WO2007149408A1 - Agents macromoléculaires biodégradables de contraste mri et procédés pour leur préparation et leur utilisation - Google Patents

Agents macromoléculaires biodégradables de contraste mri et procédés pour leur préparation et leur utilisation Download PDF

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WO2007149408A1
WO2007149408A1 PCT/US2007/014223 US2007014223W WO2007149408A1 WO 2007149408 A1 WO2007149408 A1 WO 2007149408A1 US 2007014223 W US2007014223 W US 2007014223W WO 2007149408 A1 WO2007149408 A1 WO 2007149408A1
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contrast agent
molecular weight
agents
macromolecular
contrast agents
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PCT/US2007/014223
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English (en)
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Yuda Zong
Zheng-Rong Lu
Aaron Mohs
Yi Feng
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University Of Utah Research Foundation
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Priority to CA002658828A priority Critical patent/CA2658828A1/fr
Priority to AU2007261421A priority patent/AU2007261421A1/en
Priority to EP07809652A priority patent/EP2037808A1/fr
Priority to JP2009515531A priority patent/JP2009541221A/ja
Publication of WO2007149408A1 publication Critical patent/WO2007149408A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
    • 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
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
    • A61K49/128—Linear polymers, e.g. dextran, inulin, PEG comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone

Definitions

  • This invention relates generally to biodegradable macromolecular contrast agents used in diagnostic imaging, and methods of synthesizing, purifying, using and degrading such compounds.
  • Magnetic resonance imaging is a non-invasive method for medical diagnosis.
  • Paramagnetic metal complexes are often used as contrast agents to enhance the image contrast between normal tissue and diseased tissue.
  • Paramagnetic metal ions that are typically used in diagnostic procedures include manganese (Mn 2+ ), iron (Fe 3+ ), and gadolinium (Gd 3+ ). Chelates of Gd 3+ are frequently used as MRI contrast agents because of their long electronic relaxation time and high magnetic moment.
  • Gadolinium-based contrast agents including small molecular gadolinium complexes such as Gd(III)(DTPA)
  • Macromolecular MRI contrast agents are particularly useful because of their prolonged retention time in the blood pool.
  • the half-life of albumin-(Gd-DTPA) conjugate is approximately 3 hours in the blood [3].
  • Gd-DTPA labeled dextran (MW ⁇ 75 kDa) has a long half-life of 6.1 hours as compared to 13 minutes of Gd-DTPA in rats [4].
  • Polymeric contrast agents also possess increased proton Ti relaxivity resulting from long rotational time compared to small size molecules [5]. Because of the enhanced permeability and retention, these contrast agents accumulate effectively in solid tumors and have a potential in contrast enhancement in MR cancer imaging.
  • Gd-DTPA glycosylcholine-derived macromolecular contrast agents
  • macromolecular contrast agents have potential toxicities related to slow excretion and long-term tissue Gd accumulation, thus hinders their further development.
  • use of Gd macromolecular agents may result in Gd accumulation in the bone and other tissues, resulting in toxicity and adverse side-effects.
  • (Gd-DTPA)-albumin conjugate a prototype of macromolecular MRI contrast- agent, showed high accumulation of Gd in the bone and liver consequential of its slow excretion [3], which increased possibility of cellular uptake of the agent through endocytosis and dissociation of Gd-DTPA complexes in the lysosome due to low pH and enzymatic degradation [6,7].
  • the inventors recently designed and developed biodegradable macromolecular MRI contrast agents based on polydisulfide Gd(III) complexes to facilitate excretion of Gd chelates via in vivo degradation of the macromolecular agents [10-12]. Disulfide bonds in the polymer backbone can be rapidly reduced by free plasma thiols, e.g., glutathione and cysteine, or by enzymatic degradation. It has been shown that (Gd- DTPA)-cystamine copolymers (GDCC), the First polydisulfide MRI contrast agent, produced more significant blood pool contrast enhancement in rats than a clinically available MRI contrast agent, Gd-(DTPA-BMA), and then cleared rapidly from the blood pool. GDCC exhibited minimal long-term tissue accumulation of Gd comparable to the clinically used Gd-(DTPA-BMA).
  • the present invention provides, among other things, degradable macromolecular contrast agents with a defined or controlled molecular weight and/or molecular weight distribution, hi a preferred embodiment, the contrast agents comprise polydisulfide. In another preferred embodiment, these contrast agents are complexes with metals, e.g., Mn 2+ , Fe 3+ and Gd 3+ . Examples of various contrast agents are disclosed in US Patent 6,982,324, Ref. [10], Ref. [11], or Ref. [12]. These contrast agents can be used in various medical procedures, e.g., diagnostic and treatment procedures. In one embodiment, these contrast agents are used in magnetic resonance imaging. In an alternative embodiment, these contrast agents are used in X-ray computed tomography.
  • the degradable polymer can form chelates with radioactive metal ions for scintigraphy, positron emission tomography and radiotherapy.
  • the contrast agent complexes include targeting molecules.
  • targeting molecules including, but are not limited to, antibodies, antibody fragments, peptides, other proteins and other chemical entities results in macromolecular contrast agents with targeting ability.
  • the invention provides a method of preparing degradable macromolecular contrast agents in an aqueous medium.
  • the reaction medium is a basic aqueous solution.
  • Use of aqueous solution as a medium for polymerization avoids polluting solvents, and also facilitates easy scale-up for manufacture.
  • the invention provides a method of purifying degradable macromolecular ligands and contrast agents.
  • the ligands and contrast agents are purified by chromatography methods.
  • the contrast agents are purified by ultrafiltration.
  • Biodegradable macromolecular MRI contrast agents comprising Gd can also be purified by raising pH of the contrast agent solutions to remove any residual free Gd(III) ions as Gd 2 Os precipitates.
  • the invention also provides a method of fractionating degradable macromolecular contrast agents to provide contrast agents with narrower or desired molecular weight distributions.
  • contrast agents are fractionated by chromatography methods such as size exclusion chromatography.
  • the invention also provides a method of controlling the molecular weight and/or molecular weight distribution of degradable macromolecular contrasting agents.
  • the molecular weights of the contrasting agents are controlled by varying polymerization conditions, such as reaction temperature and/or feed ratios of polymerization reactants.
  • the invention provides a method for obtaining a magnetic resonance image of a tissue or organ of a mammal by administering one or more degradable macromolecular contrast agents and obtaining a magnetic resonance image.
  • the macromolecular contrast agents are capable of being degraded by both endogenous and exogenous compounds.
  • the macromolecular contrast agents are degraded by endogenous mercaptans and/or enzymes into small stable chelates.
  • the invention also provides a method to degrade or stimulate degradation of the macromolecular contrast agents by administering one or more disulfide bond reducing compounds or other compounds that stimulate the degradation of the macromolecular contrast agents.
  • exogenous mercaptans are delivered to the mammal.
  • Another object of several embodiments of the current invention is to administer macromolecular contrast agents in conjunction with other agents.
  • physiologically acceptable agents such as diluents and carriers, are also administered.
  • One aspect of the invention includes a method for obtaining a magnetic resonance image of a tissue or organ of a mammal by administering an effective amount of one or more macromolecular contrast agents to the mammal and obtaining a magnetic resonance image.
  • one or more of the macromolecular contrast agents are degraded by endogenous mercaptans and/or enzymes.
  • one or more compounds that stimulate the degradation of said macromolecular contrast agent is also administered.
  • one or more disulfide bond reducing compounds is also administered.
  • the disulfide bond reducing compound is selected from the group consisting of one or more of the following: mercaptans, NADH, NADPH, hydrazines, phosphines, zinc, tin(II), sodium sulfide, performic acid, hydrogen peroxide.
  • Mercaptans used in various aspects of the present invention are selected from the group consisting of one or more of the following: cysteine and its derivatives, glutathione and its derivatives, cysteinylglycine and its derivatives, 2,3-dimercaptosuccinic acid and its derivatives, 2,3-dimercapto-l-propanesulfonic acid and its derivatives, 2- mercaptoethanol, penicillamine and its derivatives, mercaptoacetic acid and its derivatives, mercaptoanisole, 2-mercaptobenzoic acid and its derivatives, 4- mercaptobenzoic acid and its derivatives, 2-mercapto-5-benzimidazolesulfonic acid and its derivatives, 2-mercaptobenzothiazole, 3-mercapto-iso-butyric acid, mercaptocyclohexane, 2-mercaptoethanesulfonic acid, 2-mercaptoethylamine, 2- mercaptoethylamine hydrochloride, 3-mercap
  • the macromolecular contrast formulation comprises a first macromolecular contrast agent and a second macromolecular contrast agent, wherein the second macromolecular contrast agent is administered after the administration of said first macromolecular contrast agent.
  • at least one of the macromolecular contrast agents is administered in conjunction with one or more physiologically acceptable agents selected from the group consisting of: diluents, carriers, antibodies, antibody Fab' fragments, antibody F(ab') 2 fragments, and delivery systems.
  • At least one of the macromolecular contrast agents is administered in conjunction with one or more contrast agents selected from the group consisting of: paramagnetic metal complexes, radioactive metal complexes, therapeutic agents, proteins, DNA, RNA, drug delivery systems and gene delivery systems.
  • one or more contrast agents selected from the group consisting of: paramagnetic metal complexes, radioactive metal complexes, therapeutic agents, proteins, DNA, RNA, drug delivery systems and gene delivery systems.
  • healthy or tumorous tissues or organs including but not limited to, liver, spleen, lung, heart, kidney, tumors, ovary, pancreas, biliary system, peritoneum, muscles, head, neck, esophagus, bone marrow, lymph node, lymph vessels, nervous system, brain, spinal cord, blood capillaries, stomach, small intestine, and large intestine.
  • contrast agents of high (preferably larger than 40 kDa) molecular weight provide more prolonged and significant contrast enhancement for cardiac and vasculature imaging.
  • contrast agents of low (preferably smaller than 40 kDa) molecular weight result in more significant enhancement in tumor tissues than high molecular weight agents.
  • FIG. 1 Effects of reaction temperatures on molecular weight distributions of polymer ligand DTPA-cystine copolymers, as also illustrated in the Table 1.
  • FIG. 2 Effect of feeding ratio of DTPA dianhydride to cystine on molecular weight distributions of copolymers, as also illustrated in Table 2.
  • FIG. 3 Comparison of purification of poly(GdDTPA-co-L-cystine) (GDCP) by PD-10 columns vs. ultrafiltration.
  • FIG. 4 Time signal intensity curve of major fractions of Gd-DTPA cystamine copolymers (GDCC) using AKTA P-920 FPLC, Superose 6 10/200 GL column and a Knauer RI detector.
  • FIG. 5 Three-dimensional maximum intensity projection MR images of mice before injection (a) and 2 (b), 5 (c), 10 (d), 15 (e), 30 (f) and 60 (g) min after injection of GDCP (A: 23 kDa, B: 43 kDa, C: 109 kDa) and GDGP (D: 21 kDa, E: 43 kDa, F: 108 kDa) at a dose of 0.1 mmol Gd/kg via a tail vein.
  • GDCP A: 23 kDa, B: 43 kDa, C: 109 kDa
  • GDGP D: 21 kDa, E: 43 kDa, F: 108 kDa
  • FIG. 6 Two-dimensional axial MR images of mice with human breast cancer (MB-231) (see arrows) before injection (a) and 2 (b), 5 (c), 10 (d), 15 (e), 30 (f) and 60 (g) min after injection of GDCP (A: 23 kDa, B: 43 kDa, C: 109 kDa) and GDGP (D: 21 kDa, E: 43 kDa, F: 108 kDa).
  • GDCP A: 23 kDa
  • B 43 kDa
  • C 109 kDa
  • GDGP D: 21 kDa
  • E 43 kDa
  • F 108 kDa
  • polydisulfide ligands are prepared in organic solvents, for example, polydisulfide ligands are obtained by condensation polymerization of DTPA dianhydride and disulfide-containing diamines in DMSO.
  • Organic solvents are, in general, not environmentally friendly, especially when they are used in large scale manufacturing processes. In addition, it takes extra steps to remove the organic solvents prior to application of the polydisulfide agents.
  • the present invention provides a method for preparing degradable macromolecular contrasting agents in an aqueous medium, thus offering advantages over traditional methods in less pollution and ease of scaling up.
  • the aqueous medium is a basic aqueous solution.
  • the invention provides a method of purifying degradable macromolecular contrast agents.
  • the contrast agents can be purified by various chromatography methods, such as HPLC (high performance liquid chromatography), GPC (gel permeation chromatograph), and SEC (size exclusion chromatography).
  • HPLC high performance liquid chromatography
  • GPC gel permeation chromatograph
  • SEC size exclusion chromatography
  • the contrast agents are purified by SEC equipped with a column packed with G-25 medium.
  • the contrast agents can also be purified by various filtration methods, such as ultrafiltration using a filter with a desired molecular weight cut-off.
  • the present invention also provides a method to prepare biodegradable macromolecular MRI contrast agents with different molecular weights, and/or narrow molecular weight distribution for different clinical applications.
  • Biodegradable macromolecular MRI contrast agents with various molecular weights can be readily controlled by varying the reaction conditions, for example, by varying the reaction temperature, or by varying the feed ratio of polymerization reactants. Methods to adjust reaction conditions are exemplified in the Examples herein. It is to be noted that other reaction conditions, such as pH of the reaction medium, reaction time, mixing speed of reactants, and other factors, can also affect the molecular weight and/or molecular weight distribution.
  • the invention also provides a method to obtain a magnetic resonance image of healthy or tumorous tissues or organs, the method comprising selecting one or more contrast agents with a suitable molecular weight for a specific application.
  • a macromolecular contrast agent may have a broader molecular weight distribution than desired.
  • the paramagnetic polydisulfide with a narrower molecular weight distribution are prepared by fractionation with size exclusion chromatography. It is to be noted other methods such as ultrafiltration or dialysis can also offer partial fractionation.
  • a polydisulfide contrast agent can affect its degradation, pharmacokinetics and in vivo contrast enhancement.
  • polydisulfide Gd(III) complexes For example, polydisulfide Gd(III) complexes, (Gd-DTPA)-cystine copolymers (GDCP), (Gd-DTPA)-glutathione (oxidized form) copolymers (GDGP) and (Gd-DTP A)-cystine diethyl ester copolymers (GDCEP) behaved differently in mice.
  • the data and analysis with respect to degradation, pharmacokinetics and in vivo contrast enhancement for these polydisulfide contrasting agents are shown in FIGs. 5 and 6, and detailed in Ref.
  • the invention also provides a method to obtain magnetic resonance images of healthy or tumorous tissues or organs, the method comprising selecting one or more contrasting agents with suitable properties of pharmacokinetic, degradation, and/or in vivo contrast enhancement for a specific application.
  • the present invention provides polydisulfide MRI contrast agents of defined or controlled molecular weight and/or molecular weight distribution.
  • Polydisulfide MRI contrast agents of the present invention include, but are not limited to various contrast agents as disclosed in US Patent 6,982,324, Ref. 10, Ref. 11 or Ref. 12.
  • the contrast agents are prepared in aqueous medium.
  • the contrast agents of defined molecular weight and/or molecular weight distribution are prepared by varying reaction conditions.
  • the contrast agents of a narrow distribution range or a desired distribution range are prepared by purification or fractionation methods such as ultrafiltration, size exclusion, and dialysis.
  • the invention provides a method for obtaining magnetic resonance images of a tissue or organ of a mammal by administering an effective amount of one or more macromolecular contrast agents to the mammal and obtaining magnetic resonance images.
  • an MRI procedure is performed on a human subject.
  • tissues and organs may be examined using different aspects of this invention, including, but not limited to, liver, spleen, lung, esophagus, bone marrow, lymph node, lymph vessels, nervous system, brain, spinal cord, blood capillaries, stomach, small intestine, large intestine.
  • both normal tissues and abnormal tissues, such as tumors can be examined.
  • Another aspect of this invention relates to a method of clearing metal complexes.
  • the clearance procedure is performed after the MRI procedure has been completed or substantially completed.
  • mercaptans, or other similar agents are administered after the MRI procedure.
  • these agents facilitate the excretion process by cleaving the macromolecular backbone.
  • clearing occurs by removal of the paramagnetic metal complexes from the polymer carriers by cleavage of the disulfide bond.
  • Several embodiments are particularly advantageous because the paramagnetic metal complexes released from the macromolecules can be cleared at a rate comparable to that of the small molecular contrast agents used clinically today.
  • the macromolecular compounds have a prolonged retention time in the blood pool, favorable accumulation in the solid tumor tissues, and are cleared rapidly after MRI.
  • These macromolecular agents, and the methods described thereof, will be indispensable tools in a variety of medical procedures, including, but not limited to, angiography, plediysmography, lymphography, mammography, cancer diagnosis, and functional and dynamic MRI.
  • Cystine (5 mmol, 1.200 g, >99%) was dissolved in 2 ml aqueous solution and the pH of the solution was adjusted with NaOH to 11 at room temperature. The reactions were then carried out at three different temperatures, -10 0 C (ice-NaCl bath), 0 0 C (ice water bath) and room temperature, respectively.
  • Diethylenetriamine-N,N,N',N",N"-pentaacetic acid dianhydride (DTPA-DA) (5 mmol, 1.787 g) was added in portions within 1 h with fast stirring. The pH of the reaction mixture was maintained at 11 with saturated NaOH aqueous solution. 30% more DTPA dianhydride was added in portions in 30 minutes at constant pH 11.
  • FIG. 1 shows the molecular weight distribution of DTPA cystine copolymers prepared at different temperature. It shows that the reaction temperature has significant impact on the molecular weight distribution. High reaction temperature increases the molecular weights of copolymers.
  • Cystine (5 ⁇ unol, 1.200 g) was dissolved in 2 ml water and the pH was adjusted with NaOH to 11 at room temperature.
  • DTPA-DA of different molar ratios to cystine (0.9, 1.0, 1.1, 1.2 and 1.3) was added in portions within 1.5 h with fast stirring to the cystine solutions.
  • the pH of the reaction mixtures was maintained at pH 11 with saturated NaOH aqueous solution.
  • the molecular weight of the DTPA-cystine copolymers prepared at different molar ratios was analyzed by size exclusion chromatography with a Superose 12 column. See Table 2 and FIG. 2. High molar ratio (1.2 and 1.3) of DTPA dianhydride to cystine gives high molecular weight. The molecular weight of the copolymers was then decreased with decreasing molar ratios.
  • Cystine (10 mmol, 2.403 g) was dissolved in 5 ml of aqueous NaOH at pH 11 at room temperature and then the mixture was cooled in an ice water bath.
  • DTPA dianhydride (10 mmol, 3.573 g) was then added in portions within 1 h, maintaining at pH 11 with NaOH aqueous solution.
  • 10% (by weight) of HCl was added to adjust pH to 7 and the solution was dialyzed against deionized water using membrane with molecular weight cutoff of 6-8000 Da for 24 h.
  • the copolymer solution was lyophilized giving 3.2 g colorless solid product (54%).
  • the number (Mn) and weight (Mw) average molecular weights of the copolymers were 18 and 33 kDa as determined by SEC using AKTA FPLC system with a SuperoseTM 12 column. The system was calibrated with standard poly[N-(2- hydroxypropyl)methacrylamide] (PHPMA). Copolymerization of DTPA-Glutathione (oxidized form):
  • Glutathione (8 mmol, 4.901 g, oxidized form) was dissolved in 5 ml of aqueous NaOH at pH 11 at room temperature and then the mixture was cooled in an ice water bath.
  • DTPA dianhydride (8 mmol, 2.850 g) was then added in portions within 1 h, maintaining at pH 11 with NaOH aqueous solution.
  • 10 % (by weight) of HCl was added to adjust pH to 7 and the solution was dialyzed against deionized water using membrane with molecular weight cutoff of 6-8000 Da for 24 h.
  • the copolymer solution was lyophilized giving 4.00 g colorless solid product (52%).
  • the number (Mn) and weight (Mw) average molecular weights of the copolymers were 37 and 61 fcDa as determined by SEC using AKTA FPLC system with a SuperoseTM 6 column.
  • Cystamine hydrochloride (5 mmol, 1.126 g) was dissolved in 2 ml of de- ionized water at room temperature, and the pH was adjusted to 11 using saturated NaOH aqueous solution. Under fast stirring, DTPA dianhydride (6 mmol, 2.144 g) was then added in portions within 1 hour at room temperature, maintaining at pH 11 with NaOH aqueous solution. Five minutes after the addition of the last portion of DTPA-DA, 10% (by weight) of HCl was added to adjust pH to 7 and the solution was dialyzed against de-ionized water using membrane with molecular weight cutoff of 6-8000 Da for 24 h. The copolymer solution was lyophilized giving 1.46 g colorless solid product (50%). The number (Mn) and weight (Mw) average molecular weights of the copolymers were 35 and 42 Da as determined by size exclusion chromatography (SEC) using AKTA FPLC system with a Superose 6 column.
  • SEC size
  • the paramagnetic complexes (Gd-DTP A)-cystine copolymers (GDCP), (Gd- DTPA)-glutathione copolymers (GDGP) and (Gd-DTPA)-Cystamine (GDCC), were prepared by the complexation of DTPA-cystine copolymers (DCP), DTPA-glutathione copolymers (DGP) and DTPA-cystamine copolymers (DCC) with Gd 3+ , respectively. Briefly, 0.5 g of DCP or DGP or DCC was dissolved in de-ionized water. Xylenol orange will be added as the indicators of free Gd 3+ .
  • MWCO 10000 Da (protein).
  • the solution was stirred under elevated pressure and diluted several times in the chamber.
  • the concentrated polymer, solution was evaporated until dryness.
  • the SEC profile from the polymer purified with the ultrafiltration was similar to that purified by the SEC (FIG. 3).
  • PHPMA as standard.
  • the flow rate is set to 0.5 ml/min.
  • the characterization of major fractions is shown in FIG. 4.
  • the number average, weight average molecular weight and polydispersion index (PDI) of some combined fractions and fractions are listed in Table 4.
  • Table 4 The number average, weight average molecular weight and polydispersion index (PDI) for major fractions.
  • the in vivo contrast enhancement by GDCP and GDGP was investigated in female athymic nude mice (Charles River Lab) with human breast cancer (MB-231) using a Siemens Trio 3T scanner with a human wrist coil.
  • the mice were anesthetized by the intramuscular administration of a mixture of ketamine (80 mg/kg) and xylazine (12 mg/kg).
  • Contrast enhanced MR images of the mice were acquired using spin echo sequence before and at 2, 5, 10, 15, 30 and 60 minutes after injection of the contrast agents at a dose of 0.1 mmol-Gd/kg via a tail vein.
  • the imaging parameters were 2.7 ms TE, 7.8 ms TR, 25 0 C RF tip angle, 0.5 mm axial slice thickness.
  • Three-dimensional maximum intensity project (MIP) MR images of mice before and at various time points after injection of GDCP and GDGP with different molecular weights are shown in FIG. 5.
  • Strong contrast enhancement was observed in the liver, kidneys and blood in the heart and vasculature with all agents 2 min post-injection and the signal intensity gradually decreased thereafter. Both agents with highest MW can strongly enhanced blood vessel up to 30 minutes.
  • Both the signal intensity and enhancement duration for GDCP and GDGP were increased with molecular weight.
  • Gradual enhancement in the urinary bladder was observed for all compounds, indicating urinary clearance of the agents.
  • High molecular biodegradable agents (108 kDa) provide more prolonged and significant contrast enhancement for cardiac and vasculature imaging than the corresponding agents of low molecular weights.
  • Tl weighted axial images of tumors were also acquired with human wrist coil using spin echo sequence with 10 ms TE, 400 ms TR, 90° RF tip angle, 2 mm axial slice thickness.
  • Tl weighted tumor images showed strong enhancement by both GDCP and GDGP in the tumor periphery 2 minutes pot-injection and up to 60 minutes (FIG. 6).
  • the contrast enhancement in tumor center is weaker than in periphery.
  • the polymer agents with low molecular weight (23 kDa) resulted in more significant enhancement in the tumor tissues than high molecular weight agents.
  • DTPA-polyethylene glycol polymers dependence on molecular weight, J. Magn.

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Abstract

L'invention concerne de nouveaux procédés pour préparer des agents macromoléculaires dégradables de contraste d'imagerie par résonance magnétique. L'invention concerne des agents macromoléculaires dégradables de contraste d'imagerie par résonance magnétique de distribution moléculaire pondérale définie ou contrôlée destinés à être utilisés dans différentes procédures de diagnostic et dans des procédés de synthèse, d'utilisation de de dégradation de ces agents. Les agents macromoléculaires de contraste présentés dans plusieurs aspects de la présente invention sont des composés constitués de polydisulfure paramagnétique dégradable qui présentent une rétention prolongée dans le plasma, une perméabilité et une rétention améliorées dans de nombreux tissus, organes ou tumeurs tout en pouvant être retirés rapidement du corps.
PCT/US2007/014223 2006-06-16 2007-06-13 Agents macromoléculaires biodégradables de contraste mri et procédés pour leur préparation et leur utilisation WO2007149408A1 (fr)

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CA002658828A CA2658828A1 (fr) 2006-06-16 2007-06-13 Agents macromoleculaires biodegradables de contraste mri et procedes pour leur preparation et leur utilisation
AU2007261421A AU2007261421A1 (en) 2006-06-16 2007-06-13 Biodegradable macromolecular MRI contrast agents and methods of preparation and use thereof
EP07809652A EP2037808A1 (fr) 2006-06-16 2007-06-13 Agents macromoléculaires biodégradables de contraste mri et procédés pour leur préparation et leur utilisation
JP2009515531A JP2009541221A (ja) 2006-06-16 2007-06-13 生分解性高分子ｍｒｉ造影剤並びにその調製及び使用法

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US20160375154A1 (en) * 2015-06-26 2016-12-29 Northwestern University Gd(III)-Dithiolane Gold Nanoparticle Conjugates
US10406249B2 (en) * 2015-06-26 2019-09-10 Northwestern University Gd(III)-dithiolane gold nanoparticle conjugates

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EP2037808A1 (fr) 2009-03-25

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