CN107158413B - Nano metal oxide modified ultrasonic contrast agent and preparation method thereof - Google Patents
Nano metal oxide modified ultrasonic contrast agent and preparation method thereof Download PDFInfo
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- 239000011261 inert gas Substances 0.000 claims abstract description 16
- 230000008685 targeting Effects 0.000 claims abstract description 12
- 229950010592 dodecafluoropentane Drugs 0.000 claims abstract description 9
- NJCBUSHGCBERSK-UHFFFAOYSA-N perfluoropentane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F NJCBUSHGCBERSK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910018503 SF6 Inorganic materials 0.000 claims abstract description 5
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960000909 sulfur hexafluoride Drugs 0.000 claims abstract description 5
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 20
- 239000006087 Silane Coupling Agent Substances 0.000 claims description 11
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 10
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 10
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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
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
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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
- A61K49/22—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
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Abstract
The invention discloses a nano metal oxide modified ultrasonic contrast agent and a preparation method thereof. The ultrasonic contrast agent comprises modified chitosan and biological inert gas wrapped inside the modified chitosan, wherein the biological inert gas comprises more than one of dodecafluoropentane and sulfur hexafluoride, the outer layer of the chitosan is connected with nano metal oxide, and the modified chitosan is used as a membrane material to wrap the biological inert gas. The particle size of the ultrasonic contrast agent is 300-700 nm. The ultrasonic contrast agent has simple preparation process, low production cost and easy industrial production, overcomes the defect of low tissue penetrating power of the existing ultrasonic contrast agent, and provides the nano metal oxide modified ultrasonic contrast agent with strong tissue penetrating power and targeting property.
Description
Technical Field
The invention relates to the technical field of preparation of ultrasonic contrast agents, in particular to a nano metal oxide modified ultrasonic contrast agent and a preparation method thereof.
Background
Ultrasound Contrast Agents (UCAs) have been developed in great length from passage 1 to passage 3 during decades since the first discovery in 1967 of tiny air bubbles that enhance ultrasound visualization. Among them, the ultrasound contrast agent is focused on because of having the effects of molecular imaging, promoting thrombolysis, promoting drug transport in vivo, site-specific release, gene transfection and the like. The ultrasonic molecular imaging diagnosis technology is widely applied in clinic as a noninvasive and relatively low-cost diagnosis technology.
At present, the image definition and contrast of ultrasonic diagnosis have certain difference compared with CT and MRI, and the clinical application of the ultrasonic diagnosis is limited. The conventional ultrasonic contrast agent is micron-sized, has an average diameter of about 2-4 mu m, cannot pass through blood vessels, and is a blood pool developing agent. Because the tissue targeting property of the ultrasonic microvesicle is low, the ultrasonic microvesicle lacks of special affinity to pathological tissues, can not be effectively retained in target tissues, and can only develop target organ blood vessels in transient arterial phase, thereby greatly influencing the accuracy and specificity of diagnosis. Aiming at the problems of relatively large particle size, weak tissue penetrating power, low targeting property and the like of the conventional ultrasonic contrast agent, the development of a new molecular ultrasonic contrast technology has considerable value.
Disclosure of Invention
The invention aims to provide a nano metal oxide modified ultrasonic contrast agent with strong tissue penetration force aiming at the defect of low tissue penetration force of the conventional ultrasonic contrast agent. The ultrasonic contrast agent comprises modified chitosan and biological inert gas wrapped inside the modified chitosan, the biological inert gas comprises more than one of dodecafluoropentane and sulfur hexafluoride, the outer layer of the chitosan is connected with nano metal oxide for modification, and the modified chitosan is used as a membrane material to wrap the biological inert gas.
The invention also aims to provide a preparation method of the ultrasonic contrast agent.
The invention is realized by the following technical scheme.
A preparation method of a nano metal oxide modified ultrasonic contrast agent comprises the following steps:
(1) uniformly mixing chitosan, a silane coupling agent and a metal oxide, heating for reaction, filtering and grinding a reaction product to obtain modified chitosan;
(2) dissolving modified chitosan in water to obtain a modified chitosan aqueous solution, adding a biological inert gas, stirring and mixing uniformly to preliminarily ball the modified chitosan;
(3) adding vanillin into the solution of the primary sphere of the modified chitosan, and crosslinking; adding a buffer solution to adjust the pH value, and standing to enable the modified chitosan to be settled;
(4) and removing large standing and settling particles, centrifuging, removing supernatant, collecting solid particles, and freeze-drying to obtain the nano metal oxide modified ultrasonic contrast agent.
Further, in the step (1), the chitosan comprises chitosan with molecular weight of 2000-4000.
Further, in the step (1), the silane coupling agent is a silane coupling agent with a trade mark of KH560 or KH 550.
Further, in the step (1), the nano metal oxide includes one or more of nano zinc oxide and nano ferric oxide.
The nano metal oxide has the characteristics of small particles, large specific surface area, high surface reactivity, more active centers, no toxicity and strong adsorption capacity, and has wide application in clinical medicine; the nanometer metal oxide can induce the nanometer perforation of cell membrane and the transient oxidation of lipid, thereby changing the permeability of cell membrane, and the nanometer metal oxide can interact with protein and enzyme in cells after entering the cells, and has targeting property. Meanwhile, researches show that the nano zinc oxide and the nano ferric oxide have obvious anti-tumor effect and targeting property. Therefore, more than one nano metal oxide of nano zinc oxide and nano ferric oxide is connected on the surface of the ultrasonic contrast agent to obtain the ultrasonic contrast agent modified by the nano metal oxide, so that the ultrasonic contrast agent has the characteristics of tissue targeting, strong tissue penetrability, no toxicity and no harm, and the specificity of microbubble development is enhanced.
Further, in the step (1), the mass ratio of the chitosan to the silane coupling agent to the nano metal oxide is 1:1: 1.
Further, in the step (1), the heating reaction is carried out at a temperature of 60 to 80 ℃ for 12 hours.
Further, in the step (2), the mass ratio of the modified chitosan to water is 1: 1.
Further, in the step (2), the bio-inert gas includes one or more of dodecafluoropentane and sulfur hexafluoride.
Further, in the step (2), the stirring and mixing time is 1-2 hours.
Further, in the step (3), the crosslinking time is 2-3 hours.
Further, in step (3), the buffer is a potassium hydrogen phosphate-potassium dihydrogen phosphate buffer with pH = 8.
Further, in the step (3), the pH is adjusted to be pH = 7-8.
Further, in the step (3), the standing time is 12-15 hours.
Further, in the step (4), the rotation speed of the centrifugation is 6000-20000 r/min, and the time is 40-60 min.
Further, the modified chitosan: biological inert gas: the mass ratio of the vanillin is (10-30): (5-15): (5-10).
The nano metal oxide modified ultrasonic contrast agent prepared by any one of the preparation methods comprises modified chitosan and intramembrane gas wrapped in the modified chitosan; the nanometer metal oxide is connected to the outer surface of the modified chitosan, and has a tissue targeting effect.
Further, the particle size of the nano metal oxide modified ultrasonic contrast agent is 300-700 nm.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) according to the nano metal oxide modified ultrasonic contrast agent, the nano metal oxide is combined on the chitosan shell, so that the modified ultrasonic contrast agent particles have the characteristics of strong tissue penetrating power and tissue targeting;
(2) the nano metal oxide modified ultrasonic contrast agent has small microbubble particle size within the range of 300-700nm, and the chitosan combined nano metal oxide has tissue targeting property and can enter extravascular gaps to carry out local ultrasonic enhanced development on extravascular tissues, thereby enhancing the specificity of microbubble development, overcoming the defect of low tissue penetrating power of the existing ultrasonic contrast agent and having good application prospect in the aspect of precise medical treatment of diseases;
(3) the nano metal oxide modified ultrasonic contrast agent has low production cost and easy industrial production, and provides the nano metal oxide modified ultrasonic contrast agent with strong tissue penetrating power and tissue targeting property;
(4) the nano metal oxide modified ultrasonic contrast agent can obtain a high-contrast lumen image by utilizing the acoustic nonlinear effect of ultrasonic microbubbles under the action of ultrasonic waves, the gray value display imaging effect of the obtained B ultrasonic image is good, and the structural form of a lumen can be clearly observed.
Drawings
FIG. 1 is a schematic structural diagram of a nano metal oxide modified ultrasound contrast agent of the present invention;
fig. 2 is a B-ultrasonic development image of the nano metal oxide modified ultrasonic contrast agent in example 1.
Detailed Description
The present invention will be further described with reference to the following examples, but the embodiments of the present invention are not limited thereto.
The structural schematic diagram of the nano metal oxide modified ultrasonic contrast agent is shown in figure 1, and comprises bio-inert gas 1, modified chitosan 2 and nano metal oxide 3, wherein the outer layer of the chitosan is connected with the nano metal oxide 3, and then the modified chitosan 2 is used as a membrane material to wrap the bio-inert gas 1.
Example 1
(1) Uniformly mixing 10 parts by weight of chitosan (molecular weight is 2000), 10 parts by weight of silane coupling agent KH550 and 10 parts by weight of nano zinc oxide, heating at 60 ℃ for reaction for 12 hours, filtering a reaction product, and grinding to obtain nano zinc oxide modified chitosan;
(2) dissolving 10 parts by weight of nano zinc oxide modified chitosan into 10 parts by weight of water to obtain a modified chitosan aqueous solution, adding 5 parts by weight of dodecafluoropentane, stirring for 1 hour to uniformly mix the dodecafluoropentane and the modified chitosan to initially form spheres;
(3) adding 5 parts by weight of vanillin into the solution of the primary sphere of the modified chitosan, and crosslinking for 2 hours; adding 40 parts by weight of potassium hydrogen phosphate-potassium dihydrogen phosphate buffer solution with pH =8 and concentration of 0.05 moL/L, adjusting pH =7, precipitating the modified chitosan, and standing and settling for 12 hours;
(4) and removing large standing and settling particles, centrifuging at 6000 r/min for 60 minutes, removing supernatant, collecting solid particles, and freeze-drying to obtain the nano zinc oxide modified ultrasonic contrast agent.
The encapsulation rate of the prepared nano zinc oxide ultrasonic contrast agent is 85.2%, and in vitro experiments show that the particle size of the contrast agent is 400-680 nm, and the contrast agent has targeting property on prostate cancer cells; in the ultrasonic image, there is a significant enhancement development, as shown in fig. 2, the white and bright part in the image is the image after the micro-bubble enhancement development, and the contrast with the surrounding part without the micro-bubble enhancement development is significant.
Example 2
(1) Uniformly mixing 30 parts by weight of chitosan (molecular weight is 4000), 30 parts by weight of silane coupling agent KH550 and 30 parts by weight of nano ferric oxide, heating at 80 ℃ for reaction for 12 hours, filtering and grinding a reaction product to obtain nano ferric oxide modified chitosan;
(2) dissolving 30 parts by weight of nano ferric oxide modified chitosan in 30 parts by weight of water to obtain an aqueous solution of the modified chitosan, adding 15 parts by weight of biological inert gas (10 parts by weight of dodecafluoropentane and 5 parts by weight of sulfur hexafluoride), and stirring for 2 hours to uniformly mix the mixture so as to preliminarily ball the modified chitosan;
(3) adding 10 parts by weight of vanillin into the solution of the primary sphere of the modified chitosan, and crosslinking for 2 hours; adding 60 parts by weight of potassium hydrogen phosphate-potassium dihydrogen phosphate buffer solution with pH =8 and concentration of 0.05 moL/L, adjusting pH =7.5, precipitating the modified chitosan, and standing and settling for 15 hours;
(4) and removing large standing and settling particles, centrifuging at 12000r/min for 40 minutes, removing supernatant, collecting solid particles, and freeze-drying to obtain the nano ferric oxide modified ultrasonic contrast agent.
The encapsulation rate of the prepared nano ferric oxide ultrasonic contrast agent is 80.9 percent, and in vitro experiments show that the particle size of the contrast agent is 500-700 nm; the results of the visualization in the ultrasound image are shown in fig. 2, which significantly enhances the visualization.
Example 3
(1) Uniformly mixing 30 parts by weight of chitosan (molecular weight is 3000), 30 parts by weight of silane coupling agent KH550 and 30 parts by weight of mixed nano metal oxide (10 parts by weight of nano zinc oxide and 20 parts by weight of nano ferric oxide), heating and reacting at 80 ℃ for 12 hours, filtering and grinding a reaction product to obtain mixed nano metal oxide modified chitosan;
(2) dissolving 30 parts by weight of mixed nano metal oxide modified chitosan in 30 parts by weight of water to obtain an aqueous solution of the modified chitosan, adding 15 parts by weight of dodecafluoropentane, stirring for 2 hours to uniformly mix the dodecafluoropentane and the aqueous solution so as to preliminarily ball the modified chitosan;
(3) adding 8 parts by weight of vanillin into the solution of the primary sphere of the modified chitosan, and crosslinking for 2 hours; adding 60 parts by weight of potassium hydrogen phosphate-potassium dihydrogen phosphate buffer solution with pH =8 and concentration of 0.05 moL/L, adjusting pH =8, precipitating the modified chitosan, and standing and settling for 14 hours;
(4) and removing large particles settled by standing, centrifuging at 12000r/min for 40 minutes, discarding supernatant, collecting solid particles, and freeze-drying to obtain the mixed nano metal oxide metal substance modified ultrasonic contrast agent.
The encapsulation rate of the prepared mixed nano metal oxide modified ultrasonic contrast agent is 86.9 percent, and in vitro experiments show that the particle size of the contrast agent is 450-700 nm; the results of the visualization in the ultrasound image are shown in fig. 2, which significantly enhances the visualization.
Claims (9)
1. A preparation method of a nano metal oxide modified ultrasonic contrast agent is characterized by comprising the following steps:
(1) uniformly mixing chitosan, a silane coupling agent and a nano metal oxide, heating for reaction, filtering and grinding a reaction product to obtain modified chitosan; the chitosan comprises chitosan with the molecular weight of 2000-4000; the silane coupling agent is a silane coupling agent with a commercial brand number of KH560 or KH 550; the nano metal oxide comprises more than one of nano zinc oxide and nano ferric oxide;
(2) dissolving modified chitosan in water to obtain a modified chitosan aqueous solution, adding a biological inert gas, stirring and mixing uniformly to preliminarily ball the modified chitosan;
(3) adding vanillin into the solution of the primary sphere of the modified chitosan, and crosslinking; adding a buffer solution to adjust the pH value, and standing to enable the modified chitosan to be settled;
(4) and removing large standing and settling particles, centrifuging, removing supernatant, collecting solid particles, and freeze-drying to obtain the nano metal oxide modified ultrasonic contrast agent.
2. The method for preparing the nano metal oxide modified ultrasonic contrast agent according to claim 1, wherein in the step (1), the mass ratio of the chitosan to the silane coupling agent to the nano metal oxide is 1:1: 1; the heating reaction is carried out at the temperature of 60-80 ℃ for 12 hours.
3. The method for preparing the nano metal oxide modified ultrasonic contrast agent according to claim 1, wherein in the step (2), the mass ratio of the modified chitosan to water is 1: 1.
4. The method for preparing the nano metal oxide modified ultrasonic contrast agent according to claim 1, wherein in the step (2), the bio-inert gas comprises more than one of dodecafluoropentane and sulfur hexafluoride; the stirring and mixing time is 1-2 hours.
5. The preparation method of the nano metal oxide modified ultrasonic contrast agent according to claim 1, wherein in the step (3), the crosslinking time is 2-3 hours; the buffer is a potassium hydrogen phosphate-potassium dihydrogen phosphate buffer with pH = 8; the pH is adjusted to be pH = 7-8; the standing time is 12-15 hours.
6. The method for preparing the nano metal oxide modified ultrasonic contrast agent according to claim 1, wherein in the step (4), the rotation speed of the centrifugation is 6000 to 20000r/min, and the time is 40 to 60 min.
7. The method for preparing the nano metal oxide modified ultrasonic contrast agent according to claim 1, wherein the modified chitosan: biological inert gas: the mass ratio of the vanillin is (10-30): (5-15): (5-10).
8. The nano metal oxide modified ultrasonic contrast agent prepared by the preparation method of any one of claims 1 to 7 is characterized by comprising modified chitosan and biological inert gas wrapped in the modified chitosan; the nano metal oxide is connected to the outer surface of the modified chitosan, and has targeting effect.
9. The nano metal oxide modified ultrasonic contrast agent according to claim 8, wherein the particle size of the nano metal oxide modified ultrasonic contrast agent is 300-700 nm.
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| 刘莹莹等."硅烷偶联剂对Nano -ZnO/PLA 复合材料抑菌性能与热降解性的影响".《塑料》.2014,第43卷(第2期),第63-67页. * |
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