CN111514317A - Lymphatic system bimodal imaging contrast agent - Google Patents

Lymphatic system bimodal imaging contrast agent Download PDF

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Publication number
CN111514317A
CN111514317A CN202010330903.1A CN202010330903A CN111514317A CN 111514317 A CN111514317 A CN 111514317A CN 202010330903 A CN202010330903 A CN 202010330903A CN 111514317 A CN111514317 A CN 111514317A
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contrast agent
lymphatic system
solution
poloxamer
bimodal imaging
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CN111514317B (en
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赵应征
鲁翠涛
陈斌
杨运俊
姚情
徐荷林
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First Affiliated Hospital of Wenzhou Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • 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
    • A61K49/14—Peptides, e.g. proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres

Abstract

The invention provides a lymphatic system bimodal imaging contrast agent, which is an emulsion composed of poloxamer, aminopolyglycol phospholipid and citric acid, contains albumin microbubbles and superparamagnetic iron oxide protein nanoparticles, and is used as a lymphatic system bimodal contrast agent for ultrasonic imaging and nuclear magnetic resonance imaging. The lymphatic system bimodal imaging contrast agent overcomes the bottleneck of single radiography of the prior lymphatic system, has good stability, good tropism of the lymphatic system and high safety, adopts an indirect injection method to give, and realizes the advantage complementation of ultrasonic and nuclear magnetic resonance bimodal imaging.

Description

Lymphatic system bimodal imaging contrast agent
Technical Field
The invention relates to a contrast agent for a lymphatic system, in particular to a bimodal contrast agent for ultrasound imaging and nuclear magnetic resonance imaging of the lymphatic system.
Background
The lymphatic system is a complex network composed of lymphatic vessels, lymph nodes, and lymphoid organs. It has very important function for maintaining the balance of body fluid and body immunity. There are two main methods for in vivo visualization of lymphatic vessels, one is the direct injection method, which mainly includes lymphangiography (lymphangiography). The second method is indirect injection. The imaging of the lymphatic system has been reported mainly as follows.
(1) Lymphangiography
Lymphangiography is imaging by direct injection of Iodine Contrast Agent (ICA) into lymphatic vessels. Because of the special structure and function of lymphatic vessels, the iodine contrast agent must be accumulated in sufficient quantity in the lymphatic vessels to be observed, and the iodine contrast agent has long residence time in vivo, so that the lymphangiography cannot be repeated during long-term follow-up. In view of the invasiveness of this procedure and the difficulty of catheter manipulation, there are many, albeit rare, fatal complications, such as contrast-induced nephropathy, and lymphatic angiography is currently in less and less use.
(2) Lymph node imaging
Lymphography is an indirect injection method, where a contrast agent or reactive dye is injected into the interstitial space and then drained into the lymphatic vessels. Different imaging modalities determine different imaging techniques, some require percutaneous imaging, some require tissue dissection and stereotactic navigation, and some require X-ray for real-time imaging. The indirect lymph development operation is relatively simple and convenient, and adverse reaction caused by direct injection of an iodine contrast agent is avoided.
(3) Scintigraphy of lymphatic system
Lymphatic scintigraphy is the most common indirect lymphatic imaging technique. The mechanism is that after the radioactive nuclide is introduced, the radioactive nuclide is detected by an external radioactive probe. The most commonly used radionuclide is 99mTc, which has a relatively modest half-life (6h), emits mostly relatively low doses of photons, and usually uses two-dimensional (2D) modalities to observe lymphatic system structure and function. Compared with lymphangiography, the way of lymphatic system scintillation development and developer absorption is more consistent with physiological process, cannot directly cause lymphatic vessel damage, is easy to repeat, and has higher sensitivity. The scintigraphic imaging method also has a number of drawbacks: (1) the colloid and dye need to be injected separately because they have different transfer rates. (2) The sensitivity and spatial resolution of scintigraphy are low and the location of the lymphatic vessels and lymph nodes cannot be well identified. (3) The high background level of radioactivity can obscure localization, making the surgical procedure of radioactive navigation challenging. (4) The detection of lymph nodes ex vivo often requires manual navigation of the radiation detector, which inevitably involves radiation exposure, and special regulations to deal with radioactive waste.
(4) CT and MRI contrast
Imaging techniques such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are increasingly accepted by the general public because they are less invasive and have a shorter examination time. However, images of CT and MRI are viewed for anatomical features rather than functional and physiological properties.
(5) Ultrasound and ultrasound imaging
Conventional ultrasound is a non-invasive technique, and can accurately measure the diameter of lymph nodes through multi-plane and multi-angle imaging, and the accuracy and specificity of diagnosis are usually about 85% and 88%. The ultrasonic operation is simple, convenient and economical, the ultrasonic radiography shows the superiority of detecting lymph nodes, but the efficiency of detecting mediastinal, retroperitoneal and pelvic deep lymph nodes is low compared with CT or MRI because of the self-limitation.
Lymphography is mainly used to reflect lymphatic lesions, and single imaging has its disadvantages and problems. The ideal lymphatic system radiography should complement the advantages of different developing technologies to realize accurate judgment of lymphatic system diseases. Therefore, it is highly desirable to develop a multifunctional contrast agent that satisfies the needs of multimodal imaging of the lymphatic system and satisfies the following requirements:
(1) the compliance of patients is good, and the use is simple and quick.
(2) Has good safety and no influence on digestive tract mucosa.
(3) The nano-particles are uniformly dispersed without agglomeration, have good adhesiveness, realize natural filling and continuous filling, and keep the retentivity and the fluid property in ultrasonic and nuclear magnetic resonance bimodal imaging.
(4) One examination has the effect of multiple examinations, and the entire digestive tract is observed at one time.
At present, an ideal multifunctional contrast agent which meets the requirements at the same time is not seen, so that a novel safe and efficient multifunctional contrast agent for a lymphatic system is urgently needed to be developed.
Disclosure of Invention
In order to overcome the bottleneck of the lack of safe and efficient multifunctional contrast agents for the lymphatic system, the invention aims to provide a contrast agent for bimodal imaging of the lymphatic system.
Through a large number of experimental researches, the inventor creatively and organically combines two imaging techniques which are high in safety and have complementary action to prepare the bimodal contrast agent for ultrasound imaging and nuclear magnetic resonance imaging of a lymphatic system. The invention relates to a bimodal imaging contrast agent for a lymphatic system, which is an emulsion composed of poloxamer, aminopolyglycol phospholipid and citric acid, contains albumin microbubbles and superparamagnetic iron oxide fibrin nanoparticles, and is used as a bimodal contrast agent for lymphatic system ultrasonic imaging and nuclear magnetic resonance imaging.
In the emulsion composed of the poloxamer and the aminopolyethylene glycol phospholipid, the mass ratio of the poloxamer, the aminopolyethylene glycol phospholipid and the citric acid is 80-250: 10: 0.5-2, and the optimal mass ratio of the poloxamer, the aminopolyethylene glycol phospholipid and the citric acid is 150: 10: 1.
The poloxamer includes poloxamer with product type P124, P188, P237, P337, and P407 and modified or modified derivatives thereof, preferably poloxamer with product type P337.
The above aminopolyethylene glycol phospholipid has a molecular weight of 1K to 20K, and the preferred aminopolyethylene glycol phospholipid has a molecular weight of 4K.
The albumin microbubbles are vesicles formed from albumin as a membrane material containing a gas, and have a diameter of 2 to 5 μm, preferably 3 μm.
The concentration of the albumin microbubbles in the contrast medium is 1 × 105～1×108Preferred albumin microbubbles are at a concentration of 1 × 10 in contrast medium/mL7～5×107one/mL.
The superparamagnetic iron oxide silk fibroin nanoparticle is a particle with the diameter of 50-500 nm, and is coated with albumin as a material, preferably the superparamagnetic iron oxide silk fibroin nanoparticle has the diameter of 120-200 nm, and most preferably the superparamagnetic iron oxide nanoparticle has the diameter of 160 nm.
The contrast agent is further added with auxiliary emulsifying agent, stabilizing agent, antioxidant and pH regulator which are well known in the pharmaceutical field.
The preparation method of the lymphatic system bimodal imaging contrast agent comprises the following steps:
(1) dissolving aminopolyethylene glycol phospholipid in 2 times of ethanol, adding, and uniformly mixing to form a solution A;
(2) dissolving citric acid and poloxamer in 5 times of water by mass to form a solution B;
(3) adding the solution A into the solution B, stirring and mixing uniformly, volatilizing ethanol, adding superparamagnetic iron oxide fibroin nanoparticles, mixing uniformly, adding albumin microbubbles before use, and mixing uniformly to obtain the lymphatic system bimodal imaging contrast agent.
Another method for preparing the above-mentioned lymphatic system bimodal imaging contrast agent comprises the following steps:
(1) melting aminopolyethylene glycol phospholipid at 60 deg.C to obtain solution A;
(2) dissolving citric acid and poloxamer in 5 times of water by mass to form a solution B;
(3) and adding the solution A into the solution B, stirring, dispersing, uniformly mixing, adding superparamagnetic iron oxide fibroin nanoparticles, uniformly mixing, adding albumin microbubbles before use, and uniformly mixing to obtain the lymphatic system bimodal imaging contrast agent.
In the preparation method, a co-emulsifier, a stabilizer, an antioxidant and a pH regulator which are well known in the pharmaceutical field are further added into the solution A or the solution B.
The lymphatic system bimodal imaging contrast agent overcomes the bottleneck of the single radiography of the prior lymphatic system, and has the following advantages: (1) the contrast agent has good stability, is suitable for long-term storage and is simple and convenient to apply; (2) the tropism of the lymphatic system is good, the safety is high, and no side effect exists; (3) the dispersion is uniform, the agglomeration is avoided, the fluidity is moderate, the persistence is good, and the stability of ultrasonic and nuclear magnetic resonance bimodal imaging of a lymphatic system is ensured; (4) the administration is not direct injection, so the injury is small; (5) the ultrasonic and nuclear magnetic resonance bimodal imaging realizes advantage complementation, and ensures clear display of physiological structures and pathological structures.
The lymphatic system bimodal imaging contrast agent is an organic whole, and all components generate complementary advantages through mutual synergistic action, so that guarantee is provided for ultrasonic and nuclear magnetic resonance bimodal imaging.
Detailed Description
Hereinafter, specific embodiments of the present invention will be described in detail. It should be noted that technical features or combinations of technical features described in the following embodiments should not be considered as being isolated, and they may be combined with each other to achieve better technical effects.
EXAMPLE 1 preparation of a contrast agent for bimodal imaging of the lymphatic System
Preparation of contrast agent for experimental group: the components were measured according to the composition of the experimental groups of table 1 and the lymphatic system bimodal imaging contrast agent was prepared according to the following procedure.
The preparation method A comprises the following steps:
(1) dissolving aminopolyethylene glycol phospholipid in 2 times of ethanol, adding, and uniformly mixing to form a solution A;
(2) dissolving citric acid and poloxamer in 5 times of water by mass to form a solution B;
(3) adding the solution A into the solution B, stirring and mixing uniformly, volatilizing ethanol, adding superparamagnetic iron oxide fibroin nanoparticles, mixing uniformly, adding albumin microbubbles before use, and mixing uniformly to obtain the lymphatic system bimodal imaging contrast agent.
The preparation method B comprises the following steps:
(1) melting aminopolyethylene glycol phospholipid at 60 deg.C to obtain solution A;
(2) dissolving citric acid and poloxamer in 5 times of water by mass to form a solution B;
(3) and adding the solution A into the solution B, stirring, dispersing, uniformly mixing, adding superparamagnetic iron oxide fibroin nanoparticles, uniformly mixing, adding albumin microbubbles before use, and uniformly mixing to obtain the lymphatic system bimodal imaging contrast agent.
Preparation of contrast agent for control group: prepared according to the composition of the control group in table 1, referring to the experimental group method.
TABLE 1 composition of lymphatic system bimodal imaging contrast agents for experimental and control groups
Figure BSA0000207204510000051
Figure BSA0000207204510000061
Note: "" indicates that the component is replaced by a new component; "/" indicates that the component is missing.
EXAMPLE 2 evaluation of the Effect of the use of a contrast agent for bimodal imaging of the lymphatic System
(1) Establishing rabbit lymph node inflammatory hyperplasia model
New Zealand white rabbits, 3% sodium pentobarbital per animal were anesthetized by intravenous injection and fixed in supine position. The dorsum of the hind limb and the foot on the left side of the patient are shaved and carefully disinfected by alcohol, 1.0mL of skin test injection needles are respectively used for puncturing along webs at 1, 2 and 3 toes, 0.5mL of Freund's complete adjuvant (5mg/mL) is injected, and after two weeks, the popliteal lymph node with the size of about 2cm can be touched.
(2) In vivo observation with bimodal imaging contrast agents
Each animal was anesthetized with 3% sodium pentobarbital by intravenous injection, the dorsal position of the hind limb was fixed to the backs of the hind limbs on both sides of the animal and carefully disinfected with alcohol, 1.0mL of a skin test injection needle was used to puncture along the webs of 1, 2 and 3 digits, respectively, with the depth of puncture being in the skin and 1mL of a bimodal imaging contrast agent injected into the lymphatic system. Subsequently, the injection site was uniformly massaged for 30 seconds to promote lymphatic return. Then, ultrasonic and MRI imaging observation is carried out, and the set parameters of each group of animals are kept consistent. Multiple groups of normal animals were used simultaneously for the same imaging contrast as the control animal group.
(3) Biopsy of lymph node tissue
0.3ml of methylene blue injection is injected into each toe of the left foot of each animal, and the injection part is massaged, so that lymphatic vessels and lymph nodes in drainage areas are stained, and the observation is convenient. After all animals die through deep anesthesia, the drainage area popliteal fossa, inguinal, iliac fossa and posterior peritoneal lymph node dyed blue are exposed, respectively taken out and then placed into 10% formalin solution for fixation, and after paraffin embedding, tissue section observation is carried out.
(4) Image contrast analysis
The imaging results of ultrasonic and MRI imaging of the left foot and the right foot of each animal are evaluated by adopting a double-blind method, the biopsy results of lymph node tissues are used for verification, the stability, the imaging quality and the resolution of a lymph system bimodal imaging contrast agent, the detection accuracy rate of inflammatory lymph node swelling and the like are comprehensively evaluated, and the higher the score is, the better the application effect of ultrasonic and nuclear magnetic resonance bimodal imaging is. The results of the bimodal imaging contrast agent scoring for each set are shown in table 2.
TABLE 2 Effect of bimodal imaging contrast agent application in Experimental and control groups
Figure BSA0000207204510000071
Figure BSA0000207204510000081
As can be seen from the score of the bimodal imaging contrast agent of the lymphatic system shown in Table 2, the bimodal imaging contrast agent of each experimental group has good detection accuracy for the inflammatory lymph node swelling condition of rabbits, high preparation stability, good filling property of inflammatory lymph node parts, and good image definition of ultrasonic imaging and nuclear magnetic resonance imaging, and particularly has the best effect in experimental groups 9 and 10. In contrast, the contrast bimodal imaging contrast agent is obviously inferior to the experimental group in the detection accuracy of inflammatory lymph node swelling conditions of rabbits, and the problems of poor stability, poor filling property of inflammatory lymph node parts, and missing or poor definition of ultrasonic imaging and nuclear magnetic resonance imaging of a plurality of groups of preparations, particularly the control groups 4, 5, 6, 10 and 15 prove that the component compositions of the contrast agent in the experimental group are mutually synergistic and irreplaceable.
The above detailed description is specific to possible embodiments of the invention, and the embodiments are not intended to limit the scope of the invention, and all equivalent implementations or modifications that do not depart from the scope of the invention should be construed as being included within the scope of the invention.
In addition, various modifications, additions and substitutions in other forms and details may occur to those skilled in the art within the scope and spirit of the invention as disclosed in the claims. It is understood that various modifications, additions, substitutions and the like can be made without departing from the spirit of the invention as disclosed in the accompanying claims.

Claims (11)

1. A lymphatic system bimodal imaging contrast agent characterized by: the contrast agent is an emulsion composed of poloxamer, aminopolyethylene glycol phospholipid and citric acid, contains albumin microbubbles and superparamagnetic iron oxide protein nanoparticles, and is used as a bimodal contrast agent for lymphatic system ultrasonic imaging and nuclear magnetic resonance imaging.
2. A lymphatic system bimodal imaging contrast agent according to claim 1, characterized in that: in the emulsion composed of the poloxamer and the aminopolyethylene glycol phospholipid, the mass ratio of the poloxamer, the aminopolyethylene glycol phospholipid and the citric acid is 80-250: 10: 0.5-2, and the optimal mass ratio of the poloxamer, the aminopolyethylene glycol phospholipid and the citric acid is 150: 10: 1.
3. A lymphatic system bimodal imaging contrast agent according to claim 1, characterized in that: the poloxamer comprises poloxamer with product model numbers of P124, P188, P237, P337 and P407 and modified or modified derivatives thereof, and preferably poloxamer with product model number of P337.
4. A lymphatic system bimodal imaging contrast agent according to claim 1, characterized in that: the molecular weight of the amino polyethylene glycol phospholipid is 1K-20K, and the preferred molecular weight of the amino polyethylene glycol phospholipid is 4K.
5. A lymphatic system bimodal imaging contrast agent according to claim 1, characterized in that: the albumin microbubbles are vesicles formed by albumin which is taken as a membrane material and contains gas, the diameter of the albumin microbubbles is 2-5 μm, and the preferred diameter of the albumin microbubbles is 3 μm.
6. The bimodal imaging contrast agent for lymphatic system according to claim 1, wherein said albumin microbubbles have a concentration of 1 × 10 in contrast agent5～1×108Preferred albumin microbubbles are at a concentration of 1 × 10 in contrast medium/mL7～5×107one/mL.
7. A lymphatic system bimodal imaging contrast agent according to claim 1, characterized in that: the superparamagnetic iron oxide silk fibroin nanoparticle is a particle with the diameter of 50-500 nm, and is coated with albumin as a material, preferably 120-200 nm, and most preferably 160 nm.
8. A lymphatic system bimodal imaging contrast agent according to claim 1, characterized in that: the contrast agent is further added with auxiliary emulsifying agent, stabilizing agent, antioxidant and pH regulator which are well known in the pharmaceutical field.
9. A method of preparing a lymphatic system bimodal imaging contrast agent according to any of claims 1 to 8, characterized in that: the preparation method of the contrast agent comprises the following steps:
(1) dissolving aminopolyethylene glycol phospholipid in 2 times of ethanol, adding, and uniformly mixing to form a solution A;
(2) dissolving citric acid and poloxamer in 5 times of water by mass to form a solution B;
(3) adding the solution A into the solution B, stirring and mixing uniformly, volatilizing ethanol, adding superparamagnetic iron oxide fibroin nanoparticles, mixing uniformly, adding albumin microbubbles before use, and mixing uniformly to obtain the lymphatic system bimodal imaging contrast agent.
10. A method of preparing a lymphatic system bimodal imaging contrast agent according to any of claims 1 to 8, characterized in that: the preparation method of the contrast agent comprises the following steps:
(1) melting aminopolyethylene glycol phospholipid at 60 deg.C to obtain solution A;
(2) dissolving citric acid and poloxamer in 5 times of water by mass to form a solution B;
(3) and adding the solution A into the solution B, stirring, dispersing, uniformly mixing, adding superparamagnetic iron oxide fibroin nanoparticles, uniformly mixing, adding albumin microbubbles before use, and uniformly mixing to obtain the lymphatic system bimodal imaging contrast agent.
11. The method for preparing a contrast agent according to claim 9 to 10, wherein: and a co-emulsifier, a stabilizer, an antioxidant and a pH regulator which are well known in the pharmaceutical field are further added into the solution A or the solution B.
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