WO2009129649A1 - Biocompatible polymer and magnetic nanoparticle with biocompatibility - Google Patents
Biocompatible polymer and magnetic nanoparticle with biocompatibility Download PDFInfo
- Publication number
- WO2009129649A1 WO2009129649A1 PCT/CN2008/000823 CN2008000823W WO2009129649A1 WO 2009129649 A1 WO2009129649 A1 WO 2009129649A1 CN 2008000823 W CN2008000823 W CN 2008000823W WO 2009129649 A1 WO2009129649 A1 WO 2009129649A1
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- WIPO (PCT)
- Prior art keywords
- magnetic nanoparticle
- biocompatible polymer
- biocompatibility
- nanoparticle
- coupled
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Classifications
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/321—Polymers modified by chemical after-treatment with inorganic compounds
- C08G65/326—Polymers modified by chemical after-treatment with inorganic compounds containing sulfur
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3328—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33303—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group
- C08G65/33306—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group acyclic
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- the invention relates to a biocompatible polymer and in particular to a biocompatible polymer for covalently modifying magnetic nanoparticles.
- Magnetic resonance imaging is an appealing noninvasive approach for early cancer diagnostics and therapeutics.
- MRI utilizes radio frequency pulses and magnetic field gradients applied to a subject in a strong field to produce images.
- MRI is capable of showing several different characteristics of tissues.
- the level of tissue magnetization at specific signal recording periods during the MR imaging cycle generally determines the brightness of a particular tissue in the MRI images. Contrast is produced when tissues do not have the same level of magnetization.
- the multi-modality contrast agent includes a magnetic nanoparticle, a biocompatible polymer chemically modifying the magnetic nanoparticle, a fluorescent dye coupled to the biocompatible polymer, and a specific targeting agent coupled to the biocompatible polymer.
- the biocompatible polymers include polyethylene glycol (PEG), polylactic acid (PLA), PLA-PEG, poly(glycolic acid) (PGA), poly( ⁇ -caprolactone) (PCL), poly(methyl methacrylate) (PMMA), and the like.
- PEG polyethylene glycol
- PLA polylactic acid
- PLA-PEG poly(glycolic acid)
- PCL poly( ⁇ -caprolactone)
- PMMA poly(methyl methacrylate)
- U.S. Patent Publication No. 20070148095 discloses a silane compound for modifying magnetic nanoparticle and a method for using the nanoparticle to detect and treat tissues of interest.
- Commercially available MRI contrast enhancement agents include Feridex® (dextran-coated iron oxide) and Resovis
- the invention provides a biocompatible polymer of formula (I),
- Ri is alkyl, aryl, carboxyl, or amino
- R 2 is alkyl or aryl
- n is an integer from 5 to 1000
- m is an integer from 1 to 10.
- the invention provides a magnetic nanoparticle with biocompatibility, comprising a magnetic nanoparticle and a biocompatible polymer of formula (II) covalently coupled to the magnetic nanoparticle,
- R 1 is alkyl, aryl, carboxyl, or amino
- n is an integer from 5 to 1000
- m is an integer from 1 to 10.
- FIG. 1 is a schematic drawing showing the synthesis of the biocompatible polymer of the invention.
- FIG. 2 is a schematic drawing showing a magnetic nanoparticle modified with the biocompatible polymer of the invention.
- FIG. 1 is a schematic drawing showing the synthesis of the biocompatible polymer of the invention, wherein Rl, R2, n, and m have the same meaning as described above.
- the synthetic scheme involves converting the hydroxyl end group of polyethylene glycol (PEG) to a carboxyl group by using a succinic anhydride compound, and coupling a silane group to the PEG.
- Suitable alkyl groups for Ri and R 2 include Ci-C 20 straight chain or branched alkyl groups.
- each of Ri and R 2 independently, is a Ci-C 6 straight chain or branched alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert- pentyl, n-hexyl, and isohexyl.
- Suitable aryl groups for Ri and R 2 include C 6 -Cj 2 substituted or unsubstituted aryl groups such as phenyl, biphenyl, and naphthyl, and examples of substituents thereof include hydroxyl, haloalkyl, alkoxyl, cyano, nitro, amino, or alkylamino.
- the number of methylene units m is preferably an integer from 1 to 10.
- the number of oxyethylene units n is preferably an integer from 5 to 1000, equivalent to a molecular weight of about 200-50000 g/mole of the PEG. In one embodiment, m is about 3, and n is about 15.
- the biocompatible polymer is useful in that it can chemically modify the surface of the iron oxide nanoparticle to increase biocompatibility.
- the biocompatible polymer is useful in that it can label particles (e.g., nanoparticles, magnetic particles, magnetic nanoparticles, superparamagnetic particles), to render the particles to be further reactive toward one or more targeting, fluorescent, therapeutic, or diagnostic agents.
- the invention also provides a magnetic nanoparticle with biocompatibility, comprising a magnetic nanoparticle; a biocompatible polymer of formula (II) covalently coupled to the magnetic nanoparticle,
- FIG. 2 is a schematic drawing showing a magnetic nanoparticle modified with the biocompatible polymer of the invention.
- the magnetic nanoparticle is preferably made of at least one of Fe, Co, Ni, and oxides thereof. It will be appreciated that the nanoparticle can be made of any single or composite magnetic material, although superparamagnetic materials are particularly preferred.
- the terminal groups R 1 are transformed into active functional groups such as carboxyl or amino groups to allow coupling with fluorescent dye and/or specific targeting agents.
- Ri is not alkyl or aryl, since alkyl or aryl are not capable of coupling with targeting agents or fluorescent dye.
- Ri is a carboxyl group.
- the number of methylene units m is preferably an integer from 1 to 10.
- the number of oxyethylene units n is preferably an integer from 5 to 1000. In one embodiment, m is about 3, and n is about 15.
- the biocompatible polymer is preferably coated on the entire surface of the magnetic nanoparticle to form a core-shell structure. More preferably, the biocompatible polymer forms a monolayer coating on the magnetic nanoparticle.
- the biocompatible polymer of the invention may increase the r2 value of the magnetic nanoparticle to about 2 times that of commercial contrast agents, Feridex® and Resovist®. Accordingly, the magnetic nanoparticle may provide greater contrast enhancement when being used as an MRI contrast agent.
- the targeting agent is preferably coupled to the biocompatible polymer via covalent bonds. Commonly used targeting agents include an antibody, a protein, a peptide, an enzyme, a carbohydrate, a glycoprotein, a nucleotide, and a lipid.
- the magnetic nanoparticle may have a diameter of about 3-500nm after coupling with the targeting agent. Those skilled in the art can attach any suitable targeting agents on the nanoparticle to give specificity thereto.
- folic acid can be used to specify breast cancer cells with a folate receptor.
- the structure of the folic acid allows coupling with an amine-terminated or carboxy-terminated biocompatible polymer.
- the folic acid allows coupling with the amine-terminated biocompatible polymer by forming a -CONH- linkage.
- a fluorescent dye may be further coupled to the magnetic nanoparticle to provide an optical signal for optical imaging techniques such as NIR imaging, thus allowing real-time monitoring of foci by different imaging techniques.
- the fluorescent dye is coupled to the biocompatible polymer via covalent bonds. Suitable fluorescent dyes include organic or inorganic dyes and organometallic complexes.
- the excitation and emission wavelengths of the fluorescent dye may be ultraviolet (UV), near-infrared (NIR), or visible (VIS) light.
- the magnetic nanoparticle coupled with the targeting agent and fluorescent dye preferably has a diameter of about 15-200nm.
- Example 1 Nanoparticle preparation
- Example 2 Synthesis of biocompatible polymer mPEG-silane
- reaction mixture was added to 9L of isopropyl ether for re-precipitation, and the precipitates were collected, re-dissolved in 500ml of toluene, and centrifuged at 5000 rpm for 5 minutes to collect a supernatant. The supernatant was again, added to 9L of isopropyl ether for re-precipitation. Brown oily liquid was collected and dried under vacuum to obtain the biocompatible polymer, mPEG-silane.
- Example 3 Synthesis of biocompatible polymer COOH-PEG-silane
- 30Og (0.4mole) of PEG (molecular weight: 750) and 600ml of N-methyl-2- pyrrolidone were placed in a 1000 ml round bottom flask under vacuum (20 Torr) for more than 2 hours.
- 96g (0.96mole) of succinic anhydride and 39g (0.318mole) of 4- dimethylamino-pyridine (DMAP) were added for reaction at 30°C for two days, thus obtaining dicarboxy-terminated PEG (COOH-PEG).
- DMAP 4- dimethylamino-pyridine
- reaction mixture was added to 9L of isopropyl ether for re-precipitation, and the precipitates were collected, re-dissolved in 500ml of toluene, and centrifuged at 5000 rpm for 5 minutes to collect a supernatant. The supernatant was again, added to 9L of isopropyl ether for re-precipitation. Brown oily liquid was collected and dried under vacuum, thus obtaining the biocompatible polymer, COOH-PEG-silane.
- Solution C was added to solution D and stirred for 8 hours.
- the resulting solution was added into a dialysis membrane (Mw: 3000) and water was used for dialysis. Then, the solution was concentrated to 2ml by an ultra-filtration device to obtain iron oxide nanoparticles coupled with a targeting agent and a fluorescent dye.
- Example 7 Relaxivity test [0045] The modified iron oxide nanoparticles of Example 5 were compared for the rl and r2 relaxivity with the product of U.S. Patent Publication No. 2006/0216239 and commercial contrast agents, i.e., Feridex® and Resovist®.
- Iron oxide solutions of various concentrations were prepared and measured for the Tl or T2 relaxation time by a Minispec mq 20 from the Broker Corporation.
- a linear relationship was established between the reciprocal of relaxation time as the ordinate axis and the concentration of the solution as the abscissa axis.
- the slope of the linear relationship was the rl and r2 relaxivity.
- the r2 relaxivity of the modified iron oxide nanoparticles of the invention was about 2 times that of Feridex® and Resovist®, and about 1.4 times that of the prior art product of U.S. Patent Publication No. 2006/0216239. Accordingly, the contrast enhancement was improved due to the higher r2 relaxivity.
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Abstract
The invention discloses a biocompatible polymer for covalently modifying magnetic nanoparticles. The biocompatible polymer may be coupled to a targeting agent and/or a fluorescent dye. The invention also discloses a magnetic nanoparticle with biocompatibilities comprising the biocompatible polymer.
Description
BIOCOMPATIBLE POLYMER AND MAGNETIC NANOPARTICLE WITH
BIOCOMPATIBILITY
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] The invention relates to a biocompatible polymer and in particular to a biocompatible polymer for covalently modifying magnetic nanoparticles.
Description of the Related Art
[0002] Magnetic resonance imaging (MRI) is an appealing noninvasive approach for early cancer diagnostics and therapeutics. MRI utilizes radio frequency pulses and magnetic field gradients applied to a subject in a strong field to produce images. MRI is capable of showing several different characteristics of tissues. The level of tissue magnetization at specific signal recording periods during the MR imaging cycle generally determines the brightness of a particular tissue in the MRI images. Contrast is produced when tissues do not have the same level of magnetization.
[0003] While the imaging capabilities of MRIs have revolutionized imaging technology, the resolution is limited to the elucidations of lesions within the body on the order of 1 mm. This limitation has led to the development of contrast enhancement agents. Because of the superparamagnetic property, iron oxide nanoparticles have been found effective as contrast enhancement agents for MRIs. The magnetic nanoparticle can be modified with a biocompatible polymer to prolong the particle circulation time in blood and reduce immunogenicity. Furthermore, the magnetic nanoparticle can be modified with a fluorescent dye and a specific targeting agent to provide fluorescent properties and specific targeting functions. [0004] U.S. Patent Publication No. 20070148095 discloses a multi-modality contrast
agent with specificity for both magnetic and optical imaging. The multi-modality contrast agent includes a magnetic nanoparticle, a biocompatible polymer chemically modifying the magnetic nanoparticle, a fluorescent dye coupled to the biocompatible polymer, and a specific targeting agent coupled to the biocompatible polymer. The biocompatible polymers include polyethylene glycol (PEG), polylactic acid (PLA), PLA-PEG, poly(glycolic acid) (PGA), poly(ε-caprolactone) (PCL), poly(methyl methacrylate) (PMMA), and the like. [0005] U.S. Patent Publication No. 20070148095 discloses a silane compound for modifying magnetic nanoparticle and a method for using the nanoparticle to detect and treat tissues of interest. [0006] Commercially available MRI contrast enhancement agents include Feridex® (dextran-coated iron oxide) and Resovist® (carboxydextran-coated iron oxide).
BRIEF SUMMARY OF THE INVENTION
[0007] In one aspect, the invention provides a biocompatible polymer of formula (I),
(I) [0008] wherein Ri is alkyl, aryl, carboxyl, or amino, R2 is alkyl or aryl, n is an integer from 5 to 1000, and m is an integer from 1 to 10.
[0009] In another aspect, the invention provides a magnetic nanoparticle with biocompatibility, comprising a magnetic nanoparticle and a biocompatible polymer of formula (II) covalently coupled to the magnetic nanoparticle,
(II) [0010] wherein R1 is alkyl, aryl, carboxyl, or amino, n is an integer from 5 to 1000, and m is an integer from 1 to 10.
[0011] A detailed description is given in the following embodiments with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention can be more fully understood by reading the subsequent detailed description and examples with references made to the accompanying drawings, wherein: [0012] FIG. 1 is a schematic drawing showing the synthesis of the biocompatible polymer of the invention; and
[0013] FIG. 2 is a schematic drawing showing a magnetic nanoparticle modified with the biocompatible polymer of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The following description is of the best-contemplated mode of carrying out the invention. This description is made for the purpose of illustrating the general principles of the invention and should not be taken in a limiting sense. The scope of the invention is best determined by reference to the appended claims. [0015] The biocompatible polymer of the invention is represented by general formula (I),
(I) [0016] wherein Ri is alkyl, aryl, carboxyl, or amino, R2 is alkyl or aryl, n is an integer from 5 to 1000, and m is an integer from 1 to 10. FIG. 1 is a schematic drawing showing the synthesis of the biocompatible polymer of the invention, wherein Rl, R2, n, and m have the same meaning as described above. As shown in FIG. 1, the synthetic scheme involves converting the hydroxyl end group of polyethylene glycol (PEG) to a carboxyl group by using a succinic anhydride compound, and coupling a silane group to the PEG. Suitable alkyl groups for Ri and R2 include Ci-C20 straight chain or branched alkyl groups. In one embodiment, each of Ri and R2 independently, is a Ci-C6 straight chain or branched alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert- pentyl, n-hexyl, and isohexyl. Suitable aryl groups for Ri and R2 include C6-Cj2 substituted or unsubstituted aryl groups such as phenyl, biphenyl, and naphthyl, and examples of substituents thereof include hydroxyl, haloalkyl, alkoxyl, cyano, nitro, amino, or alkylamino. The number of methylene units m is preferably an integer from 1 to 10. The number of oxyethylene units n is preferably an integer from 5 to 1000, equivalent to a molecular weight of about 200-50000 g/mole of the PEG. In one embodiment, m is about 3, and n is about 15. [0017] The biocompatible polymer synthesized in FIG. 1 is useful in that it can chemically modify the surface of the iron oxide nanoparticle to increase biocompatibility. In addition, the biocompatible polymer is useful in that it can label particles (e.g., nanoparticles, magnetic particles, magnetic nanoparticles, superparamagnetic particles), to render the particles to be further reactive toward one or more targeting, fluorescent, therapeutic, or
diagnostic agents.
[0018] The invention also provides a magnetic nanoparticle with biocompatibility, comprising a magnetic nanoparticle; a biocompatible polymer of formula (II) covalently coupled to the magnetic nanoparticle,
(H) [0019] wherein R1 is alkyl, aryl, carboxyl, or amino, n is an integer from 5 to 1000, and m is an integer from 1 to 10. FIG. 2 is a schematic drawing showing a magnetic nanoparticle modified with the biocompatible polymer of the invention. The magnetic nanoparticle is preferably made of at least one of Fe, Co, Ni, and oxides thereof. It will be appreciated that the nanoparticle can be made of any single or composite magnetic material, although superparamagnetic materials are particularly preferred. After the biocompatible polymer is chemically bonded to the magnetic nanoparticle, the terminal groups R1 are transformed into active functional groups such as carboxyl or amino groups to allow coupling with fluorescent dye and/or specific targeting agents. However, Ri is not alkyl or aryl, since alkyl or aryl are not capable of coupling with targeting agents or fluorescent dye. In one embodiment, Ri is a carboxyl group. The number of methylene units m is preferably an integer from 1 to 10. The number of oxyethylene units n is preferably an integer from 5 to 1000. In one embodiment, m is about 3, and n is about 15. The biocompatible polymer is preferably coated on the entire surface of the magnetic nanoparticle to form a core-shell structure. More preferably, the biocompatible polymer forms a monolayer coating on the magnetic nanoparticle. [0020] Experimental results indicate that the biocompatible polymer of the invention may increase the r2 value of the magnetic nanoparticle to about 2 times that of commercial contrast
agents, Feridex® and Resovist®. Accordingly, the magnetic nanoparticle may provide greater contrast enhancement when being used as an MRI contrast agent. [0021] The targeting agent is preferably coupled to the biocompatible polymer via covalent bonds. Commonly used targeting agents include an antibody, a protein, a peptide, an enzyme, a carbohydrate, a glycoprotein, a nucleotide, and a lipid. The magnetic nanoparticle may have a diameter of about 3-500nm after coupling with the targeting agent. Those skilled in the art can attach any suitable targeting agents on the nanoparticle to give specificity thereto. For example, folic acid can be used to specify breast cancer cells with a folate receptor. The structure of the folic acid allows coupling with an amine-terminated or carboxy-terminated biocompatible polymer. For example, the folic acid allows coupling with the amine-terminated biocompatible polymer by forming a -CONH- linkage. [0022] A fluorescent dye may be further coupled to the magnetic nanoparticle to provide an optical signal for optical imaging techniques such as NIR imaging, thus allowing real-time monitoring of foci by different imaging techniques. Preferably, the fluorescent dye is coupled to the biocompatible polymer via covalent bonds. Suitable fluorescent dyes include organic or inorganic dyes and organometallic complexes. The excitation and emission wavelengths of the fluorescent dye may be ultraviolet (UV), near-infrared (NIR), or visible (VIS) light. The magnetic nanoparticle coupled with the targeting agent and fluorescent dye preferably has a diameter of about 15-200nm. [0023] Without intending to limit the present invention in any manner, the present invention will be further illustrated by the following examples.
[0024] Example 1: Nanoparticle preparation
[0025] 11.6g (0.058mole) OfFeCl2 • 4H2O, 11.6g (0.096mole) OfFeCl3 • 6H2O and 400ml of deionized water were stirred in a three-necked flask at 300 rpm at 25 °C . 170ml of a 2.5N
NaOH solution was added to the flask at a rate of 47μl/sec. When a pH value of 11-12 was measured after the addition of the 2.5N NaOH solution, 20ml of oleic acid was added and stirred for 30 minutes. Thereafter, a 6N HCl solution was slowly added to adjust the pH value to about 1, thus precipitating oleic acid encapsulated-iron oxide particles. The precipitates were collected, washed with deionized water for 4-5 times to remove excess oleic acid, and dried.
[0026] Example 2: Synthesis of biocompatible polymer mPEG-silane
[0027] 30Og (0.4mole) of methoxy-PEG (mPEG, molecular weight: 750) and 600ml of N-methyl-2-pyrrolidone were placed in a 1000 ml round bottom flask under vacuum (20 Torr) for more than 2 hours. 48g (0.48mole) of succinic anhydride and 19.5g (0.159mole) of 4- dimethylamino-pyridine (DMAP) were added for reaction at 30°C for two days.
[0028] 36ml (0.48mole) of thionyl chloride was added at a rate of 1 ml/min and the mixture was stirred for 2-3 hours. Thereafter, 133.8ml (0.96mole) of triethylamine was added at a rate of 1 ml/min. After cooled to room temperature, the mixture was filtered to remove precipitates. 94.5ml (0.4mole) of 3-aminopropyl triethoxysilane was added for reaction for at least 8 hours.
[0029] The reaction mixture was added to 9L of isopropyl ether for re-precipitation, and the precipitates were collected, re-dissolved in 500ml of toluene, and centrifuged at 5000 rpm for 5 minutes to collect a supernatant. The supernatant was again, added to 9L of isopropyl ether for re-precipitation. Brown oily liquid was collected and dried under vacuum to obtain the biocompatible polymer, mPEG-silane.
[0030] Example 3: Synthesis of biocompatible polymer COOH-PEG-silane [0031] 30Og (0.4mole) of PEG (molecular weight: 750) and 600ml of N-methyl-2-
pyrrolidone were placed in a 1000 ml round bottom flask under vacuum (20 Torr) for more than 2 hours. 96g (0.96mole) of succinic anhydride and 39g (0.318mole) of 4- dimethylamino-pyridine (DMAP) were added for reaction at 30°C for two days, thus obtaining dicarboxy-terminated PEG (COOH-PEG). [0032] 36ml (0.48mole) of thionyl chloride was added at a rate of 1 ml/min and stirred for 2-3 hours. Thereafter, 133.8ml (0.96mole) of triethylamine was added at a rate of 1 ml/min. After cooled to room temperature, the mixture was filtered to remove precipitates. Then, 94.5ml (0.4mole) of 3-aminopropyl triethoxysilane was added for reaction for at least 8 hours. [0033] The reaction mixture was added to 9L of isopropyl ether for re-precipitation, and the precipitates were collected, re-dissolved in 500ml of toluene, and centrifuged at 5000 rpm for 5 minutes to collect a supernatant. The supernatant was again, added to 9L of isopropyl ether for re-precipitation. Brown oily liquid was collected and dried under vacuum, thus obtaining the biocompatible polymer, COOH-PEG-silane.
[0034] Example 4: Coupling with biocompatible polymer
[0035] 25Og of mPEG-silane or COOH-PEG-silane was added to 1-1.2 L of a toluene solution containing 1Og of iron oxide of Example 1 and the mixture was sonicated for 2-3 hours. After addition of 1.5 L of deionized water, the mixture was purified by an ultra- filtration device and concentrated to 100ml to obtain iron oxide nanoparticles modified by a biocompatible polymer.
[0036] Example 5: Coupling with targeting agent
[0037] 226 μl of folate solution (folate/dimethyl sulfoxide: 10mg/ml) was placed in a 50ml brownish round bottom flask. 5ml of dimethyl sulfoxide (DMSO) and 176.5μl of
dicyclohexyl carbodiimide solution (dicyclohexyl carbodiimide/ DMSO: 5mg/ml) was added to the solution and stirred for 1 hour. Thereafter, 98.5μl of NHS solution (N- hydroxysuccinimide/DMSO: 5mg/ml) was added and stirred for 1 hour. Then, 289μl of ethylenediamine was added to give a solution A. [0038] ImI of the COOH-PEG-silane modified iron oxide nanoparticle of Example 4 (4.48mg/ml) and 10ml of DMSO were placed in a 50ml round bottom flask under vacuum for 1 hour. 176.5μl of dicyclohexyl carbodiimide solution (dicyclohexyl carbodiimide/ DMSO: 5mg/ml) was added to the solution and stirred for 1 hour. Thereafter, 98.5μl of NHS solution (N-hydroxysuccinimide/DMSO: 5mg/ml) was added and stirred for 1 hour to give a solution B.
[0039] 2895μl (half-volume) of solution A was added to solution B and stirred for 8 hours. The resulting solution was added into a dialysis membrane (Mw: 3000) and water was used for dialysis. Then, the solution was concentrated to 2ml by an ultra- filtration device to obtain iron oxide nanoparticles coupled with a targeting agent.
[0040] Example 6: Coupling with fluorescent dye
[0041] 1ml of CypHer5E (NIR dye from Amersham Bioscience Co., 10"6 mole/ml) was mixed with 10"6 mole of ethylenediamine and stirred for 1 hour, thus giving a solution C. [0042] The iron oxide nanoparticles coupled with folate (2mg/ml) of Example 5 were dissolved in 10ml of deionized water, followed by addition of 10" mole of l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC). After the mixture was stirred for one hour, 10"6 mole of N-hydroxysuccinimide (NHS) was added and stirred for another hour, thus giving a solution D. [0043] Solution C was added to solution D and stirred for 8 hours. The resulting solution was added into a dialysis membrane (Mw: 3000) and water was used for dialysis. Then, the
solution was concentrated to 2ml by an ultra-filtration device to obtain iron oxide nanoparticles coupled with a targeting agent and a fluorescent dye.
[0044] Example 7: Relaxivity test [0045] The modified iron oxide nanoparticles of Example 5 were compared for the rl and r2 relaxivity with the product of U.S. Patent Publication No. 2006/0216239 and commercial contrast agents, i.e., Feridex® and Resovist®.
[0046] Iron oxide solutions of various concentrations (0.1, 0.2, 0.3, 0.4, 0.5 mM) were prepared and measured for the Tl or T2 relaxation time by a Minispec mq 20 from the Broker Corporation. A linear relationship was established between the reciprocal of relaxation time as the ordinate axis and the concentration of the solution as the abscissa axis. The slope of the linear relationship was the rl and r2 relaxivity.
[0047] As shown in Table 1 , the r2 relaxivity of the modified iron oxide nanoparticles of the invention was about 2 times that of Feridex® and Resovist®, and about 1.4 times that of the prior art product of U.S. Patent Publication No. 2006/0216239. Accordingly, the contrast enhancement was improved due to the higher r2 relaxivity.
[0048] Table 1
: The diameter was determined by TEM
[0049] While the invention has been described by way of example and in terms of preferred embodiment, it is to be understood that the invention is not limited thereto. To the
contrary, it is intended to cover various modifications and similar arrangements (as would be apparent to those skilled in the art). Therefore, the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements.
Claims
1. A biocompatible polymer of formula (I),
(I) wherein R1 is alkyl, aryl, carboxyl, or amino;
R2 is alkyl or aryl; n is an integer from 5 to 1000; and m is an integer from 1 to 10.
2. The biocompatible polymer as claimed in claim 1, wherein each of Ri and R2 independently is a Ci-C20 straight chain or branched alkyl.
3. The biocompatible polymer as claimed in claim 1, wherein each of Ri and R2 independently is a C6-Ci2 substituted or unsubstituted aryl.
4. The biocompatible polymer as claimed in claim 1, wherein Ri is methyl.
5. The biocompatible polymer as claimed in claim 1, wherein R2 is ethyl.
6. The biocompatible polymer as claimed in claim 1, wherein n is 15.
7. The biocompatible polymer as claimed in claim 1, wherein m is 3.
8. A magnetic nanoparticle with biocompatibility, comprising; a magnetic nanoparticle; a biocompatible polymer of formula (II) covalently coupled to the magnetic nanoparticle, 
(II) wherein R1 is alkyl, aryl, carboxyl, or amino; n is an integer from 5 to 1000; and m is an integer from 1 to 10.
9. The magnetic nanoparticle with biocompatibility as claimed in claim 8, wherein R1 is carboxyl or amino.
10. The magnetic nanoparticle with biocompatibility as claimed in claim 8, wherein the magnetic nanoparticle is a superparamagnetic nanoparticle.
11. The magnetic nanoparticle with biocompatibility as claimed in claim 8, wherein the magnetic nanoparticle comprises at least one of Fe, Co, Ni, and oxides thereof.
12. The magnetic nanoparticle with biocompatibility as claimed in claim 9, wherein R1 is coupled to a specific targeting agent comprising an antibody, a protein, a peptide, an enzyme, a carbohydrate, a glycoprotein, a nucleotide or a lipid.
13. The magnetic nanoparticle with biocompatibility as claimed in claim 12, wherein the magnetic nanoparticle has a diameter of about 3-500nm.
14. The magnetic nanoparticle with biocompatibility as claimed in claim 12, wherein the biocompatible polymer is coupled to a fluorescent dye.
15. The magnetic nanoparticle with biocompatibility as claimed in claim 14, wherein the magnetic nanoparticle containing the fluorescent dye and the specific targeting agent has a diameter of about 15-200nm.
16. The magnetic nanoparticle with biocompatibility as claimed in claim 14, wherein the fluorescent dye exhibits at least one of ultraviolet (UV), near-infrared (NIR), and visible (VIS) light excitation or emission wavelength.
17. The magnetic nanoparticle with biocompatibility as claimed in claim 14, wherein the fluorescent dye comprises an organic dye, an inorganic dye, or an organometallic complex.
18. The magnetic nanoparticle with biocompatibility as claimed in claim 14, wherein the fluorescent dye and the specific targeting agent are coupled to the biocompatible polymer by a covalent bond.
19. The magnetic nanoparticle with biocompatibility as claimed in claim 14, wherein the specific targeting agent and the biocompatible polymer are coupled by a - CONH- linkage.
20. The magnetic nanoparticle with biocompatibility as claimed in claim 8, wherein the biocompatible polymer is coated on the magnetic nanoparticle to form a core/shell structure.
21. The magnetic nanoparticle with biocompatibility as claimed in claim 20, wherein the biocompatible polymer forms a monolayer coating on the magnetic nanoparticle.
Priority Applications (9)
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| ES08734013T ES2787502T3 (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
| PT87340139T PT2285423T (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
| PL08734013T PL2285423T3 (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
| HUE08734013A HUE049091T2 (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
| EP08734013.9A EP2285423B1 (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
| PCT/CN2008/000823 WO2009129649A1 (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
| CN200880129963.4A CN102112158B9 (en) | 2008-04-22 | 2008-04-22 | Biocompatibility macromolecule and the magnetic nanometer particles with biocompatibility |
| US12/989,402 US20110171715A1 (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
| US13/600,209 US8741615B2 (en) | 2008-04-22 | 2012-08-30 | Magnetic nanoparticle with biocompatibility |
Applications Claiming Priority (1)
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| PCT/CN2008/000823 WO2009129649A1 (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
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| US12/989,402 A-371-Of-International US20110171715A1 (en) | 2008-04-22 | 2008-04-22 | Biocompatible polymer and magnetic nanoparticle with biocompatibility |
| US13/600,209 Division US8741615B2 (en) | 2008-04-22 | 2012-08-30 | Magnetic nanoparticle with biocompatibility |
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| WO2009129649A8 WO2009129649A8 (en) | 2009-12-23 |
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| US (2) | US20110171715A1 (en) |
| EP (1) | EP2285423B1 (en) |
| CN (1) | CN102112158B9 (en) |
| ES (1) | ES2787502T3 (en) |
| HU (1) | HUE049091T2 (en) |
| PL (1) | PL2285423T3 (en) |
| PT (1) | PT2285423T (en) |
| WO (1) | WO2009129649A1 (en) |
Cited By (4)
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| JP2012232904A (en) * | 2011-04-28 | 2012-11-29 | National Institute Of Advanced Industrial Science & Technology | Methoxy oligoethyleneglycol-silane compound surface modification material |
| JP2017529119A (en) * | 2014-07-14 | 2017-10-05 | メガプロ バイオメディカル カンパニー リミテッド | Immune cell tracking method |
| WO2017191455A1 (en) * | 2016-05-05 | 2017-11-09 | Itaconix (U.K.) Limited | Adhesion promoters |
| EP3524276A1 (en) * | 2018-02-12 | 2019-08-14 | MegaPro Biomedical Co., Ltd. | Biocompatible magnetic materials |
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| WO2010071459A1 (en) | 2008-12-19 | 2010-06-24 | Victoria Link Limited | Magnetic nanoparticles |
| CN102420172B (en) * | 2011-05-13 | 2014-02-05 | 上海华力微电子有限公司 | Method for forming contact holes on shallow trench for improving performances of semiconductor device |
| US20140228552A1 (en) * | 2013-02-08 | 2014-08-14 | National Cheng Kung University | Mri contrast enhancing agent |
| CN106537234A (en) | 2014-04-07 | 2017-03-22 | 加利福尼亚大学董事会 | Highly tunable magnetic liquid crystals |
| TWI689310B (en) * | 2014-07-11 | 2020-04-01 | 巨生生醫股份有限公司 | Method of treating iron deficiency |
| CN105936820B (en) * | 2016-04-20 | 2019-07-12 | 北京工商大学 | A kind of water-soluble biological compatibility fluorescence magnetic nanocluster and preparation method thereof |
| CU24583B1 (en) * | 2018-11-06 | 2022-02-04 | Centro De Neurociencias De Cuba | METAL OXIDE NANOPARTICLES CONJUGATED WITH NAPHTHALENE DERIVATIVES AS CONTRAST AGENTS FOR THE DETECTION OF AMYLOID PLAQUES BY MAGNETIC RESONANCE (MRI) |
| CA3226771A1 (en) | 2021-08-03 | 2023-02-09 | Pharmacosmos Holding A/S | Iron complex compounds for subcutaneous use in therapy of iron deficiency in companion animals |
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Also Published As
| Publication number | Publication date |
|---|---|
| PT2285423T (en) | 2020-05-07 |
| WO2009129649A8 (en) | 2009-12-23 |
| PL2285423T3 (en) | 2020-08-24 |
| US8741615B2 (en) | 2014-06-03 |
| US20110171715A1 (en) | 2011-07-14 |
| EP2285423B1 (en) | 2020-03-18 |
| HUE049091T2 (en) | 2020-08-28 |
| CN102112158A (en) | 2011-06-29 |
| EP2285423A4 (en) | 2014-12-03 |
| ES2787502T3 (en) | 2020-10-16 |
| EP2285423A1 (en) | 2011-02-23 |
| US20120329129A1 (en) | 2012-12-27 |
| CN102112158B (en) | 2012-09-05 |
| CN102112158B9 (en) | 2018-04-06 |
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