U.S. patent application number 14/336868 was filed with the patent office on 2015-01-01 for go-gd-dtpa complex, preparation method thereof, and mri contrast agent comprising the same.
This patent application is currently assigned to RESEARCH & BUSINESS FOUNDATION SUNGKYUNKWAN UNIVERSITY. The applicant listed for this patent is RESEARCH & BUSINESS FOUNDATION SUNGKYUNKWAN UNIVERSITY. Invention is credited to Hyo Young LEE, Luyang WANG.
Application Number | 20150005483 14/336868 |
Document ID | / |
Family ID | 47911970 |
Filed Date | 2015-01-01 |
United States Patent
Application |
20150005483 |
Kind Code |
A1 |
LEE; Hyo Young ; et
al. |
January 1, 2015 |
GO-GD-DTPA COMPLEX, PREPARATION METHOD THEREOF, AND MRI CONTRAST
AGENT COMPRISING THE SAME
Abstract
Disclosed herein is a GO-Gd-DTPA (gadolinum-diethylenetriamine
pentaacetic-graphene oxide) complex, which is formed by an ester
bond of graphene oxide (GO) and gadopentetic acid (Gd-DTPA). Since
the GO-Gd-DTPA can stably exist in the body because it has high
stability in water, it is expected that it can be effectively used
as an MRI contrast agent.
Inventors: |
LEE; Hyo Young; (Suwon-si,
KR) ; WANG; Luyang; (Suwon-si, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
RESEARCH & BUSINESS FOUNDATION SUNGKYUNKWAN UNIVERSITY |
Suwon-si |
|
KR |
|
|
Assignee: |
RESEARCH & BUSINESS FOUNDATION
SUNGKYUNKWAN UNIVERSITY
Suwon-si
KR
|
Family ID: |
47911970 |
Appl. No.: |
14/336868 |
Filed: |
July 21, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13607961 |
Sep 10, 2012 |
|
|
|
14336868 |
|
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Current U.S.
Class: |
534/16 |
Current CPC
Class: |
C07F 5/00 20130101; C07F
5/003 20130101; A61K 49/105 20130101; C07D 493/22 20130101 |
Class at
Publication: |
534/16 |
International
Class: |
A61K 49/10 20060101
A61K049/10; C07F 5/00 20060101 C07F005/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 8, 2011 |
KR |
10-2011-0091054 |
Claims
1. A method of preparing a GO-Gd-DTPA (gadolinum-diethylenetriamine
pentaacetic-graphene oxide) complex, comprising the steps of: (a)
dissolving gadopentetic acid (Gd-DTPA) and graphene oxide (GO) in
an organic solvent; (b) treating the GO-Gd-DTPA with DCC
(dicyclohexylcarbodiimide) and DMAP (dimethylaminopyridine) to
esterify the GO-Gd-DTPA; (c) bonding the esterified GO-Gd-DTPA with
the graphene oxide (GO) in nitrogen gas to form a GO-Gd-DTPA
(gadolinum-diethylenetriamine pentaacetic-graphene oxide) complex;
and (d) separating the GO-Gd-DTPA complex using a filter.
2. The method of claim 1, wherein the organic solvent is DMF
(dimethylformamide) or THF (tetrahydrofuran).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional Application of U.S.
application Ser. No. 13/607,961, filed Sep. 10, 2012, which claims
the benefit under 35 U.S.C. .sctn.119(a) of Korean Application No.
10-2011-0091054 filed on Sep. 8, 2011, in the Korean Intellectual
Property Office, the disclosures of both of which are incorporated
herein by reference for all purposes.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field The present invention relates to a
GO-Gd-DTPA complex, a preparation method thereof, and an MRI
contrast agent including the same, and, more particularly, to a
novel GO-Gd-DTPA complex, the stability of which is improved
because it has high dispersibility compared to conventional MRI
contrast agents, a preparation method thereof, and an MRI contrast
agent including the same.
[0003] 2. Description of the Related Art
[0004] As imaging technologies for observing the inside of a human
body to diagnose diseases early, there are X-ray imaging, computed
tomography (CT), positron emission tomography (PET), and the like.
However, such imaging technologies are problematic in that they
cannot be used to diagnose patients that are anxious about genetic
variation because the human body is irradiated with radioactive
rays. Recently, magnetic resonance imaging (MRI), which is a
technology for detecting and imaging energy generated when
high-frequency energy is applied to an atomic nucleus and then
removed, has rapidly increased in use because it is stable compared
to conventional imaging technologies.
[0005] However, MRI needs a contrast agent in order to improve
sensitivity and peculiarity. When a contrast agent is used, it is
possible to observe internal organs, such as blood vessels,
stomach, liver and the like, which are not easy to find during
[0006] X-ray imaging, and it is possible to ascertain the
difference between normal tissue and diseased tissue (tumor), thus
enabling early diagnosis of various diseases.
[0007] Currently, as a contrast agent generally used in clinics,
transition metal ions, such as gadolinium (Gd) ions, manganese
[0008] (Mn) ions and the like, are generally used. Such transition
metal ions have a low molecular weight and very strong toxicity,
and thus research into converting the ions into a complex using a
biocompatible polymer has been actively done. However, an MRI
contrast agent has problems of a short half-life and cellular
toxicity as before. Further, since an MRI contrast agent has low
dispersibility, there is a problem in that it coagulates in the
body at the time of injecting it into the body, thus forming
particles.
[0009] As such, in order to effectively use MRI in the early
diagnosis of diseases, it is actually required to develop an MRI
contrast agent having low toxicity and high dispersibility and
stability.
SUMMARY OF THE INVENTION
[0010] Accordingly, the present invention has been devised to solve
the above-mentioned problems, and an object of the present
invention is to provide a novel GO-Gd-DTPA complex, the stability
of which is improved because it has high dispersibility compared to
conventional MRI contrast agents, a preparation method thereof, and
an MRI contrast agent including the same.
[0011] However, an object to be accomplished by the invention is
not limited to the above-mentioned object, and other objects not
mentioned will be understood by those skilled in the art from the
following description.
[0012] In order to accomplish the above object, an aspect of the
present invention provides a GO-Gd-DTPA
(gadolinum-diethylenetriamine pentaacetic-graphene oxide) complex,
which is formed by an ester bond of graphene oxide (GO) and
gadopentetic acid (Gd-DTPA).
[0013] Another aspect of the present invention provides a method of
preparing a GO-Gd-DTPA (gadolinum-diethylenetriamine
pentaacetic-graphene oxide) complex, including the steps of:
[0014] dissolving gadopentetic acid (Gd-DTPA) and graphene oxide
(GO) in an organic solvent; treating the GO-Gd-DTPA with DCC
(dicyclohexylcarbodiimide) and DMAP (dimethylaminopyridine) to
esterify the GO-Gd-DTPA; bonding the esterified GO-Gd-DTPA with the
graphene oxide (GO) in nitrogen gas to form a GO-Gd-DTPA
(gadolinum-diethylenetriamine pentaacetic-graphene oxide) complex;
and separating the GO-Gd-DTPA complex using a filter.
[0015] In the method, the organic solvent may be DMF
(dimethylformamide) or THF (tetrahydrofuran).
[0016] Still another aspect of the present invention provides an
MRI contrast agent composition including the GO-Gd-DTPA
complex.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The above and other objects, features and advantages of the
present invention will be more clearly understood from the
following detailed description taken in conjunction with the
accompanying drawings, in which:
[0018] FIG. 1 is a schematic view showing a structure of
GO-Gd-DTPA; and
[0019] FIG. 2 is a photograph showing the results of a test of
dispersibility of GO-Gd-DTPA.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0020] Hereinafter, preferred embodiments of the present invention
will be described in detail with reference to the attached
drawings.
[0021] The present inventors researched an MRI contrast agent which
does not cause cellular toxicity and which stably exists in the
body because it has high dispersibility. As a result, the present
invention was completed.
[0022] The present invention provides a GO-Gd-DTPA
(gadolinum-diethylenetriamine pentaacetic-graphene oxide) complex,
which is formed by an ester bond of graphene oxide (GO) and
gadopentetic acid (Gd-DTPA).
[0023] In order to prepare a complex which does not cause cellular
toxicity and which is stably dispersed in the body, the present
inventors bonded graphene oxide with Gd-DTPA (Magnevist.TM.,
manufactured by Bayer Co., Ltd.) which is a commonly-used
gadolinium complex. Graphene oxide is widely used in the fields of
polymers, ceramics, metals, thin films of electronic products, drug
delivery, hydrogen storage, oil and gas recovery technologies, and
the like because it is water soluble and has low toxicity. Further,
graphene oxide is advantageous in that it can be produced in large
quantities in an environment-friendly method.
[0024] The present invention provides a method of preparing a
GO-Gd-DTPA (gadolinum-diethylenetriamine pentaacetic-graphene
oxide) complex, including the steps of: (a) dissolving gadopentetic
acid (Gd-DTPA) and graphene oxide (GO) in an organic solvent; (b)
treating the GO-Gd-DTPA with DCC (dicyclohexylcarbodiimide) and
DMAP (dimethylaminopyridine) to esterify the GO-Gd-DTPA; (c)
bonding the esterified GO-Gd-DTPA with the graphene oxide (GO) in
nitrogen gas to form a GO-Gd-DTPA (gadolinum-diethylenetriamine
pentaacetic-graphene oxide) complex; and (d) separating the
GO-Gd-DTPA complex using a filter.
[0025] In the present invention, in order to bond Gd-DTPA with
graphene oxide, Gd-DTPA is dissolved in DMF (dimethylformamide) and
then treated with DCC and DMAP to activate a carboxylic group and
thus esterify Gd-DTPA, and then the esterified Gd-DTPA is bonded
with the graphene oxide (GO) to obtain a GO-Gd-DTPA complex. In the
step of bonding Gd-DTPA with graphene oxide, any organic solvent
can be used to dissolve both Gd-DTPA and graphene oxide as long as
it does not prevent the bonding between Gd-DTPA and graphene oxide.
The organic solvent may be DMF (dimethylformamide) or THF
(tetrahydrofuran). The obtained GO-Gd-DTPA complex is separated
using a nylon filter and then dried. In the step of separating the
GO-Gd-DTPA complex, the GO-Gd-DTPA complex is washed with water and
DMF to remove Gd-DTPA causing cellular toxicity, DMAP, DCC urea
(final reaction product of DCC), and the like, thus increasing
purity. As a result of analyzing the prepared GO-Gd-DTPA complex
using ICP-OES/MS (Inductively Coupled Plasma Spectroscopy), it was
ascertained that the amount of graphene oxide in the GO-Gd-DTPA
complex was 4%.
[0026] According to an embodiment of the present invention, it was
ascertained that the GO-Gd-DTPA complex had high dispersibility in
an aqueous solution compared to a conventional MRI contrast agent
(refer to Example 2).
[0027] Consequently, the GO-Gd-DTPA complex of the present
invention can be used as an MRI contrast agent because it has high
dispersibility. Therefore, the present invention provides an MRI
contrast agent composition including the GO-Gd-DTPA complex.
[0028] The MRI contrast agent composition of the present invention
can be formulated by a formulation method that is well known to
those skilled in the art, and preferably, can be formulated into an
intravenous injection or an oral administration.
[0029] The MRI contrast agent composition of the present invention
may include a pharmaceutically allowable carrier. The
pharmaceutically allowable carrier may include, but is not limited
to, a physiological salt solution, polyethylene glycol, ethanol,
vegetable oil and isopropyl myristate.
[0030] The dosage of the MRI contrast agent composition of the
present invention may be suitably selected by those skilled in the
art, although it is changed depending on the state and weight of a
patient, the degree of a disease, the form of drug, the route of
administration and the period of administration. Preferably, the
contrast agent composition of the present invention is injected
into the body in an amount of 0.001 to 100 mg/kg of body weight for
1 day, more preferably, 0.01 to 30 mg/kg of body weight for 1 day.
The MRI contrast agent composition of the present invention may
exist in an amount of 0.0001 to 10 wt %, preferably, 0.001 to 1 wt
% based on the total amount thereof.
[0031] Hereinafter, the present invention will be described in more
detail with reference to the following examples. However, these
examples are set forth only to illustrate the present invention,
and the scope of the present invention is not limited thereto.
EXAMPLES
Example 1
Method of Preparing a GO-Gd-DTPA Complex
[0032] Dicyclohexylcarbodiimide (DCC) (0.25 mg/mL) was added to
Gd-DTPA (gadopentetic acid) (0.25 mg/mL) dispersed in
dimethylformamide (DMF), and then reacted in nitrogen gas for 4
hours to activate a carboxylic group. Meanwhile, in the reaction,
dimethylaminopyridine (DMAP) (0.1 mg/mL) was used as a catalyst for
acyl group transfer. Graphene oxide (GO) was dispersed in DMF in a
concentration of 2 mg/mL. The Gd-DTPA (20 mg/50 mL) and graphene
oxide (100 mg/50 mL) dispersed in the DMF were mixed, and then
stirred at room temperature for 2 hours to prepare a GO-Gd-DTPA
complex. Thereafter, non-bonded Gd-DTPA and DMAP and DCC urea
(final reaction product of DCC), were removed from the GO-Gd-DTPA
complex using a nylon filter having a pore size of 0.2 .mu.m to
increase purity. In order to remove the non-bonded Gd-DTPA and DMAP
and the DCC urea, the GO-Gd-DTPA complex was sequentially washed
with 50 mL of deionized water three times, washed with 100 mL of
DMF once, washed with 50 mL of deionized water three times, and
then finally washed with 100 mL of acetone. Thereafter, the washed
GO-Gd-DTPA complex was completely dried in a vacuum oven at
80.degree. C. to obtain GO-Gd-DTPA complex powder.
Example 2
Dispersibility Test
[0033] In order to ascertain whether the prepared GO-Gd-DTPA
complex can be stably used as an MRI contrast agent, the
dispersibility thereof was measured. The GO-Gd-DTPA complex was
dispersed in deionized (DI) water, and then observed for 24 hours.
When the concentration of the GO-Gd-DTPA complex in DI water was 5
mg/mL, it was ascertained that particles settling down to the
bottom were observed. Further, when the concentration thereof was 2
mg/mL, it was ascertained that particles settling down to the
bottom were not observed. Furthermore, when the concentration
thereof was 1 mg/mL, it was ascertained that the GO-Gd-DTPA complex
was stably dispersed in deionized (DI) water due to the fact that
crystals were not formed and its transparency was increased. The
concentration of a conventional gadolinium complex, in which
gadolinium is bonded with CNT (carbon nanotubes) in DI water to
inject gadolinium into the body, was 1.2 mg/mL. Therefore,
comparing the GO-Gd-DTPA complex of the present invention with the
conventional gadolinium complex, it can be ascertained that the
GO-Gd-DTPA complex of the present invention was stably dispersed in
an aqueous solution compared to the conventional gadolinium
complex.
[0034] As described above, since the GO-Gd-DTPA complex of the
present invention can stably exist in the body because it has low
toxicity and high dispersibility compared to a conventional
gadolinium complex, it is expected that this GO-Gd-DTPA complex can
be effectively used as an MRI contrast agent. Further, since the
GO-Gd-DTPA complex of the present invention can be easily produced
in a short period of time and oxide graphene can be produced in
large quantities in an environment-friendly method, it is expected
that this GO-Gd-DTPA complex can be used to produce an inexpensive
MRI contrast agent in large quantities.
[0035] Although the preferred embodiments of the present invention
have been disclosed for illustrative purposes, those skilled in the
art will appreciate that various modifications, additions and
substitutions are possible, without departing from the scope and
spirit of the invention as disclosed in the accompanying
claims.
* * * * *