WO2018137633A1

WO2018137633A1 - Liquid embolic material and preparation method therefor

Info

Publication number: WO2018137633A1
Application number: PCT/CN2018/073903
Authority: WO
Inventors: 刘奕辰; 邱海平; 向建平
Original assignee: 珠海神平医疗科技有限公司
Priority date: 2017-01-24
Filing date: 2018-01-24
Publication date: 2018-08-02
Also published as: CN108079366A

Abstract

Disclosed are a liquid embolic material and a preparation method therefor and the use thereof. The liquid embolic material comprises nanocomposite particles (1) and a dispersant, wherein the nanocomposite particles are made of Fe3O4 nanoparticles (11) wrapped in agarose as a core, and an EVOH polymer (12) wrapped around the surface of the core; the weight ratio of the agarose and the Fe3O4 nanoparticles is 5:1 to 10:1; the weight ratio of the Fe3O4 nanoparticles (11) wrapped in agarose to the EVOH polymer (12) is 25:2 to 25:5; and the nanocomposite particles are dispersed in the dispersant. Also disclosed is a method for preparing the liquid embolic material. Using the superparamagnetic effect of the Fe3O4 nanoparticles, under the guidance of an external magnetic field, through targeting localization, the liquid embolic material can fully embolize a complex microvascular aneurysm and complex vascular malformations where it is difficult for a microcatheter to be completely in place.

Description

Liquid embolic material and preparation method thereof

The present application claims priority to Chinese Patent Application No. CN201710059181.9, filed on Jan. 24, 2017. This application cites the entire text of the above-mentioned Chinese patent application.

Technical field

The invention relates to a liquid embolic material and a preparation method thereof.

Background technique

Arteriovenous malformation (AVM) is a genetic variation in the congenital local cerebral blood vessels. There is a lack of capillaries between the cerebral artery and the cerebral vein in the lesion, causing the arteries and veins to communicate directly, forming a short circuit between the arteries and veins, resulting in a series of cerebral hemodynamic disorders. Clinically, acute brain and arteriovenous may cause intracranial hemorrhage, which is also the second leading cause of spontaneous subarachnoid hemorrhage in the brain. Hemangiomas are formed in arteriovenous vessels due to internal and external factors such as mechanical damage, vascular sclerosis, hypertension, proliferation of vascular smooth muscle cells, bacterial or viral infection, induction of venous valve disease, or blood flow impact. Cerebral aneurysms are the leading cause of subarachnoid hemorrhage, leading to stroke in patients. The incidence of cerebral arteriovenous malformation is about 1/7 to 1/4 of that of cerebral aneurysms, twice as many as males, and the peak age is 20 to 39 years old. The average age is 25 years old. The deficiency of cerebral arteriovenous malformation in patients over 60 years old 5%. The mortality caused by rupture of cerebral aneurysms is above 50%. Therefore, embolization or occlusion at the earliest stage of the occurrence of cerebral aneurysms is one of the best cures.

Treatment of cerebral aneurysms and AVM can be treated with surgery and intervention. Surgical treatment of aneurysms mainly uses an aneurysm clip to clamp the aneurysm neck, thereby blocking the circulation of blood in the aneurysm. The AVM can perform a total resection of the surgery. However, this method of surgery takes a long time, the wound is large, the patient needs to recover for a long time, and the surgical treatment method may cause damage of the aneurysm and AVM. In recent years, with the development of vascular imaging, the use of surgical methods, through the delivery of various embolic materials into the cerebral aneurysm and AVM to block, embolization has gradually replaced the traditional surgery.

A variety of embolic materials have been disclosed, mainly divided into solid embolic materials and liquid embolic materials. The solid material is mainly a platinum coil. However, the method of using a platinum coil has a low embolic rate, is prone to recurrence, and may even form a wide range of thrombus and cause problems such as cerebral infarction. The liquid embolic material can be directly injected into the aneurysm cavity or into the AVM to adapt to different shapes and sizes, so that no gap is left between the tumor wall and the embedding material, thereby achieving permanent occlusion. At the same time, the liquid embolic material has the advantage of being easy to operate, and can be directly injected into the aneurysm cavity or the AVM through the microcatheter, so the liquid embolic material is an ideal embolic material. The prior art liquid embolic material comprises: (1) an adhesive liquid embolic material n-butyl cyanoacrylate viscous material, which has the disadvantage that "sticky tube" is prone to occur; (2) non-adhesive liquid embolic material, mainly Onyx gel, a suspension composed of EVOH, DMSO (dimethyl sulfoxide) and strontium powder particles in a certain proportion, is a novel intravascular non-adhesive liquid embolic agent, etc., and its disadvantages include the properties of the onyx gel itself. It does not bind closely to the diseased vessel wall. And both types of materials are not well embolized for microvascular aneurysms and vascular malformations that are difficult to fully fit in complex microcatheters.

The embolic material in CN103536972B is selected from ethylene vinyl polymer copolymer (EVOH), which has the disadvantage that the release process of the embolic material is uncontrollable. CN106535942A discloses a homogeneous nanocomposite cluster suspended in a liquid medium having a size of from about 1 nm to about 1000 nm, the nanocomposite comprising core nanoparticles and a coating, the core nanoparticles being superparamagnetically oxidized Iron (SPIO) nanoparticles, the coating is a silanized coating, which has the disadvantage that the suspension has a short settling time, resulting in a shorter operating time window. The prior art CN103483626B also discloses a magnetic agarose microsphere which uses superparamagnetic Fe ₃ O ₄ as the core of the magnetic core, and then fills the magnetic core into the agarose microsphere to obtain magnetic agarose microspheres, magnetic agar. The sugar microspheres have good biocompatibility, and the disadvantage is that the agarose is easily decomposed in the human blood environment, resulting in the release of iron ions and causing ectopic embolization.

Summary of the invention

In view of the prior art, the liquid embolic material is easy to stick or is not well adhered to the diseased blood vessel wall, so that the microvascular aneurysm and the vascular malformation which are difficult to fully embed in the complicated microcatheter are not well embedd. The invention provides a liquid embolic material and a preparation method thereof, which can embolize microvascular aneurysms and vascular malformations.

In order to solve the above technical problems, one of the technical solutions adopted by the present invention is a liquid embolic material comprising nano composite particles and a dispersing agent, wherein the nano composite particles are agarose-coated Fe ₃ O ₄ nanoparticles as a core. The EVOH polymer is coated on the surface of the core to form a shell; the weight ratio of the agarose to the Fe ₃ O ₄ nanoparticles is 5:1 to 10:1; the agarose-coated Fe ₃ O ₄ nanoparticles and the The weight ratio of the EVOH polymer is from 25:2 to 25:5; the nanocomposite particles are dispersed in the dispersant.

Preferably, the agarose-coated Fe ₃ O ₄ nanoparticles have a diameter of 100 to 1000 nm; the nanocomposite particles have a viscosity of 30 to 1000 cps; and the polydispersity index of the Fe ₃ O ₄ nanoparticles (PDI) ≤ 1.2; and/or the dispersing agent is dimethyl sulfoxide.

More preferably, the weight ratio of the agarose to the Fe ₃ O ₄ nanoparticles is 10:1; and/or the weight of the agarose-coated Fe ₃ O ₄ nanoparticles and the EVOH polymer The ratio is 10:1.

Even more preferably, the agarose-coated Fe ₃ O ₄ nanoparticles have a diameter of 300 nm; the nanocomposite particles have a viscosity of 100 cps; and/or the PDI is 1.12.

Unless defined otherwise, all technical terms and technologies used herein have the same meaning as commonly understood by one of ordinary skill in the art.

This selection is Fe ₃ O ₄ magnetic substance, it should be understood that the magnetic substance or a magnetic metallic element may be selected from compounds such as _{_{_{Fe 2 O 3, MnFe 2 O}}} 4, CoFe 2 O 4, NiFe 2 O 4, FyFe ₂ O ₄ or one or more of oxides of ruthenium, osmium, iridium, osmium, iridium, osmium or iridium.

"Arteriovenous malformation", "AVM" or "vascular malformation" refers to a group of diseases in which at least one abnormal communication occurs in an artery or vein, resulting in a local tumor-like substance consisting mainly of blood vessels, which may be congenital or acquired. Sexual.

"Formation of an embolic body" refers to the partial or total occlusion of blood vessels that are filled with blood, such as by selective insertion of an embolic material into a blood vessel to selectively occlude a blood vessel. For example, an embolization is formed to occlude an artery or vein to correct a dysfunction such as an arteriovenous malformation or to block or slow the flow of blood to a solid tumor.

"Injection" refers to the injection or infusion of a liquid embolic material into a particular location in the body by a syringe, catheter, needle or other means. "Treatment" refers to reducing or ameliorating the development, severity, and/or duration of a disease or condition thereof.

The liquid embolic material used herein can be any shape, and in embodiments, the liquid embolic material is substantially spherical or spherical. However, it should be understood that in certain embodiments, the liquid embolic material described herein is not limited to a precise spherical or spheroidal shape. The liquid embolic material can be sterilized by any method known in the art, such as X-ray, gamma ray irradiation or beta ray irradiation.

In order to solve the above technical problem, one of the technical solutions adopted by the present invention is a method for preparing the above liquid embolic material, which comprises the following steps in sequence:

(1) Preparation of agarose encapsulated Fe ₃ O ₄ nanoparticles;

(2) preparing nano composite particles, wherein the nano composite particles are further composed of EVOH and further coated with agarose-coated Fe ₃ O ₄ nanoparticles;

(3) Dispersing the nanocomposite particles in a dispersing agent.

Preferably, the step (1) further comprises:

(11) The ethylene glycol solution of FeCl _3, agarose and NH4Ac mixing said FeCl _3, agarose, and NH ₄ Ac weight ratio of 10: 1: 5; Preferably, the mixing is from 2 to Stir at 200 to 300 rpm for at least one hour under 3kw ultrasonic conditions;

(12) The reaction is carried out at a temperature of 2 to 3 atm and 200 ° C, and after the reaction, it is cooled to obtain a black product; preferably, the reaction is carried out in a polytetrafluoroethylene autoclave.

More preferably, said step (1) further comprises: washing said black product and drying to obtain a black powder. Preferably, the washing is alternately washed with ethanol and water for 2 to 5 times; and/or, the drying is vacuum drying.

Preferably, said step (2) comprises:

(21) mixing the black powder and the EVOH polymer into a dimethyl sulfoxide solvent; preferably, the mixing is carried out in ultrasound;

(22) After stirring, nanocomposite particles dispersed in the dimethyl sulfoxide are obtained.

More preferably, the agitation is mechanical agitation, the mechanical agitation time is at least 2 hours; and/or the agitation speed is 400 to 500 rpm. Preferably, the agitation speed is 450 rpm.

In order to solve the above technical problems, one of the technical solutions adopted by the present invention is the application of a liquid embolic material in preparing a drug or molecular imaging reagent for diagnosing and treating tumor or vascular malformation.

Based on the common knowledge in the art, the above various preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progressive effect of the present invention is that the liquid embolic material of the present invention is injected into the aneurysm cavity or the arteriovenous vascular malformation, and after being guided to a specific site by the magnetic device, the nanocomposite particles are precipitated from the dimethyl sulfoxide solvent into the blood. Thereby forming a plug body. The core-shell structure in the liquid embolic material greatly increases the density of the embolic body, thereby increasing the development efficiency and making the embolization more dense. By utilizing the superparamagnetic effect of the Fe ₃ O ₄ nanoparticles, the liquid embolic material can be targeted by the external magnetic field, and the complex microvascular artery which is difficult to fully fit the microcatheter is well embedd. Tumors and complex vascular malformations.

DRAWINGS

1 is a schematic view showing the structure of a nanocomposite particle according to an embodiment of the present invention, wherein 1 is a nanocomposite particle, 11 is agarose-coated Fe ₃ O ₄ nanoparticle, and shell 12 is an EVOH polymer.

2 is a flow chart showing the preparation of agarose-coated Fe ₃ O ₄ nanoparticles according to Example 1 of the present invention.

Figure 3 is a flow chart showing the preparation of the liquid embolic material of Example 2 of the present invention.

4 is a schematic view showing the operation of embedding a liquid embolic material in an AVM according to Embodiment 2 of the present invention, wherein 100 is a plug material, 110 is a microcatheter, and 120 is an external magnetic field.

Figure 5 is a flow chart showing the preparation of a liquid embolic material according to Embodiment 3 of the present invention.

6 is a schematic view showing the operation of embolization of a liquid embolization material in a cerebral aneurysm according to Embodiment 3 of the present invention, wherein 200 is an embolic material, 210 is a microcatheter, 220 is an external magnetic field, 230 is a blood vessel, and 240 is a brain aneurysm.

detailed description

The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

The liquid embedding material provided by the invention comprises agarose-coated Fe ₃ O ₄ nanoparticles, an ethylene/vinyl alcohol copolymer (EVOH) polymer and a dispersing agent, and the EVOH polymer is wrapped in agarose-coated Fe. The surface of the ₃ O ₄ nanoparticles forms nanocomposite particles. The nanocomposite particles are agarose-coated Fe ₃ O ₄ nanoparticles as the core and the EVOH polymer as the shell, and the nanocomposite particles are dispersed in the dispersant. Dimethyl sulfoxide can be used as a dispersing agent.

Referring to Fig. 1, Fig. 1 is a schematic view showing the structure of a nanocomposite particle 1 comprising a core 11 and a shell 12, wherein the core 11 is composed of agarose-coated Fe ₃ O ₄ nanoparticles, and the shell 12 is composed of an EVOH polymer.

Example 1 Preparation of agarose-coated Fe ₃ O ₄ nanoparticles

Referring to Figure 2, Figure 2 is a flow chart for the preparation of agarose-coated Fe ₃ O ₄ nanoparticles. First, step S1 is performed, 400 g of FeCl ₃ ·6H ₂ O is dissolved in a glass reaction bottle containing 2 L of ethylene glycol under ultrasonic conditions; then, step S2 is performed, and 40 g is added thereto at a temperature of 160 ° C. Agarose and 200 g of NH ₄ Ac were mechanically stirred at 250 rpm for 1 hour to obtain a mixed solution; then, step S3 was performed, and the mixed solution was transferred to an autoclave containing polytetrafluoroethylene; step S4 was further performed at 2 atm to 3atm (standard atmospheric pressure), reaction at 200 ° C for 12 hours; after the reaction, cooled to room temperature to obtain a black product; then step S5 is performed, the black product is repeatedly and alternately washed with ethanol and water several times, and then collected by a magnetic field. Black product; finally, step S6 is performed, and the collected black product is dried in a vacuum for 24 hours to obtain a black powder composed of agarose-coated Fe ₃ O ₄ nanoparticles, agarose-coated Fe ₃ O ₄ nanometer. The particle diameter of the particles ranges from 100 nanometers to 1000 nanometers. The PDI is made less than 1.2 by the above conventional control and preparation processes in the art such as temperature, time and stirring uniformity.

Example 2 EVOH-coated agarose Fe ₃ O ₄ nanoparticles (weight ratio 25:2)

1. Preparation: Referring to Figure 3, Figure 3 is a flow chart for the preparation of a liquid embolic material. First, step S11 is performed, 100 g of the black powder of Example 1 and 8 g of the EVOH polymer are dispersed in 100 ml of dimethyl sulfoxide solvent under ultrasonic conditions; then, step S12 is performed, and mechanical stirring is performed at 500 rpm for 2 hours. A liquid embolic material is obtained, which contains a large amount of nanocomposite particles in which agarose-coated Fe ₃ O ₄ nanoparticles are cores and EVOH polymers are shells. The agarose-coated Fe ₃ O ₄ nanoparticles have a diameter of 100 nm, and the liquid embolic material has a low viscosity and a viscosity value of about 30 centipoise. PDI is measured by proton nuclear magnetic resonance combined with laser particle size analyzer. The calculation formula is PDI=M _w /M _n , and the PDI in the preparation method is 1.09.

2. In vitro experimental data:

Embolization density: 1.5-2.0g/ml, data fluctuations are due to changes in formulation and batch;

Embolization time: 60 to 90 seconds;

Diffuse (permeability): Simulates the use of embolic material in the clinic, testing the ratio of forward and backward reflux in a small vessel model filled with a small sphere of 500 micrometers in diameter. This product is 5 times the safety limit distance of reflux, and the existing clinical embedding material, namely EVOH-coated Ta nanoparticles, is 2.3 times the safety limit distance of reflux.

Backflow rate: almost no reflux, and the empirical value of existing material reflux is 20%-50%.

3. Effect: Referring to Fig. 4, Fig. 4 is a working principle diagram of embedding of the liquid embolic material in the AVM of the present embodiment. The experimental means used in the evaluation of the effect is a conventional technique in the art. In the present embodiment, after the liquid embolic material 100 is injected into the arterial blood vessel of the AVM 100 through the microcatheter 110, the liquid embolic material 100 has a low viscosity and a strong penetrating ability, and is externally Under the guidance of the magnetic field 120, it is easily dispersed to the distal end by targeted positioning, and the nanocomposite particles are precipitated from the dimethyl sulfoxide solvent in the blood to form an embolic body, which is well embolized.

Example ₃ EVOH-coated agarose Fe ₃ O ₄ nanoparticles (weight ratio 25:5)

The agarose-coated Fe ₃ O ₄ nanoparticles were prepared in the same manner as in Example 1 except that 80 g of agarose was added to the reaction.

1. Preparation: Referring to Fig. 5, Fig. 5 is a flow chart for preparing a liquid embolic material of the present embodiment. First, step S21 is performed, 100 g of the obtained black powder and 20 g of the EVOH polymer are dispersed in 100 ml of dimethyl sulfoxide solvent under ultrasonic conditions; then, step S22 is performed, and mechanical stirring is performed at 400 rpm for 2 hours to obtain a liquid. The embolic material contains a large amount of nano-composite particles in which agarose-coated Fe ₃ O ₄ nanoparticles are cores and EVOH polymers are shells. The agarose-coated Fe ₃ O ₄ nanoparticles have a diameter of 1000 nm. The liquid embolic material has a high viscosity, a viscosity of 1000 centipoise and a PDI of 1.18.

2. Working principle: Referring to Fig. 6, Fig. 6 is a working principle diagram of embolization of the liquid embolic material in the cerebral aneurysm of the present embodiment. In the present embodiment, the liquid embolic material (200) is injected into the position of the mouse brain aneurysm (240) from the blood vessel 230 through the microcatheter 210, and the liquid embolic material (200) can be cistern under the guidance of the external magnetic field (220). The wall of the aneurysm is solidified. The liquid embolic material (200) of the present embodiment has high viscosity and can achieve the purpose of reducing dead space as much as possible, and thus is particularly suitable for use in an embolization material for irregular brain aneurysms.

3. Experimental data:

The embolization time and embolization rate were calculated based on the computer MITK (Medical Imaging Interaction Toolkit), that is, the CT embedding rate was calculated by CT three-dimensional reconstruction and then based on the three-dimensional reconstruction model. For specific usage and analysis methods, see the MITK official website (http://docs.mitk.org/nightly/HowToNewProject.html).

Embolization time: 30 seconds to 90 seconds (existing product embolization time: 30 seconds - 2 minutes);

Embolization rate: vascular closure rate of 70% (about 50% of existing products);

Magnetic guide: 10-20G, visible magnetically guided material movement under development;

Development intensity: clearly visible, same as the control group;

Toxicity: No significant toxic substances; the control group was based on DMSO and had some toxicity, but there was no significant difference.

Example 4 EVOH-coated agarose Fe ₃ O ₄ nanoparticles (weight ratio 25:2.5)

The agarose-coated Fe ₃ O ₄ nanoparticles were prepared in the same manner as in Example 1. First, step S21 is performed, 100 g of the black powder of Example 1 and 10 g of the EVOH polymer are dispersed in 100 ml of dimethyl sulfoxide solvent under ultrasonic conditions; then, step S22 is performed, and mechanical stirring is performed at a speed of 450 rpm. Two hours, a liquid embolic material was obtained, which contained a large amount of nanocomposite particles in which agarose-coated Fe ₃ O ₄ nanoparticles were core and EVOH polymer was a shell. The agarose-coated Fe ₃ O ₄ nanoparticles have a diameter of 300 nm. The liquid embolic material has a high viscosity, a viscosity of 100 centipoise and a PDI of 1.12. The liquid embolic material is injected into the cerebral aneurysm from the blood vessel through the microcatheter, and the liquid embolic material can be solidified along the wall of the cerebral aneurysm under the guidance of the external magnetic field.

Embolization time and embolization rate are automatically calculated based on computer simulation.

Embolization time: 60 seconds to 90 seconds;

Embolization density: 2.0g/ml

Embolization rate: vascular closure rate of 75%;

Development intensity: clearly visible, same as the control group;

In the series of the above examples, the content of the vinyl group in the EVOH polymer was 60% by mol. The agarose-coated Fe ₃ O ₄ nanoparticles interact with each other through hydrogen bonding, and further hydrogen bonds with the EVOH polymer to finally obtain agarose-coated Fe ₃ O ₄ nanoparticles as a core to EVOH polymer. As a nanocomposite particle of the shell, the nanocomposite particle is discretely distributed in a dimethyl sulfoxide solvent, and a hydrogen bond combined with a micelle formed by a self-assembly method, which is a self-reinforced rubber-like composite embolic material.

Comparative Example 1 Nanocomposite particles without Fe ₃ O ₄

1. Preparation of agarose-coated FeSO ₄ nanoparticles

The procedure was the same as in Example 1 except that FeCl ₃ ·6H ₂ O in S1 was replaced by FeSO ₄ to obtain a yellow-brown powder.

2. Preparation of EVOH-coated agarose FeSO ₄ nanoparticles

First, step S21 is performed, and 100 g of the yellow-brown color powder and 10 g of the EVOH polymer in step 1 are dispersed in 100 ml of dimethyl sulfoxide solvent under ultrasonic conditions; then, step S22 is performed, and mechanical stirring is performed at 450 rpm for 2 hours. A control embedding material is obtained, which contains a large amount of nano-composite particles in which agarose-coated FeSO ₄ nanoparticles are core and EVOH polymer is shell. The agarose-coated FeSO ₄ nanoparticles have a diameter of 200 nm and the liquid embolic material has a viscosity of 100 cps and a PDI of 1.15.

3. Effect: In the present embodiment, after the liquid embolic material is injected into the arterial blood vessel of the AVM through the microcatheter, the liquid embolic material has low viscosity and strong penetrating ability, but the polymer does not contain Fe ₃ O ₄ nanoparticles and cannot be outside. Targeted by a magnetic field. After the liquid embolic material is injected into the cerebral aneurysm from the blood vessel through the microcatheter, the liquid embolic material cannot be solidified by the wall of the cerebral aneurysm under the guidance of the external magnetic field.

Comparative Example 2EVOH-coated Fe ₃ O ₄ Nanoparticles

In addition, the present invention also attempts to prepare agarose-free Fe ₃ O ₄ nanoparticles as a comparative example. It has been found experimentally that if agarose is not contained, Fe ₃ O ₄ particles cannot be stabilized in solution, and the suspension stability time is very short. .

Comparative Example 3 agarose-coated Fe ₃ O ₄ nanoparticles

The invention prepares Fe ₃ O ₄ nanoparticles without EVOH as a comparative example, and found that if EVOH is not contained, it will cause ectopic embolism caused by direct contact of iron particles with blood after agarose degradation as in the prior art. .

Comparative Example 4: Different ratios of agarose and Fe ₃ O ₄ nanoparticles

Agarose different weight ratios of the present invention is prepared wrapped Fe ₃ O ₄ nanoparticles, agarose, and when the weight Fe ₃ O ₄ nanoparticles ratio is <5: 1, not completely wrapped agarose Fe ₃ O ₄ nanoparticles This causes the Fe ₃ O ₄ nanoparticles to diffuse in the suspension to a location that should not be reached. When the weight ratio of the agarose to the Fe ₃ O ₄ nanoparticles is >10:1, the developability of the suspension is insufficient, which is not clinically applicable.

In addition, the present invention also prepared agarose-coated Fe ₃ O ₄ nanoparticles and EVOH polymers in different weight ratios. When the weight ratio of the agarose-coated Fe ₃ O ₄ nanoparticles to the EVOH polymer is >25:2, the EVOH concentration is too low, resulting in insufficient embolization effect. When the weight ratio of the agarose-coated Fe ₃ O ₄ nanoparticles to the EVOH polymer is <25:5, the developability of the suspension is insufficient, which is not clinically applicable.

Comparative Example 5: Different PDI of Fe ₃ O ₄ nanoparticles

The invention prepares Fe ₃ O ₄ nanoparticles with different PDI. When the PDI is greater than 1.2, the size difference of the agarose-encapsulated Fe ₃ O ₄ nanoparticles is significant, resulting in a large difference in the sedimentation speed of the particles in the suspension, and the suspension is stable. Slightly lower than the nanoparticles with PDI ≤ 1.2.

Comparative Example 6: Different viscosities of nanocomposite particles

When the viscosity of the nanocomposite particles is <30 cP, the dispersion of the composite particles is too strong, and in a few cases, ectopic embolization in the clinic is caused. When the viscosity of the nanocomposite particles is >1000 cP, the dispersion of the composite particles is too poor, and in a few cases, the clogging of the injection route in the clinic is caused.

Comparative Example 7: Different particle sizes of nanocomposite particles

When the diameter of the nanocomposite particles is <100 nm, the dispersion of the composite particles is too strong, and in a few cases, it may cause ectopic embolization in the clinic. When the diameter of the nanocomposite particles is >1000 nm, the dispersion of the composite particles is too poor, and in a few cases, the clogging of the injection channel in the clinic is caused.

After the liquid embolic material in the embodiment of the present invention is injected into the aneurysm cavity or AVM, the nanocomposite particles are precipitated from the dimethyl sulfoxide solvent in the blood to form an embolic body. The core-shell structure in the liquid embolic material greatly increases the density of the embolic body, thereby increasing the development efficiency and making the embolization more dense. By utilizing the superparamagnetic effect of the Fe ₃ O ₄ nanoparticles, the liquid embolic material can be targeted by the external magnetic field, and the complex microvascular artery which is difficult to fully fit the microcatheter is well embedd. Tumors and complex vascular malformations.

In the end, it is to be noted that the present invention is not limited to the above embodiments, and various changes and modifications can be made to the present invention, and any modifications made within the spirit and principles of the present invention, Equivalent substitutions, improvements, etc., are intended to be included within the scope of the appended claims.

Claims

A liquid embolic material comprising nanocomposite particles and a dispersing agent, wherein the nanocomposite particles are agarose-coated Fe 3 O 4 nanoparticles as a core, and the EVOH polymer is coated on a surface of the core to form a shell; agarose, and the weight of the nanoparticles Fe 3 O 4 ratio of 5: 1 to 10: 1; the weight of the parcel agarose Fe 3 O 4 nanoparticles and the polymer is EVOH ratio of 25: 2 ~ 25:5; the nanocomposite particles are dispersed in the dispersant.
The liquid embolic material according to claim 1, wherein the agarose-coated Fe 3 O 4 nanoparticles have a diameter of 100 to 1000 nm; and the nanocomposite particles have a viscosity of 30 to 1000 cps; The polydispersity index PDI ≤ 1.2 of the Fe 3 O 4 nanoparticles; and/or the dispersing agent is dimethyl sulfoxide.
The liquid embolic material according to claim 2, wherein the weight ratio of the agarose to the Fe 3 O 4 nanoparticles is 10:1; and/or the agarose-coated Fe 3 O The weight ratio of 4 nanoparticles to the EVOH polymer was 10:1.
The liquid embolic material according to claim 3, wherein the agarose-coated Fe 3 O 4 nanoparticles have a diameter of 300 nm; the nanocomposite particles have a viscosity of 100 cps; and/or The PDI is 1.12.
A method of preparing a liquid embolic material according to any one of claims 1 to 4, characterized in that it comprises the following steps:

(1) preparing agarose-coated Fe 3 O 4 nanoparticles;

(2) preparing nano composite particles, wherein the nano composite particles are further composed of EVOH and further coated with agarose-coated Fe 3 O 4 nanoparticles;

(3) Dispersing the nanocomposite particles in a dispersing agent.
The preparation method according to claim 5, wherein the step (1) comprises:

(11) The ethylene glycol solution of FeCl 3, agarose and NH4Ac mixing said FeCl 3, agarose, and NH 4 Ac weight ratio of 10: 1: 5; Preferably, the mixing is from 2 to Stirring at 200 to 300 rpm for at least one hour under 3kw ultrasonic conditions; more preferably, the stirring speed is 250 rpm;

(12) The reaction is carried out at a temperature of 2 to 3 atm and 200 ° C, and after the reaction, it is cooled to obtain a black product; preferably, the reaction is carried out in a polytetrafluoroethylene autoclave.
The preparation method according to claim 6, wherein the step (1) further comprises: washing and drying the black product to obtain a black powder; preferably, the washing is alternated with ethanol and water. Washing, a total of 2 to 5 times; and / or, the drying is vacuum drying.
The preparation method according to claim 7, wherein the step (2) further comprises:

(21) mixing the black powder and the EVOH polymer into a dimethyl sulfoxide solvent; preferably, the mixing is carried out in ultrasound;

(22) After stirring, nanocomposite particles dispersed in the dimethyl sulfoxide are obtained.
The method according to claim 8, wherein the agitation is mechanical agitation, the mechanical agitation time is at least 2 hours; and/or the agitation speed is 400 to 500 rpm; preferably, the agitation speed is 450 rpm.
Use of the liquid embolic material according to any one of claims 1 to 4 for the preparation of a medicament or molecular imaging reagent for diagnosing, treating a tumor or vascular malformation.