CN119818469A - Succinate nano-drug, preparation method and application thereof - Google Patents
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Abstract
本发明提供一种琥珀酸盐纳米药物、其制备方法及应用，由琥珀酸铵和油酸钠通过微乳液法制备得到。当琥珀酸盐纳米药物进入肿瘤细胞后，能够触发细胞焦亡并刺激主要组织相容性复合体I(MHC‑I)表达上调。细胞焦亡的发生将释放大量的损伤相关分子模式(DAMPs)以触发免疫激活；MHC‑I表达上调将促进肿瘤细胞的免疫递呈。在细胞焦亡诱导的免疫激活和MHC‑I表达上调共同作用下，琥珀酸盐纳米药物不仅可以有效激活全身抗肿瘤免疫反应，而且能有效增加肿瘤细胞抗原递呈，从而高效抑制肿瘤生长和转移，提升免疫检查点阻断治疗效果。该琥珀酸盐纳米药物制备简单，反应条件温和，不含重金属元素，生物安全性高，表现出良好的应用前景。The present invention provides a succinate nano drug, a preparation method and application thereof, which is prepared by a microemulsion method from ammonium succinate and sodium oleate. When the succinate nano drug enters tumor cells, it can trigger cell pyroptosis and stimulate the upregulation of major histocompatibility complex I (MHC-I). The occurrence of cell pyroptosis will release a large number of damage-associated molecular patterns (DAMPs) to trigger immune activation; upregulation of MHC-I expression will promote the immune presentation of tumor cells. Under the combined effects of immune activation induced by cell pyroptosis and upregulation of MHC-I expression, the succinate nano drug can not only effectively activate systemic anti-tumor immune response, but also effectively increase tumor cell antigen presentation, thereby efficiently inhibiting tumor growth and metastasis, and improving the therapeutic effect of immune checkpoint blockade. The succinate nano drug is simple to prepare, mild reaction conditions, does not contain heavy metal elements, has high biosafety, and shows good application prospects.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a succinate nano-drug, a preparation method and application thereof.
Background
Tumor immunotherapy is a therapeutic approach to combat cancer by activating the body's autoimmune system. In recent years, immunotherapy typified by Immune Checkpoint Blocking (ICB) therapy has been widely used clinically, and has shown great promise and advantages. However, the low immune response rate (typically around 20%) in existing immunotherapy still greatly limits the further development of tumor immunotherapy. Tumor immune escape is one of the main causes of failure of cancer immunotherapy, for example, the deletion or down-regulation of MHC-I expression on the surface of cancer cells can cause patients to resist ICB therapy, thereby evading immune killing. MHC-I is located on the cell surface and has the primary function of presenting antigen to T cells to distinguish self (autologous cells and tissues) from non-self (invading or modified self). When an immune response occurs, CD8 + T cells recognize and bind to peptide fragments (called antigens) presented on the MHC-I molecules on the surface of cancer cells, thereby killing the cancer cells. Thus, the MHC-I antigen presentation pathway is a key mechanism that determines CD8 + T cell specificity and activation, and is also an important target for cancer immunotherapy. However, more and more studies have shown that cancer cells can down-regulate MHC-I positive regulators or up-regulate MHC-I negative regulators by a variety of mechanisms to interfere with the MHC-I antigen presentation pathway, reducing the level of MHC-I expression on the surface of tumor cells. The effect greatly reduces the recognition and killing of CD8 + T cells on tumor cells, increases the chance of tumor immune escape, and further generates immune therapy resistance. In summary, MHC-I, an important antigen presenting molecule, plays a critical role in tumor antigen presentation. Targeting up-regulation of MHC-I expression may become an effective immune escape suppression strategy, thereby providing a new idea for enhancing clinical tumor immunotherapy.
The current study suggests that mutations or deletions of key genes affecting the MHC-I antigen presenting pathway (Traf 3, B2M, TAP1/2, JAK, etc.) are the major contributors to the down-regulation of MHC-I antigen presentation in most tumors. The prior art has been directed to increasing MHC-I molecule expression by gene knockout, for example, as taught by Liu Xiaole and Myles Brown at university of harvard in the united states, which has shown that knockout of the Traf3 gene can significantly up-regulate MHC-I molecule expression, thereby significantly increasing the efficacy of immune checkpoint inhibitors in tumor therapy (Cancer discover, 2021,11,1524-1541).
The prior art mainly adopts a strategy of improving MHC-I molecule expression by gene knockout, which is easy to cause off-target toxicity and further application is limited by higher treatment cost. Therefore, how to effectively improve tumor cell MHC-I expression and reduce tumor immune escape is still a key scientific problem which is currently faced with and needs to be solved urgently.
Disclosure of Invention
The invention aims to provide a succinate nano-drug, a preparation method and application thereof, wherein the succinate nano-drug can stimulate MHC-I expression to be up-regulated, so that the ICB treatment effect is improved, the preparation is simple, the reaction condition is mild, no heavy metal element is contained, the biological safety is high, and the application prospect is good.
The invention provides a succinate nano-drug which is prepared from ammonium succinate and sodium oleate by a microemulsion method.
Preferably, the particle size of the succinate nano-drug is 10-200 nm.
Preferably, the molar ratio of the ammonium succinate to the sodium oleate is 1 (1-5).
The invention provides a preparation method of succinate nano-drugs as described above, comprising the following steps:
and mixing sodium succinate and sodium oleate solution, and reacting by a microemulsion method to obtain the succinate nano-drug.
Preferably, the sodium oleate solution comprises sodium oleate and an organic solvent, wherein the organic solvent comprises a mixture of n-hexane, absolute ethyl alcohol and oleylamine, and the volume ratio of n-hexane to absolute ethyl alcohol to oleylamine is (5-15): (1-5): 1.
Preferably, the concentration of sodium oleate in the sodium oleate solution is 0.5-2.5 mg/mL.
Preferably, after dispersing ammonium succinate in water, mixing the dispersion of sodium succinate with sodium oleate solution;
the concentration of ammonium succinate in the ammonium succinate dispersion is 50-500 mg/mL.
Preferably, the mixing of the sodium succinate and the sodium oleate solution is performed under the stirring condition, and the stirring speed is 200-1000 rpm.
Preferably, the reaction temperature is 15-40 ℃, and the reaction time is 3-60 min.
The invention provides an anti-tumor drug, which comprises the succinate nano-drug or the succinate nano-drug prepared by the preparation method.
The invention provides a succinate nano-drug which is prepared from ammonium succinate and sodium oleate by a microemulsion method. When succinate nano-drugs enter tumor cells, rapid decrease in acid lysosomes of the tumor cells is explained to release a large amount of Na + ions and succinate ions, which cause the ion concentration and osmotic pressure in the tumor cells to be increased and succinic acid to accumulate, thereby triggering cell apoptosis and stimulating MHC-I expression to be up-regulated. The occurrence of apoptosis will release a number of damage-associated molecular patterns (DAMPs) to trigger immune activation, and upregulation of MHC-I expression will promote immune presentation by tumor cells. Therefore, under the combined action of the activation of cell apoptosis-induced immunity and the up-regulation of MHC-I expression, the succinate nano-drug not only can effectively activate the whole-body anti-tumor immune response, but also can effectively increase the antigen presentation of tumor cells, thereby effectively inhibiting the growth and metastasis of tumors and improving the ICB treatment effect. The succinate nano-drug has the advantages of simple preparation, mild reaction conditions, no heavy metal elements, high biological safety and good application prospect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a transmission electron micrograph of a succinate nano-drug obtained in example 1 of the present invention;
FIG. 2 is an X-ray diffraction pattern of the succinate nano-drug obtained in example 1 of the present invention;
FIG. 3 is a transmission electron micrograph of a succinate nano-drug obtained in example 2 of the present invention;
FIG. 4 is a transmission electron micrograph of a succinate nano-drug obtained in example 3 of the present invention;
FIG. 5 is the data of upregulation of MHC-I expression in tumor cells stimulated by succinate nano-drug obtained in example 1 of the present invention;
FIG. 6 is a photograph showing the cell morphology of a treated mouse breast cancer cell (4T 1) with the succinate nano-drug obtained in example 1 of the present invention;
FIG. 7 shows cytotoxicity data of succinate nanomedicine obtained in example 1 of the present invention after treatment of 4T1 cells;
FIG. 8 shows the change of tumor of mice after treatment with succinate nano-drug, wherein A is a photograph of tumor of mice, B is a curve of tumor volume of mice over time, and C is a curve of body weight of mice over time;
fig. 9 shows the expression of different immune cells in mice treated with succinate nanomedicine, a graph a shows the maturation of dendritic cells in the spleen of mice, B graph B shows the statistics of mature dendritic cells in the spleen of mice, C graph C shows the statistics of CD4 + T cells in the tumor of mice, D graph shows the statistics of CD4 + T cells in the tumor of mice, E graph shows the statistics of CD8 + T cells in the tumor of mice, and F graph shows the statistics of CD8 + T cells in the tumor of mice.
Detailed Description
The invention provides a succinate nano-drug which is prepared from ammonium succinate and sodium oleate by a microemulsion method.
In the invention, the succinate nano-drug is a nano-particle of sodium succinate, and the particle size is preferably 10-200 nm, more preferably 50-150 nm.
In the invention, the molar ratio of the ammonium succinate to the sodium oleate is preferably 1 (1-5).
The invention also provides a preparation method of the succinate nano-drug, which comprises the following steps:
and mixing sodium succinate and sodium oleate solution, and reacting by a microemulsion method to obtain the succinate nano-drug.
The invention preferably disperses ammonium succinate in water to obtain ammonium succinate dispersion, then mixes the ammonium succinate dispersion with sodium oleate solution under stirring, reacts by a microemulsion method, and centrifugally collects precipitate after the reaction is finished to obtain the succinate nano-drug.
In the present invention, the concentration of ammonium succinate in the ammonium succinate dispersion is preferably 50 to 500mg/mL, more preferably 100 to 400mg/mL, such as 50mg/mL,100mg/mL,150mg/mL,200mg/mL,250mg/mL,300mg/mL,350mg/mL,400mg/mL,450mg/mL,500mg/mL, and preferably a range having any of the above values as an upper limit or a lower limit.
In the present invention, the sodium oleate solution preferably includes sodium oleate and an organic solvent, the organic solvent preferably includes a mixture of n-hexane, anhydrous ethanol and oleylamine, and the volume ratio of n-hexane, anhydrous ethanol and oleylamine is preferably (5-15): 1-5): 1, more preferably (8-12): 2-4): 1, most preferably (9-11): 2-4): 1, and in particular, in an embodiment of the present invention, may be 10:3:1.
In the present invention, the concentration of sodium oleate in the sodium oleate solution is preferably 0.5 to 2.5mg/mL, more preferably 1 to 2mg/mL, such as 0.5mg/mL,1mg/mL,1.5mg/mL,2mg/mL,2.5mg/mL, preferably a range having any of the above values as an upper limit or a lower limit.
In the present invention, the molar ratio of the ammonium succinate to the sodium oleate in the sodium oleate solution is preferably 1 (1-5), more preferably 1 (2-4), such as 1:1,1:1.5,1:2,1:2.5,1:3,1:3.5,1:4,1:4.5,1:5, preferably ranges from any of the above values to the upper or lower limit.
In the present invention, the stirring speed during the mixing is preferably 200 to 1000rpm, more preferably 300 to 800rpm.
In the invention, the reaction temperature of the microemulsion method is preferably 15-40 ℃, more preferably 20-30 ℃, and most preferably the reaction is performed at room temperature, the reaction time of the microemulsion method is preferably 3-60 min, more preferably 5-50 min, such as 3min,5min,10min,15min,20min,25min,30min,35min,40min,45min,50min,55min,60min, and preferably the range value with any value as the upper limit or the lower limit is adopted.
The invention also provides an anti-tumor drug, which comprises the succinate nano-drug.
When succinate nano-drugs enter tumor cells, rapid decrease in acid lysosomes of the tumor cells is explained to release a large amount of Na + ions and succinate ions, which cause the ion concentration and osmotic pressure in the tumor cells to be increased and succinic acid to accumulate, thereby triggering cell apoptosis and stimulating MHC-I expression to be up-regulated. The occurrence of apoptosis will release a number of damage-associated molecular patterns (DAMPs) to trigger immune activation, and upregulation of MHC-I expression will promote immune presentation by tumor cells. Therefore, under the combined action of the activation of cell apoptosis-induced immunity and the up-regulation of MHC-I expression, the succinate nano-drug not only can effectively activate the whole-body anti-tumor immune response, but also can effectively increase the antigen presentation of tumor cells, thereby effectively inhibiting the growth and metastasis of tumors and improving the ICB treatment effect. The succinate nano-drug has the advantages of simple preparation, mild reaction conditions, no heavy metal elements, high biological safety and good application prospect.
In order to further illustrate the present invention, the following examples are provided to describe in detail a succinate nano-drug, its preparation method and application, but should not be construed as limiting the scope of the present invention.
Example 1
20 Mg of sodium oleate was dispersed in a mixed solution containing 10ml of n-hexane, 3 ml of ethanol and 1ml of oleylamine, while 5 mg of ammonium succinate was dispersed in 10 μl of deionized water. At room temperature, 10. Mu.l of an aqueous ammonium succinate solution was added dropwise to the sodium oleate mixture at a stirring rate of 1000rpm, and the reaction was continued at room temperature of 25℃for 10 minutes. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
The morphology of the succinate nano-drug is characterized by adopting a transmission electron microscope, and the result is shown in the figure 1, so that the succinate nano-drug prepared by the microemulsion method can be seen to be spherical particles with uniform size. Meanwhile, the structure of the succinate nano-drug is characterized by adopting X-ray diffraction, and the result is shown in figure 2, so that the succinate nano-drug has a sodium succinate pure-phase structure.
Example 2
20Mg of sodium oleate was dispersed in a mixed solution containing 10 ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5 mg of ammonium succinate was dispersed in 50 μl of deionized water. 50. Mu.l of an aqueous ammonium succinate solution were added dropwise to the sodium oleate mixture at room temperature with stirring at 1000rpm, and the reaction was continued for 10 minutes at room temperature of 25 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
Example 3
20 Mg of sodium oleate was dispersed in a mixed solution containing 10 ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5 mg of ammonium succinate was dispersed in 100 μl of deionized water. 100. Mu.l of an aqueous ammonium succinate solution was added dropwise to the sodium oleate mixture at room temperature with stirring at 1000rpm, and the reaction was continued for 10 minutes at room temperature of 25 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
Example 4
7 Mg of sodium oleate was dispersed in a mixed solution containing 10ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5mg of ammonium succinate was dispersed in 50 μl of deionized water. 50. Mu.l of an aqueous ammonium succinate solution were added dropwise to the sodium oleate mixture at room temperature with stirring at 1000rpm, and the reaction was continued for 10 minutes at room temperature of 25 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
Example 5
35 Mg of sodium oleate was dispersed in a mixed solution containing 10 ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5 mg of ammonium succinate was dispersed in 50 μl of deionized water. 50. Mu.l of an aqueous ammonium succinate solution were added dropwise to the sodium oleate mixture at room temperature with stirring at 1000rpm, and the reaction was continued for 10 minutes at room temperature of 25 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
Example 6
20Mg of sodium oleate was dispersed in a mixed solution containing 10ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5mg of ammonium succinate was dispersed in 50 μl of deionized water. 50. Mu.l of an aqueous ammonium succinate solution were added dropwise to the sodium oleate mixture at room temperature with stirring at 1000rpm, and the reaction was continued for 3 minutes at room temperature of 25 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
Example 8
20 Mg of sodium oleate was dispersed in a mixed solution containing 10 ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5 mg of ammonium succinate was dispersed in 50 μl of deionized water. 50. Mu.l of an aqueous ammonium succinate solution were added dropwise to the sodium oleate mixture at room temperature with stirring at 1000rpm, and the reaction was continued for 60 minutes at room temperature of 25 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
Example 9
20 Mg of sodium oleate was dispersed in a mixed solution containing 10 ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5 mg of ammonium succinate was dispersed in 50 μl of deionized water. 50. Mu.l of an aqueous ammonium succinate solution were added dropwise to the sodium oleate mixture at 28℃with stirring at 1000rpm, and the reaction was continued for 10 minutes at 28 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
Example 10
20 Mg of sodium oleate was dispersed in a mixed solution containing 10 ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5 mg of ammonium succinate was dispersed in 50 μl of deionized water. 50. Mu.l of an aqueous ammonium succinate solution were added dropwise to the sodium oleate mixture at 15℃with stirring at 1000rpm, and the reaction was continued for 10 minutes at 15 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
Example 11
20 Mg of sodium oleate was dispersed in a mixed solution containing 10 ml of n-hexane, 3 ml of ethanol and 1 ml of oleylamine, while 5 mg of ammonium succinate was dispersed in 50 μl of deionized water. 50. Mu.l of an aqueous ammonium succinate solution were added dropwise to the sodium oleate mixture at 40℃with stirring at 1000rpm, and the reaction was continued for 10 minutes at 40 ℃. And centrifuging and collecting the precipitate to obtain the succinate nano-drug.
The invention detects MHC-I on the surface of mouse tumor cells after induction of succinate nano-drugs obtained in the example 1. Tumors of mice after treatment were prepared as single cell suspensions, then incubated with fluorescent-labeled MHC-I antibodies, and detected with a flow cytometer after incubation. The detection results are shown in fig. 5, and the synthesized succinate nano-drug can stimulate the up-regulation of tumor cell MHC-I expression.
In-vitro cell apoptosis detection experiments are carried out on the succinate nano-drugs obtained in the embodiment 1, wherein the test method comprises the steps of inoculating 4T1 cells into a 12-hole plate at the density of 10 ten thousand cells per hole, culturing for 12 hours in a RMPI culture medium, adding 200 micrograms per milliliter of succinate nano-drugs, incubating for 12 hours, and shooting the cell morphology by using an inverted fluorescence microscope. The results of the assay are shown in FIG. 6, and the occurrence of cell apoptosis is demonstrated by the apparent bubbling of succinate nano-drug treated cells.
The invention performs in vitro cytotoxicity analysis test on the succinate nano-drug obtained in the example 1, wherein the test method comprises the steps of measuring cytotoxicity by adopting an MTT method, inoculating 4T1 cells into a 96-well plate at the density of 6000 cells per well, culturing for 12 hours in an RMPI culture medium, adding succinate nano-drug with different concentrations (the concentration range is 0-200 mu g.mL -1), incubating for 24 hours, detecting cell proliferation by utilizing an MTT detection method, and the test result is shown in figure 7, wherein the prepared succinate nano-drug can kill tumor cells with high efficiency.
The immune activation effect and the tumor inhibition effect of the succinate nano-drug obtained in the example 1 are detected. BALB/C mice bearing 4T1 tumors were randomly allocated to three groups (6 each) and two intratumoral injections of succinate nanomaterials (succinate nanomaterials dispersed in PBS solution, administered with succinate nanoparticles at a concentration of 40.0mg Na +(kg BW)-1 (prepared in example 1, corresponding to C 4H4Na2O4 NPs in fig. 8 and 9), succinate small molecule reagent (sodium succinate free small molecule, corresponding to C 4H4Na2O4)(40.0mg Na+(kg BW)-1 in fig. 8 and 9) or PBS (corresponding to PBS in fig. 8 and 9) were performed on day 1 and day 3 during treatment the tumor volume (V) was calculated by measuring the length (L) and width (W) of each tumor with calipers during treatment using the following formula.
In addition, weight data was also collected. At the end of treatment, mice were sacrificed to resect major organs and tumors for further use. According to standard procedures we obtained a single cell suspension of spleen by digestion. The spleen single cell suspension was then examined by flow cytometry (guava easyCyteTM) using fluorescein-labeled anti-mouse antibodies (FITC anti-mouse CD11c, APC anti-mouse CD86, PE anti-mouse CD 80) to find immature DCs. In addition, single cell suspensions of tumors were also obtained and detection of T cells (FITC anti-mouse CD4, PE anti-mouse CD3, APC anti-mouse CD8a, 7-ADD) was performed using fluorescein-labeled anti-mouse antibodies. The detection results are shown in fig. 8 and 9, and the succinate nano-drug can effectively activate the immune response of the organism and effectively inhibit the growth of tumors. In addition, the body weight of the mice is not obviously reduced, and the mice show good biological safety.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
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2025
- 2025-01-08 CN CN202510028370.4A patent/CN119818469A/en active Pending
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