Computed tomography (CT) imaging synergistic contrast agent and preparation method thereof

Abstract

The invention discloses a CT (Computed Tomography) imaging synergistic contrast agent and a preparation method thereof, and provides a method for preparing an imaging synergistic contrast agent by wrapping contrast agent molecules with hydrogel. According to the technical scheme of the preparation method, the principle of rapid prototyping of temperature-sensitive hydrogel is utilized, and in the hydrogel prototyping process, contrast agent molecules are solubilized into the hydrogel; the hydrogel is injected into a focus part to realize local imaging synergy. Compared with the prior art, the preparation method has the advantages that (1) the preparation process is simple, the gelation time is short, and the preparation method is suitable for clinical operation; (2) in the prepared hydrogel contrast agent, the contrast agent is uniform in dispersion, good in dispersity, high and controllable in concentration and high in stability; and (3) the whole preparation process is simple in process and low in cost, and industrial amplification and industrial large-scale production can be easily realized.

Description

Technical Field

[0001] This invention relates to a contrast agent for enhancing CT imaging and its preparation method, specifically to a method for encapsulating a contrast agent in a hydrogel system to achieve the contrast agent's solubilizing effect and enhance imaging performance. Background Technology

[0002] Clinically, contrast agents are among the most commonly used drugs in radiological procedures, primarily for visualizing blood vessels and body cavities. For example, iodine contrast agents are commonly used in CT (computed tomography) imaging, and gadolinium contrast agents are commonly used in MRI (magnetic resonance imaging). Due to differences in individual patients and the diseases being examined, the radiation dose and imaging plane of the contrast agent vary. Therefore, although there are minimum concentration requirements for contrast agents, the dosage requirements differ from individual to individual, and high concentrations can lead to side effects. In addition, contrast agent allergy is also a major manifestation of side effects. For example, some people are allergic to iodine contrast agents, easily experiencing allergic reactions such as rashes and fever. Severe allergic reactions can also lead to symptoms such as shortness of breath and difficulty breathing. Furthermore, iodine in iodine contrast agents may affect thyroid function, potentially stimulating thyroid cells, causing them to become overactive, leading to excessive secretion of thyroid hormones and inducing hyperthyroidism. Side effects of gadolinium contrast agents typically include rashes, facial flushing, and kidney damage. Recent studies have shown that gadolinium contrast agents can cross the placental barrier in small amounts, and animal experiments have demonstrated that high doses may cause birth defects. This indicates that some diseases require high concentrations of contrast agents, but systemic injection of contrast agents can lead to allergic reactions. Therefore, local injection of high-concentration contrast agents is an effective method for managing contrast agent allergies.

[0003] Imaging enhancement with contrast agents is a crucial means of addressing the aforementioned problems. Increasing the local concentration of contrast agents can enhance imaging and effectively reduce allergic reactions. For example, multiple contrast agent elements can be encapsulated together using a carrier to achieve a synergistic effect. Chinese Invention Patent 201110108045.7 utilizes silicon nanomaterials to encapsulate gadolinium, resulting in gadolinium-gold composite silicon nanomaterials. Chinese Invention Patent 201511031874.4 uses a silica-modified gold nanorod core with a gadolinium-containing silica layer as the outer layer, achieving multiple imaging functions including CT, MRI, and photoacoustic imaging. Furthermore, Chinese Invention Patent 202011268862.4 prepares a multifunctional contrast agent by modifying the surface of a zwitterionic 1,3-propanesulfonic acid lactone 1,3-PS and Gd-DOTA chelate with polyamide-amine (PAMAM) dendritic macromolecules and encapsulating gold (Au) nanoparticles internally. However, these technical routes are cumbersome and not suitable for clinical application. Therefore, developing simple and effective efficiency-enhancing methods remains a significant challenge. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing a contrast agent that enhances CT imaging. This method utilizes the principle of rapid molding of thermosensitive hydrogels, during which contrast agent molecules are dissolved into the hydrogel. The hydrogel is then injected into the lesion site to achieve local imaging enhancement.

[0005] Another object of the present invention is to provide a contrast agent product for enhancing CT imaging obtained by the above preparation method.

[0006] The objective of this invention is achieved through the following technical solution: a method for preparing a contrast agent to enhance CT imaging, comprising the following steps: (1) Preparation of thermosensitive hydrogel raw materials: A thermosensitive hydrogel raw material is obtained by using a thermosensitive polymer material as a matrix and adding auxiliary reinforcing agents and crosslinking agents, wherein the weight ratio of the thermosensitive polymer material to the reinforcing agent and crosslinking agent is 40-60%:30-50%:1-10%; wherein the thermosensitive polymer material is one or more of gelatin, carrageenan, hydroxybutyl chitosan, and thermosensitive cellulose; the crosslinking agent is a salt compound, including one or more of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; and the reinforcing agent is a saccharide compound, including one or more of glucose, glucomannan, dextran, and heteropolysaccharides. (2) Preparation of hydrogel contrast agent: The obtained thermosensitive hydrogel raw material is mixed with a contrast agent aqueous solution at a weight ratio of 1-10%:60-99%, and heated to 60-100℃ with stirring. After stirring for 3-10 minutes, a hot liquid is obtained. At this temperature, the hot liquid is dialyzed through a dialysis membrane. The contrast agent content in the liquid is controlled by controlling the dialysis time. The contrast agent aqueous solution is an iodine contrast agent including iopromide, iohexol, meglumine diatrizoate, sodium diatrizoate, iodized oil, and iodixanol, or a gadolinium contrast agent including gadodiamine, gadopentetate meglumine, gadoteric acid meglumine, gadoterol, disodium gadoxetate, gadobutrol, and gadobutrol, as well as a gold dispersion and a ferric oxide dispersion. The hot liquid is injected into the lesion site while still hot to form a hydrogel contrast agent.

[0007] The present invention also provides a contrast agent for enhancing CT imaging, which is prepared according to the method described above.

[0008] Compared with the prior art, the advantages of this invention are: (1) The preparation process is simple and the gelation time is fast, making it suitable for clinical operation; (2) The prepared hydrogel contrast agent has uniform dispersion, good dispersibility, high and controllable concentration, and high stability; (3) The entire preparation process is simple and inexpensive, and it is relatively easy to achieve industrial scale-up and large-scale production. Attached Figure Description

[0009] Figure 1 Example 1: Scanning electron microscopy (SEM) images of the hydrogel contrast agent, including surface and cross-sectional SEM images; Figure 2 Water content of hydrogel contrast agents in Examples 1-4; Figure 3 Tensile strength of hydrogel contrast agents in Examples 1-4. Detailed Implementation

[0010] To make the objectives, technical solutions, and advantages of this invention clearer, the following specific embodiments are used to describe the technical solutions of this invention in detail.

[0011] Example 1 A contrast agent for enhancing CT imaging is prepared according to the following steps: (1) Preparation of thermosensitive hydrogel raw materials: Using 0.02g gelatin and 0.03g carrageenan as a matrix, 0.04g glucomannan and 0.01g potassium chloride were added to obtain gelatin hydrogel raw material; (2) Preparation of hydrogel contrast agent: 1g of the obtained gelatin hydrogel was mixed with 80g of gadobutrol contrast agent with a concentration of 1mmol / mL, and heated to 80℃ with stirring for 3 minutes. At this temperature, the hot liquid was dialyzed through a dialysis membrane for 1 hour, 2 hours, 4 hours and 6 hours respectively. The hot liquid was injected into the lesion site while it was still hot to form gelatin hydrogel / gadobutrol contrast agent.

[0012] The gelation time and SEM images of the gelatin hydrogel / gadobutrol contrast agent are shown in the figure. Figure 1 Moisture content see Figure 2 See tensile strength Figure 3 The CT imaging performance of different dialysis times was tested.

[0013] The results showed that the gelation time of the gelatin hydrogel / gadobutrol contrast agent was 12 seconds; the structure was porous; the water content was 98.8%; the tensile strength was 0.034 MPa; and the CT intensity at different times was 13100 HU, 11500 HU, 9800 HU and 6700 HU (the CT value of pure gadobutrol contrast agent was 7800 HU).

[0014] Example 2 A contrast agent for enhancing CT imaging is prepared according to the following steps: (1) Preparation of thermosensitive hydrogel raw materials: Using 0.05g of gelatin as a matrix, 0.04g of glucose and 0.01g of calcium chloride were added to obtain gelatin hydrogel raw material; (2) Preparation of hydrogel contrast agent: 1g of the obtained gelatin hydrogel was mixed with 60g of iohexol contrast agent with a concentration of 300 mgI / mL, and heated to 80°C with stirring for 5 minutes. At this temperature, the hot liquid was dialyzed through a dialysis membrane for 1 hour each time. The hot liquid was then injected into the lesion site while still hot to form gelatin hydrogel / iohexol contrast agent.

[0015] Detection of gelatin hydrogel / iohexol contrast agent gelation time and water content ( Figure 2 ) and tensile strength ( Figure 3 The results showed that the gelation time of the gelatin hydrogel / iohexol contrast agent was 20 seconds; the water content was 98.0%; and the tensile strength was 0.033 MPa.

[0016] Example 3 A contrast agent for enhancing CT imaging is prepared according to the following steps: (1) Preparation of thermosensitive hydrogel raw materials: Using 0.06g of hydroxybutyl chitosan as a matrix, 0.03g of dextran and 0.02g of potassium chloride were added to obtain hydroxybutyl chitosan hydrogel raw material; (2) Preparation of hydrogel contrast agent: 1g of the obtained hydroxybutyl chitosan hydrogel was mixed with 90g of diatrizoate meglumine contrast agent with a concentration of 370 mgI / mL, and heated to 80°C with stirring for 5 minutes. At this temperature, the hot liquid was dialyzed through a dialysis membrane for 1 hour each time. The hot liquid was then injected into the lesion site while still hot to form hydroxybutyl chitosan hydrogel / diatrizoate meglumine contrast agent.

[0017] Determination of gelation time and water content of hydroxybutyl chitosan hydrogel / diatrizoate meglumine contrast agent ( ) Figure 2 ) and tensile strength ( Figure 3 The results showed that the gelation time of the gelatin hydrogel / iohexol contrast agent was 15 seconds; the water content was 98.1%; and the tensile strength was 0.031 MPa.

[0018] Example 4 A contrast agent for enhancing CT imaging is prepared according to the following steps: (1) Preparation of thermosensitive hydrogel raw materials: Using 0.04g carrageenan as a matrix, 0.04g dextran and 0.01g calcium chloride were added to obtain carrageenan hydrogel raw material; (2) Preparation of hydrogel contrast agent: 1g of carrageenan hydrogel was mixed with 80g of gadobutrol contrast agent with a concentration of 1mmol / mL, and heated to 80°C with stirring for 6 minutes. At this temperature, the hot liquid was dialyzed through a dialysis membrane for 1 hour each time. The hot liquid was then injected into the lesion site while still hot to form carrageenan hydrogel / gadobutrol contrast agent.

[0019] Detection of gelation time of carrageenan hydrogel / gadobutrol contrast agent, such as Figure 2 The moisture content shown and Figure 3 The tensile strength is shown. The results show that the gelation time of the gelatin hydrogel / iohexol contrast agent is 13 seconds; the water content is 97.8%; and the tensile strength is 0.036 MPa.

[0020] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit the concept and scope of protection of the present invention. Modifications or equivalent substitutions made by those skilled in the art without departing from the spirit and scope of the technical solutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing a contrast agent to enhance CT imaging, characterized in that, Includes the following steps: (1) Preparation of thermosensitive hydrogel raw material: using thermosensitive polymer material as matrix, adding auxiliary reinforcing agent and crosslinking agent, wherein the weight ratio of thermosensitive polymer material to reinforcing agent and crosslinking agent is 40-60%:30-50%:1-10%, to obtain thermosensitive hydrogel raw material; wherein the thermosensitive polymer material is one or more of gelatin, carrageenan, hydroxybutyl chitosan, and thermosensitive cellulose; the crosslinking agent is a salt compound, including one or more of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; the reinforcing agent is a sugar compound, including one or more of glucose, glucomannan, dextran, and heteropolysaccharides; (2) Preparation of hydrogel contrast agent: The obtained thermosensitive hydrogel raw material and contrast agent aqueous solution are mixed at a weight ratio of 1-10%: 60-99%, heated to 60-100℃ under stirring, and stirred for 3-10 minutes to obtain a hot liquid. At this temperature, the hot liquid is dialyzed through a dialysis membrane. The contrast agent content in the liquid is controlled by controlling the dialysis time. The contrast agent aqueous solution is an iodine contrast agent including iopromide, iohexol, meglumine diatrizoate, sodium diatrizoate, iodized oil, and iodixanol, or a gadolinium contrast agent including gadodiamine, gadopentetate meglumine, gadoteric acid meglumine, gadoterol, disodium gadoxetate, gadobemequinone, and gadobutrol, as well as a gold dispersion and a ferric oxide dispersion. The hot liquid is injected into the lesion site while it is hot to form a hydrogel contrast agent.

2. The method for preparing the contrast agent for enhancing CT imaging according to claim 1, characterized in that, Prepare according to the following steps: (1) Preparation of thermosensitive hydrogel raw materials: Using 0.02g gelatin and 0.03g carrageenan as a matrix, 0.04g glucomannan and 0.01g potassium chloride were added to obtain gelatin hydrogel raw material; (2) Preparation of hydrogel contrast agent: 1g of the obtained gelatin hydrogel was mixed with 80g of gadobutrol contrast agent with a concentration of 1mmol / mL, and heated to 80℃ with stirring for 3 minutes. At this temperature, the hot liquid was dialyzed through a dialysis membrane for 1 hour, 2 hours, 4 hours and 6 hours respectively. The hot liquid was injected into the lesion site while it was still hot to form gelatin hydrogel / gadobutrol contrast agent.

3. The method for preparing the contrast agent for enhancing CT imaging according to claim 1, characterized in that, Prepare according to the following steps: (1) Preparation of thermosensitive hydrogel raw materials: Using 0.05g of gelatin as a matrix, 0.04g of glucose and 0.01g of calcium chloride were added to obtain gelatin hydrogel raw material; (2) Preparation of hydrogel contrast agent: 1g of the obtained gelatin hydrogel was mixed with 60g of iohexol contrast agent with a concentration of 300 mgI / mL, and heated to 80°C with stirring for 5 minutes. At this temperature, the hot liquid was dialyzed through a dialysis membrane for 1 hour each time. The hot liquid was then injected into the lesion site while still hot to form gelatin hydrogel / iohexol contrast agent.

4. The method for preparing the contrast agent for enhancing CT imaging according to claim 1, characterized in that, Prepare according to the following steps: (1) Preparation of thermosensitive hydrogel raw materials: Using 0.06g of hydroxybutyl chitosan as a matrix, 0.03g of dextran and 0.02g of potassium chloride were added to obtain hydroxybutyl chitosan hydrogel raw material; (2) Preparation of hydrogel contrast agent: 1g of the obtained hydroxybutyl chitosan hydrogel was mixed with 90g of diatrizoate meglumine contrast agent with a concentration of 370 mgI / mL, and heated to 80 ℃ with stirring for 5 minutes. At this temperature, the hot liquid was dialyzed through a dialysis membrane for 1 hour each time. The hot liquid was then injected into the lesion site while still hot to form hydroxybutyl chitosan hydrogel / diatrizoate meglumine contrast agent.

5. The method for preparing the contrast agent for enhancing CT imaging according to claim 1, characterized in that, Prepare according to the following steps: (1) Preparation of thermosensitive hydrogel raw materials: Using 0.04g carrageenan as a matrix, 0.04g dextran and 0.01g calcium chloride were added to obtain carrageenan hydrogel raw material; (2) Preparation of hydrogel contrast agent: 1g of carrageenan hydrogel was mixed with 80g of gadobutrol contrast agent with a concentration of 1mmol / mL, and heated to 80°C with stirring for 6 minutes. At this temperature, the hot liquid was dialyzed through a dialysis membrane for 1 hour each time. The hot liquid was then injected into the lesion site while still hot to form carrageenan hydrogel / gadobutrol contrast agent.

6. A contrast agent for enhancing CT imaging, characterized in that... Prepared according to any one of claims 1-5.

Images