutanamide. The polyimidazole can then be exhaustively substituted with ethyl bromide and treated with a stoichiometric amount of iron (III) chloride to generate the paramagnetic polymer. The paramagnetic polymers may be optimized by tuning the concentration and chemistry of the ion pair, as well as the size and chemistry of the polymer backbone. In many embodiments, this can be achieved with a synthetic strategy that provides systematic and independent control over the degree of polymerization, nature and concentration of ionic liquid moieties, and polymer architecture.

[0049] FIG. 3 is a flowchart of a method of forming a paramagnetic polymer, according to one or more embodiments of the present disclosure. As shown in FIG. 3, an ion covalently tethered to a polymer backbone 301 is associated 303 with a counter- ion 302 sufficient to form a paramagnetic polymer. In many embodiments, at least one of the ion and counter-ion includes one or more of a transition metal and rare-earth metal. The tethered ion may include one or more of a paramagnetic cation, paramagnetic anion, non-paramagnetic cation, and non-paramagnetic anion. The counter-ion may include one or more of a paramagnetic cation, paramagnetic anion, non-paramagnetic cation, and non-paramagnetic anion. In some embodiments, the tethered ion is a non-paramagnetic cation and the counter-ion is a paramagnetic anion. In some embodiments, the tethered ion is a non-paramagnetic anion and the counter-ion is a paramagnetic cation. In some embodiments, the tethered ion is a paramagnetic cation and the counter-ion is a non-paramagnetic anion. In some embodiments, the tethered ion is a paramagnetic anion and the counter-ion is a non-paramagnetic cation. In some embodiments, the tethered ion is a paramagnetic cation and the counter-ion is a paramagnetic anion. In some embodiments, the tethered ion is a paramagnetic anion and the counter-ion is a paramagnetic cation. Any of the paramagnetic cations, paramagnetic anions, non-paramagnetic cations, and non-paramagnetic anions described herein may be used as the tethered ion and/or counter-ion. [0050] Associating may include bringing the ion to immediate or close proximity to the counter-ion. For example, associating may include electrostatically associating the ion with the counter-ion via electrostatic interactions. The electrostatic interactions may vary, depending on the size and molecular anisotropy of the cations and anions. For example, in some embodiments, the electrostatic interactions may be weak electrostatic interactions to moderate electrostatic interactions due to the size and molecular anisotropy of the cations and anions. The weak electrostatic interactions and anisotropic molecular structure of the cation-anion pairs tethered to the polymer backbone may resemble ionic liquids, which are salts that melt at low temperatures.

[0051] The paramagnetic polymer composition of the present disclosure may be used as a contrast agent and/or theranostic agent, as well as other applications relying on magnetism. For example, in many embodiments, the paramagnetic polymer composition may be used as a contrast agent (e.g., a T₁ agent) for magnetic resonance imaging (MRI) applications. Accordingly, embodiments of the present disclosure further describe a contrast agent for magnetic resonance imaging (MRI) applications. The contrast agents for MRI applications may comprise a paramagnetic polymer based on a polymerized ionic liquid. The polymerized ionic liquid may comprise a polymer backbone, an ion covalently tethered to the polymer backbone; and a counter-ion, wherein at least one of the ion and counter-ion includes one or more of a transition metal, rare-earth metal, and ligand, wherein the counter-ion electrostatically associates with the tethered ion to form the paramagnetic polymer. Any of the paramagnetic cations, paramagnetic anions, non- paramagnetic cations, and non-paramagnetic anions described herein may be used as the ion (e.g., tethered ion) and/or counter-ion.

[0052] The contrast agent may comprise a paramagnetic polymer based on a polymerized ionic liquid. In many embodiments, the polymerized ionic liquid is magnetic and/or biocompatible. As one example, some embodiments relate to contrast agents based on imidazolium as the tethered cation, and poly(ethylene glycol) as the polymer backbone, and trichlorobromoferrate (III) as the counter-anion. This example, however, shall not be limiting. Any of the paramagnetic polymers, tethered ions, counter-ions, and polymer backbones of the present disclosure may be used here. In particular, any of the paramagnetic cations, paramagnetic anions, non-paramagnetic cations, and non-paramagnetic anions described herein may be used as the tethered ion and/or counter-ion. [0053] In many embodiments, the relaxivity, specific in vivo distribution, stability, excretability, and toxicity may be tuned via selection of one or more of the polymer backbone, cation, and anion. In addition, a size of the paramagnetic polymer may range from about 10 nm to about 100 nm. In some embodiments, a magnetic susceptibility of the contrast agent is about 10^"2

In some embodiments, a relaxivity is about 3 L.mmol^.s^"1.

[0054] The contrast agents of the present disclosure can be designed with controlled blood circulation times, 1H relaxation environment within the imaged tissue, and cytotoxicity. These properties depend on the radius of gyration, relaxivity, and biocompatibility of the contrast agent; which can be tuned in polymers through the molecular weight (M_n), nature and concentration of paramagnetic moieties (XIL), and architecture of the chain. Rational material design can be accomplished with a synthetic strategy that provides systematic and independent control over these molecular properties. In one embodiment based on a combination of living copolymerization, click chemistry, nucleophilic substitution, and Lewis acid-base chemistry; the M_n, x_IL, and architecture of the polymer can be tuned through the monomer to initiator ratio, the relative amounts of monomers, and the degree of branching of the initiator. The resulting paramagnetic polymers have radius of gyration and fraction of ionic groups that can respectively range from 10 to 100 nm, and 0 to 100 %. The incorporation of transition metals, or rare-earth metals with partially filled outer-shell orbitals in coordinate complex ions provides the paramagnetism to affect the 1H relaxation and generate contrast. The resulting relaxivity can not only depend on the nature and concentration of the metal, but also on the ligand ability to induce energetic differences between the outer-shell orbitals and favor the formation of high-spin complexes. Consequently, the range of relaxivities accessible with paramagnetic polymers may be analogous to that of organometallic complexes (1-15 L.mmo^.s^"1) and tuned by choice of a different metal-ligand pairs. The interconnection between contrast and toxicity evidently depends on concentration of contrast agent, yet it can be optimized in paramagnetic polymers to elucidate a maximum nontoxic dose that allows for medical imaging in a clinical setting. Finally, paramagnetic polymers can be functionalized via click chemistry with motifs (i.e., carbohydrates) that promote cell-polymer interactions to control the biodistribution during in vivo targeting.

[0055] Embodiments of the present disclosure also describe methods of using a paramagnetic polymer comprising providing a paramagnetic polymer to a subject and applying a magnetic field in proximity to the subject. Any of the paramagnetic polymers and/or contrast agents described herein may be used. The subject may include any living being. The magnetic field may include an external magnetic field.

[0056] The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examiners suggest many other ways in which the invention could be practiced. It should be understand that numerous variations and modifications may be made while remaining within the scope of the invention.

EXAMPLE 1

A Polymerized Ionic Liquid Based on Poly(Ethylene Glycol) and

Trichlorobromoferrate (III)

[0057] A magnetic and biocompatible polymerized ionic liquid based on poly(ethylene glycol) and the ionic liquid anion trichlorobromoferrate(III) (FeCl₃Br^") was synthesized via a combination of epoxide ring opening anionic polymerization, thiol-ene click chemistry, nucleophilic substitution, and Lewis acid-base chemistry to provide exceptional control over the molecular structure of the polymer and scalability appropriate for extensive physical characterization. The polymerized ionic liquid containing FeCl₃Br^" was paramagnetic with a magnetic susceptibility of at 30°C of 30 x 10^"6 emu/g.Oe, as characteristic of materials based on anions containing transition metals with partially filled d-orbitals. In addition the polymerized ionic liquid significant modified the magnetic environment experienced by the 1H of water, as revealed by a decrease in the spin-lattice relaxation time (e.g., Ti) of ^XH determined from nuclear magnetic resonance ( MR) from 8 seconds to 0.3 seconds. The structure- property relationships demonstrated makes polymerized ionic liquids based on PEG and FeCl₃Br^" suitable as Ti-weighted MRI contrast agent. In addition, the magnetic and biocompatible nature of polymerized ionic liquids is promising for development of novel therapeutic agents (i.e., drugs, proteins, and antibodies) based on polymer conjugates that exhibit controlled residence time within the human body; and magnetic functionality for MRI imaging, and facilitated targeting.

[0058] FIG. 4 is a schematic diagram of a paramagnetic polymer formed via epoxide ring opening anionic polymerization and thiol-ene click chemistry, according to an embodiment of the present disclosure. In particular, the reaction mechanism illustrated in FIG. 4 relates to the formation and/or synthesis of a paramagnetic polymer based on imidazolium and trichlorobromoferrate(III). As shown in FIG. 4, the reactants include an initiator (I), ethylene oxide (EO), and allyl glycidyl ether (AGE). The reaction mechanism begins with epoxide ring opening anionic polymerization. This reaction step provides control over the synthesis of the polymer backbone. Following epoxide ring opening polymerization, the intermediate product is contacted with a thiol via a thiol-ene click chemistry, which also provides control over the synthesis of the polymer backbone. Two equivalents of EtBr and 1 equivalent of FeCl₃ are provided to form the magnetic polymerized ionic liquid. As shown in FIG. 4, the degree of polymerization (N) is about 407 and the fraction of ionic liquid in the polymer (x_IL) is about 0.09. Generally, the residence time of the magnetic polymerized ionic liquid is related and/or proportional to the concentration of initiator, degree of polymerization, and radius of gyration. In addition, the magnetic contrast and toxicity is generally related to and/or proportional to the fraction of ionic liquid in the polymer and the T₁ relaxation time.

[0059] FIG. 5 is a graphical view of cell viability at different concentrations, according to an embodiment of the present disclosure. Cell viability (%) versus concentration (mg/mL) is plotted for both magnetic polymerized ionic liquids and poly(ethylene glycol). As shown in FIG. 5, at concentrations below 0.5 mg/mL, magnetic polymerized ionic liquid did not inhibit cell proliferation of breast epithelial cell line MCF-lOa.

[0060] FIG. 6 is a graphical view of cell hemolysis at different concentrations, according to an embodiment of the present disclosure. Unlike Triton X-100, cell viability generally remained unharmed with respect to poly(ethylene glycol), magnetic polymerized ionic liquid, and PBCS and citrate buffer (10:90), even at high concentrations. As shown in FIG. 6, the design strategy proved to be effective at translating biocompatibility of poly(ethylene glycol) into magnetic polymerized ionic liquid.

[0061] FIG. 7 is a graphical view illustrating linear reversible magnetization generated in response to an external magnetic field, according to an embodiment of the present disclosure. As shown in FIG. 7, the magnetic susceptibility of the magnetic polymerized ionic liquid is about 0.016 emu.molFe^"1, indicating a magnetic susceptibility comparable to that of ionic liquid (x_IL is about 0.010 emu.molpe^"1 and for reference XAI is about 0.174 emu.mol_Ai^"1). In particular, the polymer exhibited a paramagnetic response under the influence of an external magnetic field. The incorporation of transition or rare-earth metals (e.g., Fe ) with partially filled outer-shell orbitals was essential for understanding the relationship between the chemistry of anion-cation pair and magnetic susceptibility. The anions containing iron(III) provided the spins necessary for magnetization under an external magnetic field. A Superconducting Quantum Interference Device (SQUID) demonstrated the solid-state magnetism of the polymer. The linear reversible magnetization generated in response to an external magnetic field demonstrated translation of the paramagnetism of transition or rare-earth metals to the polymer. (FIG. 7). The slope enabled determination of the magnetic susceptibility ~10^"2 emu. Oe^.mo ¹ at 30°C in a poly(imidazolium) paired with trichlorobromoferrate(III) anions. The invention was optimized by tuning the concentration and chemistry of the metal and ligands incorporated onto the polymer and thus the spin strength necessary to achieve higher magnetic susceptibilities.

[0062] The incorporation of transition or rare-earth metals with partially filled outer-shell orbitals also provided the spin necessary to affect the magnetic environment experienced by the 1H nuclei of water, and generated contrast for MRI. Given that contrast enhancement arose due to changes in the spin-lattice (Ti) relaxation time of the 1H nuclei of water, it was important to understand changes in 1H relaxation in aqueous solutions of polymer. The paramagnetic polymer decreased T₁ of 1H nuclei of water by an order of magnitude. Moreover, the paramagnetic polymer had a relaxivity (r₁ ~ 3 L.mmol^.s^"1 at 37 °C) comparable with clinically relevant MRI contrast agents based on gadolinium chelates. Cytotoxicity and hemolysis assays demonstrated the polymer had the biocompatibility necessary to generate a contrast enhancement of 11%, which sufficed for medical imaging. The invention may be optimized by tuning concentration and chemistry of the cation-anion pair, as well as the size of the polymer, to ultimately control the relaxivity, specific in vivo distribution, stability, excretability, and lack of toxicity required for medical imaging. If molecularly designed with characteristic sizes ranging from 10 to 100 nm, this work may yield theranostic agents with the blood circulation time and magnetic functionality required for MRI.

[0063] FIG. 8 is a graphical view of a longitudinal relaxation curve, according to an embodiment of the present disclosure. As shown in FIG. 8, the magnetic polymerized ionic liquid enhanced the 1H nuclei relaxation rate. In particular, the following formula was used to determine the relaxation rate: where (τ) is the magnetization, ₀ is an initial magnetization, and Ύ is the longitudinal or spin-lattice relaxation time. The spin-lattice relaxation time in water (Ti (H₂0)) is about 14.00 ± 0.72 s and in magnetic polymerized ionic liquid (Ti(magnetic polymerized ionic liquid)) is about 5.93 ± 1.54 s.

[0064] FIG. 9 is a graphical view of relaxation rate (1/T) as a function of molar concentration of iron, according to an embodiment of the present disclosure. The relaxation rate (1/T) was plotted using the following formula:

As shown in FIG. 9, the relaxivity (k₂) is about 2.42 mM^'V¹. The relaxivity of the magnetic polymerized ionic liquid is comparable to Gd-based chelates (3-5 mM^'V¹) and indicates it sufficient rate enhancement for MRI contrast.

[0065] Other embodiments of the present disclosure are possible. Although the description above contains much specificity, these should not be construed as limiting the scope of the disclosure, but as merely providing illustrations of some of the presently preferred embodiments of this disclosure. It is also contemplated that various combinations or sub-combinations of the specific features and aspects of the embodiments may be made and still fall within the scope of this disclosure. It should be understood that various features and aspects of the disclosed embodiments can be combined with or substituted for one another in order to form various embodiments. Thus, it is intended that the scope of at least some of the present disclosure should not be limited by the particular disclosed embodiments described above.

[0066] Thus the scope of this disclosure should be determined by the appended claims and their legal equivalents. Therefore, it will be appreciated that the scope of the present disclosure fully encompasses other embodiments which may become obvious to those skilled in the art, and that the scope of the present disclosure is accordingly to be limited by nothing other than the appended claims, in which reference to an element in the singular is not intended to mean "one and only one" unless explicitly so stated, but rather "one or more." All structural, chemical, and functional equivalents to the elements of the above-described preferred embodiment that are known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the present claims. Moreover, it is not necessary for a device or method to address each and every problem sought to be solved by the present disclosure, for it to be encompassed by the present claims. Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims.

[0067] The foregoing description of various preferred embodiments of the disclosure have been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure to the precise embodiments, and obviously many modifications and variations are possible in light of the above teaching. The example embodiments, as described above, were chosen and described in order to best explain the principles of the disclosure and its practical application to thereby enable others skilled in the art to best utilize the disclosure in various embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the disclosure be defined by the claims appended hereto

[0068] Various examples have been described. These and other examples are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A paramagnetic polymer composition, comprising:

a polymer backbone;

a non-paramagnetic ion covalently tethered to the polymer backbone; and

a paramagnetic counter-ion electrostatically associated with the non-paramagnetic ion, wherein the paramagnetic ion includes one or more of a transition metal and rare-earth metal.

2. The composition of claim 1, wherein the non-paramagnetic ion is a cation including aromatic heterocycles.

3. The composition of claim 1, wherein the non-paramagnetic ion is a cation including one or more of imidazole, triazole, tetrazole, trialkylamines, cyclopropenium, and trialkylphosphines.

4. The composition of claim 1, wherein the paramagnetic counter-ion is an anion including one or more of Gd, Mn, and Fe and one or more of chloride, bromide, iodide, fluoride, water, di ethylene triamine pentaacetic acid (DTP A), 4,7,10- tetraazacyclododecane-l,4,7, 10-tetraacetic acid (DOPA), and astatide.

5. The composition of claim 1, wherein the paramagnetic counter-ion is anion including one or more of FeCl₄ ^", Fe₂Ov^", Fe₃Clio^", FeBr₄ ^", FeBr₃Cl^", and FeBrCl₃ ^", GdDTPA^2", and GdDOTA^".

6. The composition of claim 1, wherein the non-paramagnetic ion is an anion including one or more of C0₂ ^" and FIP0₃ ^".

7. The composition of claim 1, wherein the paramagnetic counter-ion is a cation including one or more of Fe(DOPA)⁺, Mn(bipy)₃ ²⁺, and Gd(DTPA)Lys₂ ⁴⁺.

8. A paramagnetic polymer composition, comprising: a polymer backbone;

a paramagnetic ion covalently tethered to the polymer backbone, wherein the paramagnetic ion includes one or more of a transition metal and rare-earth metal; and

a non-paramagnetic counter-ion electrostatically associated with the paramagnetic ion.

9. The polymer of claim, wherein the paramagnetic ion is a cation including one or more of Mn(py)₆ ²⁺ and Fe(DOPA)⁺.

10. The polymer of claim, wherein the non-paramagnetic counter-ion is an anion including one or more of CI^", HC0₃ ^", and H₂P0₄ ^".

11. The polymer of claim, wherein the paramagnetic ion is an anion including one or more Fe(DOPA)₃ ^3" and Gd(DTPA)^2".

12. The polymer of claim, wherein the non-paramagnetic counter-ion is a cation including one or more of Na⁺, K⁺, and Ca²⁺.

13. A paramagnetic polymer composition, comprising:

a polymer backbone;

a paramagnetic ion covalently tethered to the polymer backbone; and

a paramagnetic counter-ion electrostatically associated with the paramagnetic ion;

wherein each of the tethered paramagnetic ion and paramagnetic counter-ion includes one or more of a transition metal and rare-earth metal.

14. The paramagnetic polymer of claim 13, wherein the paramagnetic tethered ion is a cation including one or more of Mn(py)₆ ²⁺ and Fe(DOPA)⁺.

15. The paramagnetic polymer of claim 13, wherein the paramagnetic counter- ion is an anion including one or more of Gd, Mn, and Fe and one or more of chloride, bromide, iodide, fluoride, water, diethylene triamine pentaacetic acid (DTP A), 4,7, 10- tetraazacyclododecane-l,4,7, 10-tetraacetic acid (DOPA), and astatide.

16. The paramagnetic polymer of claim 13, wherein the paramagnetic tethered ion is an anion including one or more of Fe(DOPA)₃ ^3" and Gd(DTPA)^2".

17. The paramagnetic polymer of claim 13, wherein the paramagnetic counter- ion is a cation including one or more of Fe(DOPA)⁺, Mn(bipy)₃ ²⁺, and Gd(DTPA)Lys₂ ⁴⁺.

18. A contrast agent for magnetic resonance imaging (MRI) applications, comprising:

a paramagnetic polymer based on a polymerized ionic liquid, comprising:

a polymer backbone;

an ion covalently tethered to the polymer backbone; and a counter-ion, wherein the counter-ion electrostatically associating with the tethered ion to form the paramagnetic polymer; wherein at least one of the ion and counter-ion includes one or more of a transition metal and rare-earth metal.

19. The contrast agent of claim 10, wherein the ion including a transition metal and/or rare-earth metal promotes 1H relaxation.

20. The contrast agent of claim 10, wherein the contrast agent is magnetic and/or biocompatible.