CN120053698A - Fluorescent emission nano hydrogel with neovascular targeting near infrared II region and preparation and application thereof - Google Patents
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Abstract
本发明公开了一种具有新生血管靶向性近红外II区荧光发射纳米水凝胶及其制备和应用。本发明所提供的纳米水凝胶的制备方法，包括如下步骤：(1)将含有有机胺的有机小分子和含有硼酸基的有机小分子溶于含酸乙醇溶液中，得到碳点前驱体溶液；(2)将所述步骤(1)的碳点前驱体溶液通过溶剂热反应，得到碳点；(3)将所述步骤(2)的碳点的乙醇分散液加入到岩藻多糖溶液中，超声，得到粗产物；(4)将所述步骤(3)的粗产物通过离心、透析和冷冻干燥处理，即得到所述纳米水凝胶。本发明以具有新生血管靶向性的岩藻多糖为原料，以碳点为荧光发射及光动力治疗功能体，通过加入不同含量，可以实现近红外II区荧光发射纳米水凝胶的制备并应用于异常新生血管成像及相应的光动力治疗。
The present invention discloses a near-infrared II region fluorescence emission nano-hydrogel with neovascularization targeting and its preparation and application. The preparation method of the nano-hydrogel provided by the present invention comprises the following steps: (1) dissolving an organic small molecule containing an organic amine and an organic small molecule containing a boric acid group in an acid-containing ethanol solution to obtain a carbon dot precursor solution; (2) subjecting the carbon dot precursor solution of step (1) to a solvent thermal reaction to obtain carbon dots; (3) adding the ethanol dispersion of the carbon dots of step (2) to a fucoidan solution, ultrasonicating, to obtain a crude product; (4) subjecting the crude product of step (3) to centrifugation, dialysis and freeze drying to obtain the nano-hydrogel. The present invention uses fucoidan with neovascularization targeting as a raw material and carbon dots as a fluorescence emission and photodynamic therapy functional body. By adding different contents, the preparation of near-infrared II region fluorescence emission nano-hydrogel can be realized and applied to abnormal neovascularization imaging and corresponding photodynamic therapy.
Description
Technical Field
The invention relates to the technical field of biology, in particular to a fluorescence emission nano hydrogel with a new blood vessel targeting near infrared II region, and preparation and application thereof.
Background
Vascular dysfunction, including abnormalities in vascular structure, hemodynamics, and expression of molecules associated with vascular function, is closely related to the occurrence and progression of various diseases. For example, diabetic retinopathy is the leakage and blockage of retinal microvasculature caused by chronic progressive diabetes, thereby causing a range of fundus lesions. As another example, damage to the cerebrovascular network may result in cell death and impaired brain function due to a loss or significant reduction in blood supply. Tumor angiogenesis and abnormal vascular structures thereof not only participate in the development of tumors by providing oxygen and nutrition, but also have profound effects on the tumor microenvironment, thereby being beneficial to increasing drug resistance and invasiveness. Therefore, monitoring vascular abnormalities, particularly vascular structure and hemodynamic abnormalities, is of great importance in guiding the diagnosis and treatment of related diseases. The fluorescence in the near infrared region II (900-1800 nm) can reach deeper tissue penetration, higher spatial resolution and signal to noise ratio relative to the fluorescence in the visible light and near infrared region I, and has wide application prospect in the fields of tissue imaging and optical treatment. The nano hydrogel based on the carbon dots has the advantages of good biocompatibility, biodegradability and the like, integrates photoluminescence characteristics and optical treatment functions of the carbon dots, and can promote living near infrared fluorescence imaging and potential clinical practice.
For example, chinese patent No. CN114652843B provides a targeting therapeutic ocular neovascular nanoparticle and a method for preparing the same, the nanoparticle comprises a targeting precursor molecule and a microminiature nanoparticle, the targeting precursor molecule is formed by coupling two 4,4' -bipyridine-zinc (II) molecules and a neovascular targeting polypeptide by a benzene ring, and the microminiature nanoparticle is a gold/platinum-indocyanine green nanocomposite. Thus constructing the image-guided fundus neovascularization therapeutic nano-drug. The synthesis process parameters of the nano-drug are complex, strict control is needed, gold and platinum are used as raw materials, and the cost is high.
Disclosure of Invention
In view of the above, the invention provides a fluorescence emission nano hydrogel with a new blood vessel targeting near infrared II region, and preparation and application thereof.
The preparation method of the nano hydrogel provided by the invention comprises the following steps:
(1) Dissolving organic small molecules containing organic amine and organic small molecules containing boric acid groups in an acid-containing ethanol solution to obtain a carbon dot precursor solution;
(2) Carrying out solvothermal reaction on the carbon dot precursor solution in the step (1) to obtain carbon dots;
(3) Adding the ethanol dispersion liquid of the carbon points in the step (2) into a fucoidin solution, and performing ultrasonic treatment to obtain a crude product;
(4) And (3) performing centrifugation, dialysis and freeze drying on the crude product obtained in the step (3) to obtain the nano hydrogel.
Optionally, in the step (1), the organic amine-containing small organic molecule is selected from at least one of ethylenediamine, aniline, o-phenylenediamine, m-phenylenediamine or p-phenylenediamine, and the boric acid group-containing small organic molecule is selected from at least one of phenylboric acid, 1, 4-phenyldiboronic acid or 3-aminophenylboric acid.
Optionally, in the step (1), the concentration of the organic small molecules containing organic amine in the carbon dot precursor solution is 1g/L to 10g/L, and the concentration of the organic small molecules containing boric acid groups is 1g/L to 10g/L.
Optionally, in the step (1), a molar ratio of the organic amine-containing small organic molecule to the boric acid group-containing small organic molecule in the carbon dot precursor solution is 1:1 to 1:5.
Optionally, in the step (2), the solvothermal reaction is performed in a hydrothermal kettle, the reaction temperature is 140-200 ℃, and the reaction time is 6-24 hours.
Optionally, in the step (3), the mass percentage concentration of the fucoidin is 0.5-3%, and the amount of the added carbon point is 0.5-3 g/L.
Optionally, the ethanol dispersion of carbon dots in step (3) is added dropwise to the fucoidan solution.
Optionally, in the step (4), the rotational speed of the centrifugation is 5000rpm-8000rpm, the dialysis time is 7 days-14 days, deionized water is used as the dialysate, the dialysate replacement frequency is once daily, the freeze-drying temperature is-20 to-80 ℃, and the drying time is 3-7 days.
The nano hydrogel prepared by the method also belongs to the protection scope of the invention.
The application of the nano hydrogel in the neovascular fluorescence imaging and photodynamic therapy also belongs to the protection scope of the invention.
The beneficial effects are that:
The invention takes natural polysaccharide fucoidin as raw material, and prepares boric acid group-containing carbon dots capable of generating near infrared II region fluorescence. And crosslinking fucoidin with carbon points containing boric acid groups by utilizing boric acid ester bond reaction to prepare the nano hydrogel. Compared with the prior art, the nano hydrogel can enrich nano functional carbon points in the nano hydrogel, and realize high-efficiency near infrared II-region fluorescence image-guided photodynamic therapy.
Drawings
For purposes of illustration and not limitation, the invention will now be described in accordance with its preferred embodiments, particularly with reference to the accompanying drawings, in which:
FIG. 1is a transmission electron micrograph of the nano-hydrogel prepared in example 1 of the present invention.
FIG. 2 is a near infrared fluorescence emission spectrum of the nano-hydrogel prepared in example 1 of the present invention.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods, unless otherwise indicated or techniques for treatment were employed.
Fucoidan used in the experiments was purchased from merck, and other chemical reagents were purchased from Shanghai Ala Biotechnology Co.
Example 1 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The embodiment provides a fluorescence emission nano hydrogel with a new blood vessel targeting near infrared II region, and the preparation method comprises the following steps:
(1) Preparing a carbon point precursor solution, namely preparing an acid-containing ethanol solution to obtain an acid-containing ethanol solution (prepared by hydrochloric acid), wherein the concentration of hydrochloric acid in the acid-containing ethanol solution is 1mol/L, and then dissolving ethylenediamine and 2-carboxyphenylboronic acid in the acid-containing ethanol solution to obtain the carbon point precursor solution, wherein the concentration of ethylenediamine is 1g/L, the concentration of 2-carboxyphenylboronic acid is 1g/L, and the molar ratio of ethylenediamine to 2-carboxyphenylboronic acid is 1:1.
(2) And (3) taking 30mL of the carbon dot precursor solution obtained in the step (1), putting the carbon dot precursor solution into a hydrothermal kettle with the volume of 100mL, and reacting for 6h in the hydrothermal kettle at the reaction temperature of 140 ℃ to obtain the hydrothermal product carbon dot.
(3) Dissolving 1 gram of fucoidin into 99 grams of sterile phosphate buffer solution, preparing to obtain fucoidin solution with the mass percent concentration of 1 percent, dispersing carbon points obtained in the step (2) into ethanol, dropwise adding the ethanol dispersion liquid of the carbon points into the fucoidin solution, and stirring at the stirring speed of 1200rpm/min. The final concentration of carbon dots was 1g/L, giving a crude product.
(4) Centrifuging the crude product obtained in the step (3) at 5000rpm for 10min, dialyzing for 7 days, and freeze-drying (Toshiba) at-20deg.C for 4 days to obtain the final product.
The nano hydrogel prepared in this example was tested:
1. photodynamic therapy Properties of nanohydrogels
The nano hydrogel was dispersed in a medium (purchased from ScienCell) dedicated to human umbilical vein endothelial cells (HUVEC, purchased from ATCC) at a concentration of 100mg/mL, and the HUVEC was subjected to a light treatment with a light wavelength of 808nm for 2min at a light intensity of 0.2W/cm 2. Under illumination, the photodynamic process of the nano-hydrogel generates singlet oxygen so as to kill HUVEC, and the model is used for evaluating the killing effect of the nano-hydrogel on the neovascular endothelial cells. Cell viability was measured by CCK-8.
2. Size morphology of nanohydrogels
The size morphology of the nano-hydrogels was obtained from transmission electron micrographs (FEI TECNAI F, zemoer femoris technologies) and the diameter of the nano-hydrogels was 46±7nm (fig. 1) and contained a certain number of carbon dots.
3. Fluorescence properties of nanohydrogels
The fluorescence properties of the carbon dots are obtained by a near infrared fluorescence emission spectrometer (FLS 1000, edinburgh instrument), and the test light source is laser with the concentration of 10mg/mL.
From the near infrared fluorescence emission spectrum, the fluorescence emission intensity of the nano-hydrogel is highest at 1260nm under the excitation of 808nm near infrared light (fig. 2), and the band is located in the NIR II region (1000-1700 nm), and the fluorescence emission is derived from carbon points in the nano-hydrogel.
Example 2 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the neovascular targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (3), the final concentration of carbon dots is 2g/L.
Example 3 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the neovascular targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (3), the final concentration of carbon dots is 3g/L.
Example 4 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the neovascular targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (3), the final concentration of carbon dots is 4g/L.
Example 5 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the new blood vessel targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (3), the mass percentage concentration of the fucoidin solution is adjusted to be 2%.
Example 6 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the new blood vessel targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (3), the mass percentage concentration of the fucoidin solution is adjusted to be 3%.
And detecting the nano hydrogel prepared in the examples 1-6.
(1) Diameter of nano hydrogel detection method is the same as in example 1.
(2) The detection method of the fluorescence emission peak position of the nano hydrogel is the same as that of example 1.
(3) The procedure for the detection of the survival (%) of HUVEC without light was as in example 1.
(4) HUVEC survival (%) under light detection method was the same as in example 1.
The test results are shown in Table 1.
TABLE 1
The nano hydrogel is formed by crosslinking through physical interactions of boric acid groups on the surfaces of carbon points, boric acid ester bonds between orthohydroxyl groups in fucoidin molecular chains, hydrogen bonds, van der Waals forces and the like. As can be seen from table 1, the diameter of the nanohydrogel has a significant trend to increase with the increase of the carbon dot concentration (example 1, example 2, example 3 and example 4) or the fucoidan concentration (example 1, example 5 and example 6). The fluorescence emission peak position of the nano hydrogel is determined by a carbon point, and the concentration change does not influence the fluorescence emission peak position depending on the structure and chemical composition of the carbon point. In addition, the photodynamic effect is generated by carbon dots, and the photodynamic killing effect on cells is enhanced along with the increase of the concentration of the carbon dots, so that the fucoidin does not generate obvious toxicity on the survival of the cells.
Example 7 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the neovascular targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (2), the reaction temperature in a hydrothermal kettle is 160 ℃ and the reaction time is 6 hours.
Example 8 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the neovascular targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (2), the reaction temperature in a hydrothermal kettle is 180 ℃, and the reaction time is 6 hours.
Example 9 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the neovascular targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (2), the reaction temperature in a hydrothermal kettle is 200 ℃, and the reaction time is 6 hours.
Example 10 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the neovascular targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that in the step (2), the reaction temperature in a hydrothermal kettle is 200 ℃ and the reaction time is 12 hours.
Carbon points in the nano-hydrogels prepared in examples 7 to 10 are detected, and the detection method is as follows:
1. Size morphology of carbon dots
The size morphology of the carbon dots was obtained by transmission electron microscopy (FEI TECNAI F, zemer feier technologies).
2. Fluorescent Properties of carbon dots
The fluorescence properties of the carbon dots are obtained by a near infrared fluorescence emission spectrometer (FLS 1000, edinburgh instrument), and the test light source is laser with the concentration of 1mg/mL.
3. Singlet oxygen quantum yield of carbon dots by chemical analysis using 1, 3-diphenyl benzofuran as singlet oxygen detection probe and methylene blue as reference, the detection results are shown in Table 2.
TABLE 2
The morphology and fluorescence emission characteristics of the carbon dots can be regulated and controlled by regulating and controlling the temperature and time of the solvothermal reaction condition. In comparative examples 1, 7 and 8, the particle diameter of carbon dots was gradually increased with the increase of the reaction temperature and the increase of the reaction time (examples 9 and 10), the quantum yield of carbon dots was improved, and the fluorescence emission peak was red-shifted to some extent. The nano hydrogel realizes near infrared II region imaging and photodynamic process through the carbon dots, so that the nano hydrogel has higher neovascular killing effect and near infrared fluorescence imaging effect along with the improvement of the quantum yield of the carbon dots and the red shift of fluorescence emission peaks.
Example 11 Performance detection of nanohydrogels
The specific method and procedure were the same as in example 1, except that in step (4), the concentration of the nano-hydrogel was 50. Mu.g/mL.
Example 12 Performance detection of nanohydrogels
The specific method and procedure were the same as in example 1, except that in step (4), the concentration of the nano-hydrogel was 200. Mu.g/mL.
Example 13 Performance detection of nanohydrogels
The specific method and steps are the same as those of example 1, except that in step (4), the illumination time is 30s.
Example 14 Performance detection of nanohydrogels
The specific method and steps are the same as those of example 1, except that in step (4), the illumination time is 5min.
Example 15 Performance detection of nanohydrogels
The specific method and procedure were the same as in example 1, except that in step (4), the light intensity was 0.1W/cm 2.
Example 16 Performance detection of nanohydrogels
The specific method and procedure were the same as in example 1, except that in step (4), the light intensity was 0.4W/cm 2.
TABLE 3 Table 3
Comparative example 1 and examples 11-16, the concentration of the nanohydrogels and the illumination parameters were controlled to produce different killing effects on HUVEC. As the concentration increases (example 11, example 1, and example 12), the illumination time increases (example 13, example 1, and example 14) or the illumination intensity increases (example 15, example 1, and example 16), HUVEC survival rates decrease, indicating a progressively increasing photodynamic cell killing effect.
Example 17 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the new blood vessel targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that ethylenediamine is used instead of aniline with equimolar concentration.
Example 18 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the new blood vessel targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that ethylenediamine is used instead of o-phenylenediamine with equimolar concentration.
Example 19 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the new blood vessel targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that ethylenediamine is used to replace the ethylenediamine with m-phenylenediamine with equimolar concentration.
Example 20 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the new blood vessel targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that ethylenediamine is used instead of p-phenylenediamine with equimolar concentration.
Example 21 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the new blood vessel targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that the 2-carboxyphenylboronic acid is replaced with 3-carboxyphenylboronic acid with the same molar concentration.
Example 22 preparation of fluorescence-emitting nanohydrogel with New-vessel targeting near-infrared region II
The specific method and steps for preparing the fluorescent emission nano hydrogel with the new blood vessel targeting near infrared II region in the embodiment are the same as those in the embodiment 1, except that the 2-carboxyphenylboronic acid is replaced with 4-carboxyphenylboronic acid with the same molar concentration.
The nano-hydrogels prepared in examples 17 to 22 were tested, and the test method was the same as that of examples 1 to 6.
The test results are shown in Table 4.
TABLE 4 Table 4
In comparative examples 1, 17, 18, 19 and 20, the addition of benzene rings in the precursor molecules did not significantly affect the particle size of the nano-hydrogels, while the fluorescence emission peaks had a red shift due to the conjugation of the benzene rings, the nano-hydrogels did not significantly toxicity to HUVEC under no light, and HUVEC cells could be significantly killed under light. The prepared nano-hydrogels can generate near infrared II fluorescence no matter the position of the boric acid group relative to the carboxyl on the benzene ring, and can kill HUVEC under illumination in comparative example 1, example 21 and example 22.
Example 23 demonstration of the photodynamic therapy Effect of neovascular on the basis of nanohydrogel targeting
A model of a blood vessel of a fundus choroid of a mouse (strain: C57/BL6j, purchased from Jiangsu Jiujiakang biotechnology Co., ltd.) was constructed, 5. Mu.L of the nano-hydrogel prepared in example 1 was injected into a vitreous body of the mouse (microinjector from Hamiltonian), and after photodynamic therapy, a fluorescent intensity of vascular leakage was detected by fundus fluorescence contrast (Micron IV; phoenix Co.) using sodium fluorescein as a contrast agent (Abmole Co.).
Example 24 verification of photodynamic therapy Effect of neovascular based on nanohydrogel targeting
This example differs from example 23 in that the injected nanohydrogel was replaced with a carbon dot dispersion that does not contain fucoidan.
TABLE 5
| Test item | Example 23 | Example 24 |
| Value of Pre-treatment leakage fluorescence intensity | 15000 | 15580 |
| Post-treatment leakage fluorescence intensity values | 100 | 12000 |
In comparative examples 23 and 24, when fucoidan is not present, carbon dots do not have a targeting property for new blood vessels, so that photodynamic processes cannot exert a therapeutic effect on new blood vessels, leakage due to new blood vessels cannot be effectively inhibited, and fluorescence contrast is expressed as strong fluorescence intensity.
The above embodiments do not limit the scope of the present invention. It will be apparent to those skilled in the art that various modifications, combinations, sub-combinations and alternatives can occur depending upon design requirements and other factors. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of the present invention.
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