CN111686263B - Targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis and preparation method thereof - Google Patents
Targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis and preparation method thereof Download PDFInfo
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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
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
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Abstract
The invention relates to a targeted ultrasound contrast agent for enhancing the ultrasonic diagnosis of arteriosclerosis of lower limbs and a preparation method thereof, the targeted ultrasound contrast agent for enhancing the ultrasonic diagnosis of arteriosclerosis of lower limbs is prepared from an ultrasonic contrast agent of an amino-modified lipid membrane and fibrin targeted polypeptide, the enrichment of the contrast agent at the affected part of arteriosclerosis of lower limbs is realized, the contrast duration is obviously prolonged, and the ultrasonic imaging effect of arteriosclerosis of lower limbs is obviously enhanced.
Description
Technical Field
The invention belongs to the field of diagnostic reagents, and particularly relates to a targeted ultrasound contrast agent for enhancing the ultrasonic diagnosis of lower limb arteriosclerosis and a preparation method thereof.
Background
Ultrasonic diagnosis refers to a method for scanning a tissue structure by using an ultrasonic sound beam, processing a received signal and then obtaining a morphological image of a tissue organ for disease diagnosis, and has the advantages of non-invasiveness, intuition, no radiation and the like which are incomparable with other examination methods. Ultrasound contrast agents are thus generated due to the non-ideal characterization of ultrasound tissue in a section of tissue. The ultrasound contrast agent is a substance capable of enhancing image contrast in ultrasound diagnosis, and can improve the sensitivity and specificity of the ultrasound diagnosis, and the existing ultrasound contrast agents include Optison, Sonazoid, Sonovue, definitity, Imagen, sherifram and the like.
Lower limb arteriosclerosis, i.e. lower limb arteriosclerosis obliterans, is caused by the formation of atherosclerotic plaques in the lower limb, which leads to stenosis and occlusion of the lower limb arteries, and thus chronic ischemia of the tissues. Although the use of ultrasound contrast agents in the ultrasound diagnosis of lower limb arteriosclerosis has been reported, for example, wu dong mei et al reported the use of sononovei (SonoVue) in ultrasound imaging to assess skeletal muscle perfusion disorder of lower limb vein sclerosis obliterans; the Wangwei et al also report the diagnostic value of sononovacin on lower limb arteriosclerosis, but in the lower limb venous diagnosis process, sononovacin cannot target the affected part of lower limb arteriosclerosis, so the required dosage of the contrast agent is high, the contrast duration is very short, generally only 5 minutes of action is needed, the detection window period is short, and the continuous and large-amount administration of the contrast agent has low patient compliance, high cost and certain side effect, and cannot effectively meet the requirement of clinical ultrasound detailed examination.
The invention aims to provide an ultrasonic contrast agent which has long contrast duration and lower dosage and can be used for targeted enhancement of ultrasonic diagnosis of arteriosclerosis of lower limbs.
Disclosure of Invention
The invention aims to provide a targeted ultrasound contrast agent for enhancing the ultrasonic diagnosis of arteriosclerosis of lower limbs and a preparation method thereof.
In one aspect, the invention provides a targeted ultrasound contrast agent for enhancing the ultrasonic diagnosis of lower limb arteriosclerosis, which is prepared from an ultrasound contrast agent with an amino-modified lipid membrane and a fibrin targeted polypeptide
Preferably, the ultrasound contrast agent of the amino-modified lipid membrane is an ultrasound contrast agent containing PEG amino in the lipid membrane.
Preferably, the weight ratio of the ultrasound contrast agent containing PEG amino groups to the fibrin targeting polypeptide in the lipid membrane is 90-99: 1; more preferably, the weight ratio of the ultrasound contrast agent comprising a PEG amino group to the fibrin targeting polypeptide in the lipid membrane is 92-97: 1; most preferably, the weight ratio of the ultrasound contrast agent comprising a PEG amino group to the fibrin targeting polypeptide in the lipid membrane is 95: 1.
Preferably, the ultrasound contrast agent containing PEG amino in the lipid membrane is sononovacin containing DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in the lipid membrane; more preferably, the content of the DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in the sononovacin containing the DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in the lipid membrane is 0.05-10% of the lipid membrane; most preferably, the content of the DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in the sononovacin containing the DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in the lipid membrane is 2 percent of that of the lipid membrane.
Preferably, the fibrin-targeting polypeptide is selected from the group consisting of: thymopentin, thymopentin alpha 1 or RGD peptide, more preferably, the vitamin targeting polypeptide is thymopentin; most preferably, the fibrin targeting polypeptide is a mixture of thymopentin and RGD peptide, preferably, the weight ratio of thymopentin to RGD peptide is 1-5: 1; more preferably, the weight ratio of the thymopentin to the RGD peptide is 2-4: 1; most preferably, the weight ratio of thymopentin to RGD peptide is 3: 1.
In another aspect, the invention provides a preparation method of a targeted ultrasound contrast agent for enhancing the ultrasound diagnosis of arteriosclerosis of lower limbs, which comprises the following steps:
(1) preparing an ultrasonic contrast agent of an amino modified lipid membrane;
(2) preparing a targeted ultrasound contrast agent: and (2) adding the ultrasonic contrast agent for preparing the amino modified lipid membrane and the fibrin targeted polypeptide prepared in the step (1) into water for injection, and oscillating for 5-15min at the temperature of 20-30 ℃ to obtain the targeted ultrasonic contrast agent.
Preferably, the ultrasonic contrast agent of the amino-modified lipid membrane is prepared by adding DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in formula amount into the lipid membrane ingredients.
The invention has the beneficial effects
The surface of the lipid membrane of the ultrasonic contrast agent is modified, so that the lipid membrane can be combined with fibrin targeting polypeptide, thereby realizing the targeted ultrasonic contrast agent which can target the arteriosclerosis affected part of the lower limb, realizing the enrichment of the contrast agent at the arteriosclerosis affected part of the lower limb, obviously prolonging the contrast duration and obviously enhancing the ultrasonic imaging effect of the arteriosclerosis of the lower limb.
The targeted ultrasound contrast agent realizes the enrichment of the contrast agent at the affected part of the lower limb arteriosclerosis, so the dosage required by the contrast of the ultrasound contrast agent is obviously reduced, thereby being beneficial to reducing the cost and avoiding the side effect of the contrast agent.
Detailed Description
The present invention is described in more detail below to facilitate an understanding of the present invention.
Example 1: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of Sonoweiwei with DSPE-PEG (2000) Amine content of 2% of lipid membrane, 1 part of thymopentin and a proper amount of water for injection, and the preparation method comprises the following steps:
(1) preparing an ultrasound contrast agent comprising DSPE-PEG (2000) Amine in a lipid membrane: adding DSPE-PEG (2000) Amine with a formula amount into a lipid membrane ingredient to prepare an ultrasonic contrast agent containing DSPE-PEG (2000) Amine in a lipid membrane;
(2) preparing a targeted ultrasound contrast agent: and (2) adding the ultrasonic contrast agent containing DSPE-PEG (2000) Amine and thymopentin in the lipid membrane prepared in the step (1) into water for injection, and oscillating for 10min at 25 ℃ to obtain the targeted ultrasonic contrast agent.
Example 2: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of Sonoweiwei with the DSPE-PEG (2000) Amine content of 2 percent of lipid membrane, 1 part of thymosin alpha and a proper amount of water for injection, and the injection is prepared according to the method of the embodiment 1.
Example 3: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of sononovacin with DSPE-PEG (2000) Amine content of 2% of lipid membrane, 1 part of RGD peptide and a proper amount of water for injection, and the preparation method is carried out according to the embodiment 1.
Example 4: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of Sonoweiwei with DSPE-PEG (2000) Amine content of 2% of lipid membrane, 0.75 part of thymopentin, 0.25 part of RGD peptide and a proper amount of water for injection, and the preparation method is carried out according to the method of the embodiment 1.
Example 5: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of Sonoweiwei with DSPE-PEG (2000) Amine content of 2% of lipid membrane, 0.5 part of thymopentin, 0.5 part of RGD peptide and a proper amount of water for injection, and the preparation method is carried out according to the method of the embodiment 1.
Example 6: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of Sonoweiwei with DSPE-PEG (2000) Amine content of 2% of lipid membrane, 0.25 part of thymopentin, 0.75 part of RGD peptide and a proper amount of water for injection, and the preparation method is carried out according to the method of the embodiment 1.
Example 7 Targeted ultrasound contrast agent for enhancing ultrasound diagnosis of arteriosclerosis of lower extremities
97 parts of Sonoweiwei with the DSPE-PEG (2000) Amine content of 2 percent of lipid membrane, 1 part of thymopentin and a proper amount of water for injection, and the preparation method is carried out according to the embodiment 1.
Example 8: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of Sonoweiwei with the DSPE-PEG (2000) Amine content of 3 percent of lipid membrane, 1 part of thymopentin and a proper amount of water for injection, and the preparation method is carried out according to the method of the embodiment 1.
Example 9: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of 4-arm-amino-polyethylene glycol sononovalv with the content of 2 percent of lipid membrane, 1 part of thymopentin and a proper amount of water for injection, and the preparation method is carried out according to the method of the embodiment 1.
Example 10: targeted ultrasonic contrast agent for enhancing ultrasonic diagnosis of lower limb arteriosclerosis
95 parts of 6-arm-amino-polyethylene glycol sononovalv with the content of 2 percent of lipid membrane, 1 part of thymopentin and a proper amount of water for injection, and the preparation method is carried out according to the method of the embodiment 1.
Comparative example 1: ultrasonic contrast agent for arteriosclerosis of lower limbs
95 parts of sononorvitamin, 1 part of thymopentin and a proper amount of water for injection, and the preparation method is carried out according to the method of the embodiment 1.
Comparative example 2: ultrasonic contrast agent for arteriosclerosis of lower limbs
95 parts of Sonoweiwei with the DSPE-PEG (2000) Amine content of 2 percent of lipid membrane and a proper amount of water for injection, and the injection is prepared according to the method of the embodiment 1.
Effect example 1: influence of targeted ultrasonic contrast agent on ultrasonic diagnosis of lower limb arteriosclerosis
1.1 test substance:
the ultrasound contrast agent and sononovacin described in examples 1-10 and comparative examples 1-2 were adjusted to 2.0x108Micro bubbles/mL.
1.2 Experimental methods:
28 male SD rats with the age of 10 weeks, weighing 370-380g, after being adaptively raised for 1 day, the rats are randomly divided into an example 1-10 group, a comparative example 1-2 group and a control 1-2 group, the rats are all subjected to high-fat diet for three weeks, vitamin D300 wu/kg is injected into the left hind limb and the right hind limb of the rats on the 1 st, 7 th and 14 th days of the high-fat diet, sterile purified water is injected into the left hind limb-popliteal artery of the rats in 0.2mL, an ultrasonic contrast agent is injected into the tail vein of the rats on the 21 st day of the high-fat diet, wherein the ultrasonic contrast agent is injected into the groups of the examples 1-10 and the comparative examples 1-2 in 0.1mL, acoustic novavin is injected into the group of the control 1 in 0.1mL, acoustic novavin is injected into the group of the control 2 in 0.2mL, a PhiliE 33 Matrix ultrasonic diagnostic apparatus is used, the probe frequency is 8MHz, the ultrasonic contrast duration and the peak intensity ratio of the left hind limb and the peak intensity of each group of the rats are recorded, the specific experimental results are shown in table 1, wherein:
the contrast duration is the time from the beginning of contrast enhancement to the disappearance of the enhancement;
peak intensity ratio experimental group average peak intensity/control 1 group average peak intensity.
1.3 results of the experiment
The experimental results in table 1 show that sononovadin has a contrast duration of about 6min, a short duration, and also includes a time period with weak contrast enhancement effect in the early and late contrast periods, so that the single administration of sononovadin cannot effectively meet the requirement of clinical ultrasound detailed examination, and even if the administration is doubled, the contrast duration cannot be doubled, and is only lengthened by about 24.04%, and the peak intensity is also increased by about 46%. Therefore, simply increasing the dosage of sononovacin not only significantly increases the detection cost and reduces the compliance of patients, but also fails to significantly improve the problem of short duration of sononovacin contrast.
TABLE 1 Effect of the Targeted ultrasound contrast Agents of the present invention on the duration and Peak intensity of lower extremity Atherosclerosis contrast
| Group of | Duration of contrast (min) | Peak intensity ratio |
| Control 1 group | 5.99±0.22 | 1 |
| Control 2 group | 7.43±0.30* | 1.46 |
| Example 1 | 18.32±2.09** | 1.84 |
| Example 2 | 14.18±1.29** | 1.61 |
| Example 3 | 18.55±1.82** | 1.68 |
| Example 4 | 30.38±2.26*** | 2.16 |
| Example 5 | 24.68±1.66** | 1.73 |
| Example 6 | 19.62±1.50** | 1.65 |
| Example 7 | 17.40±1.34** | 1.90 |
| Example 8 | 18.01±1.56** | 1.68 |
| Example 9 | 18.23±1.64** | 1.85 |
| Example 10 | 19.35±1.70** | 1.92 |
| Comparative example 1 | 6.04±0.56 | 1.08 |
| Comparative example 2 | 5.79±0.53 | 0.98 |
P <0.05 compared to control 1 group; p < 0.01; p <0.001.
After the surface of the lipid membrane of the ultrasonic contrast agent is modified and combined with the fibrin targeting polypeptide, the contrast duration is obviously prolonged under the condition of the same administration dosage, particularly, the contrast agent of the group in the embodiment 4 has the most obvious effect, the contrast duration is prolonged by 4.07 times compared with sononovacin, and the peak intensity is increased by 2.16 times, so that the requirement of clinical detailed examination can be effectively ensured.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (7)
1. A targeted ultrasound contrast agent for enhancing the ultrasonic diagnosis of arteriosclerosis of lower limbs is characterized in that the targeted ultrasound contrast agent is prepared from an amino-modified lipid membrane ultrasound contrast agent and fibrin targeted polypeptide; the ultrasonic contrast agent of the amino modified lipid membrane is an ultrasonic contrast agent containing PEG amino in the lipid membrane; the fibrin targeting polypeptide is thymopentin or a mixture of thymopentin and RGD peptide, and the weight ratio of the thymopentin to the RGD peptide is 2-4: 1.
2. The targeted ultrasound contrast agent for enhancing ultrasonic diagnosis of arteriosclerosis of lower limbs as claimed in claim 1, wherein the weight ratio of the ultrasound contrast agent containing PEG amino group in the lipid membrane to the fibrin-targeted polypeptide is 90-99: 1.
3. The targeted ultrasound contrast agent for enhancing ultrasonic diagnosis of arteriosclerosis of lower limbs as claimed in claim 1 or 2, wherein the ultrasound contrast agent containing PEG amino in the lipid membrane is sononovacin containing DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in the lipid membrane.
4. The targeted ultrasound contrast agent for enhancing ultrasonic diagnosis of arteriosclerosis of lower limbs as claimed in claim 3, wherein the content of DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in sononovacin containing DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in the lipid membrane is 0.05-10% of the lipid membrane.
5. Use of the targeted ultrasound contrast agent according to any one of claims 1 to 4 for the preparation of a diagnostic ultrasound agent for enhancing arteriosclerosis of the lower extremities.
6. The method for preparing the targeted ultrasound contrast agent for enhancing the ultrasonic diagnosis of arteriosclerosis of lower limbs as set forth in any one of claims 1 to 4, which comprises the steps of:
(1) preparing an ultrasonic contrast agent of an amino modified lipid membrane;
(2) preparing a targeted ultrasound contrast agent: and (3) adding the ultrasonic contrast agent of the amino modified lipid membrane prepared in the step (1) and the fibrin targeted polypeptide into water for injection, and oscillating for 5-15min at the temperature of 20-30 ℃ to obtain the composition.
7. The preparation method of claim 6, wherein the ultrasound contrast agent with the amino-modified lipid membrane is prepared by adding DSPE-PEG (2000) Amine, 4-arm-amino-polyethylene glycol or 6-arm-amino-polyethylene glycol in a formula amount into the lipid membrane ingredients.
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