Polycyclodextrin / dimethoxyglycin composite nanoparticle as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a polycyclodextrin / dimethoxyglycin composite nanoparticle and a preparation method and application thereof, the composite nanoparticle is composed of a polycyclodextrin carrier and a dimethoxyglycin inhibitor, the polycyclodextrin is beta-cyclodextrin which is modified by poly (isobutylene-maleic anhydride) and contains a substituent group; the substituent groups are amino group-containing groups and hydroxyl group-containing groups. The composite nanoparticles can effectively improve the stability of DMOG, realize release of a polyamine responsive drug and capture of polyamine molecules, can realize a dual synergistic effect in the same drug carrier, improve the bioavailability of the drug, reduce toxic and side effects, regulate and control the physical and chemical properties of the drug molecules, improve the inflammatory microenvironment, and improve the anti-inflammatory activity of the drug. And inflammation is effectively relieved by removing excessive polyamine. Meanwhile, the cyclodextrin cavity is matched with the sizes of the polyamine molecules and the drug molecules, so that favorable conditions are provided for drug delivery and polyamine capture.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a polycyclodextrin / dimethoxyoxalylglycine composite nanoparticle and a preparation method and application thereof. Background Art

[0002] Chronic inflammation is closely related to the occurrence and development of many diseases, and is accompanied by changes in the microenvironment, such as changes in reactive oxygen species (ROS), pH, enzymes, and polyamine content. Natural polyamines are a class of low molecular weight fatty amines that participate in the growth and differentiation of cells and can be used as biomarkers for a variety of diseases. They are closely related to the occurrence and development of a variety of diseases. In addition, polyamine metabolism plays an important role in guiding the fate selection of mouse CD4+T cells, and is of great significance for the treatment of polyamine metabolism in inflammatory diseases. Studies have shown that the content of polyamines in the tissues and gingival crevicular fluid of patients with periodontal inflammation is significantly increased, which can aggravate periodontal inflammation and promote bacterial proliferation. Its concentration is closely related to the severity of periodontitis. Imbalance in polyamine metabolism at the site of inflammation can lead to cell dysfunction or apoptosis, and removing excess polyamines can effectively relieve inflammation.

[0003] Cyclodextrin molecules have a slightly conical hollow cylindrical three-dimensional ring structure. In its hollow structure, the upper end (larger opening end) is composed of secondary hydroxyl groups of C2 and C3, and the lower end (smaller opening end) is composed of primary hydroxyl groups of C6, which are hydrophilic. The cavity forms a hydrophobic area due to the shielding effect of the CH bond. Among many macrocyclic molecules, it can act as a host to envelop various appropriate guests such as organic molecules, inorganic ions, and gas molecules. Cyclodextrin molecules form host-guest inclusion complexes with various drug molecules through host-guest interactions, improve the water solubility of drug molecules, increase drug stability, improve the bioavailability of drugs, reduce toxic side effects, and achieve the regulation of the physicochemical properties of drug molecules. It has been used as an additive for drug preparations. The size of the cyclodextrin cavity matches that of polyamine molecules and drug molecules, providing favorable conditions for drug delivery and polyamine capture. Its hydrophobic inner cavity and hydrophilic outer surface enable it to form inclusion compounds and molecular assembly systems with many organic and inorganic molecules based on van der Waals forces, hydrophobic interactions, and matching effects between host and guest molecules, making it an interesting research object for chemistry and chemical engineering researchers.

[0004] Dimethyloxalylycine (DMOG), as a small molecule inhibitor, can inhibit the activity of proline hydroxylase and stabilize the expression of hypoxia-inducible factor HIF-1α, thereby promoting angiogenesis and bone tissue repair. Although DMOG has been proven to have a variety of biological effects, its poor stability, short half-life, and easy clearance are important reasons that restrict its clinical development. Due to the asymmetric structure of DMOG, DMOG is easily hydrolyzed to form MOG in culture medium or water medium, and MOG needs to be transported into cells through monocarboxylate transporter 2 (MCT2). In addition, MOG can also be transported into cells through MCT1 or MCT4, but the transport efficiency is lower than that of MCT2. MCT2 is only expressed in human tumor tissues, so it is crucial to find a suitable carrier to transport DMOG and improve the stability of DMOG. The existing technology uses cyclodextrin molecules as carriers to form inclusion complexes with DMOG, but there is a problem of low drug encapsulation rate, and there is no in-depth study of the effect of inclusion complex formation on the stability of DMOG. Summary of the invention

[0005] The purpose of the present invention is to provide a polycyclodextrin / dimethoxyoxalylglycine composite nanoparticle and a preparation method and application thereof, so as to overcome the shortcomings of the prior art. The synthesized polycyclodextrin / dimethoxyoxalylglycine composite nanoparticle can effectively improve the stability of dimethoxyoxalylglycine molecules, realize polyamine-responsive drug release and capture of polyamine molecules, realize dual synergistic effects in the same drug carrier, and improve the inflammatory microenvironment.

[0006] In order to achieve the above object, the technical solution of the present invention is:

[0007] In a first aspect, the present invention provides a polycyclodextrin / dimethoxyoxylglycine composite nanoparticle, wherein the composite nanoparticle is composed of a polycyclodextrin carrier and a dimethoxyoxylglycine inhibitor, wherein the polycyclodextrin is polymerized by poly(isobutylene-maleic anhydride) and substituted β-cyclodextrin.

[0008] In some other embodiments, the structural formula of the substituted β-cyclodextrin is as shown in Formula I: R1 is selected from -CH2OH, -CH2NH2, -CH2NH(CH2)3NH2, -CH2NH(CH2CH2NH)2CH2CH2NH2 and -CH2NH(CH2CH2NH)3CH2CH2NH2; R2 is selected from -NH2 and -OH; wherein R1 and R2 are not substituents containing amino and hydroxyl groups at the same time;

[0009]

[0010] In some other embodiments, the molar ratio of the polycyclodextrin to dimethoxyoxalylglycine is 1:(1-5).

[0011] In some other embodiments, the molecular weight of the poly(isobutylene-maleic anhydride) is 3-10 kDa; and the molar ratio of the poly(isobutylene-maleic anhydride) to the substituted β-cyclodextrin is 1:(6-10).

[0012] In a second aspect, the present invention provides a method for preparing the polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to the first aspect, comprising the following steps:

[0013] (1) adding poly(isobutylene-maleic anhydride), substituted β-cyclodextrin and a catalyst into a solvent for heating reaction, dialyzing and freeze-drying to obtain polycyclodextrin;

[0014] (2) Adding polycyclodextrin and dimethoxyoxalylglycine into an inorganic solvent and mixing them, and drying them to obtain polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles.

[0015] In some other embodiments, in step (1), the catalyst is selected from N,N-diisopropylethylamine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide;

[0016] The molar ratio of the added amount of the catalyst to the substituted beta-cyclodextrin is 1:(10-30).

[0017] In some other embodiments, in step (1), the solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and deionized water; and the amount of the solvent added is 5-20 mL.

[0018] In some other embodiments, in step (1), the conditions of the heating reaction are: the heating temperature is 30-70° C., and the heating time is 6-20 h;

[0019] Alternatively, the dialysis is performed using a dialysis bag for 2-3 days.

[0020] In some other embodiments, in step (2), the inorganic solvent is water and phosphate buffered saline; the mixing is stirring or ultrasonic time is 12h-24h;

[0021] Alternatively, the drying is freeze-drying.

[0022] In a third aspect, the present invention provides use of the polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles described in the first aspect in preparing anti-inflammatory drugs.

[0023] Beneficial effects of the present invention:

[0024] 1. The polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles prepared by the present invention improve the stability of dimethoxyoxalylglycine molecules, and realize polyamine-responsive drug release and capture of polyamine molecules, and can achieve dual synergistic effects in the same drug carrier, improve the bioavailability of drugs, reduce toxic side effects, and realize the regulation of the physicochemical properties of drug molecules.

[0025] 2. The polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles prepared by the present invention can significantly improve the inflammatory microenvironment, reduce the level of cellular oxidative stress by removing excess polyamines, and effectively relieve inflammation. At the same time, the cyclodextrin cavity matches the size of polyamine molecules and drug molecules, providing favorable conditions for drug delivery and verification of microenvironment improvement. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0027] Figure 1 This is the reaction route for preparing polycyclodextrin in Example 1 of the present invention;

[0028] Figure 2 This is a particle size distribution diagram of polycyclodextrin and polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles of Example 1 of the present invention;

[0029] Figure 3 The polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles of Example 1 of the present invention 1 H- 1 H

[0030] NOESY spectrum;

[0031] Figure 4 This is a diagram showing the effect of polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles in improving the stability of dimethoxyoxalylglycine and delaying hydrolysis according to Examples 1 and 3 of the present invention;

[0032] Figure 5 This is a diagram showing the effect of polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles in Example 1 of the present invention on removing intracellular ROS;

[0033] Figure 6 This is a diagram showing the effect of polycyclodextrin / dimethoxyoxadiopyridine composite nanoparticles in clearing intracellular polyamines under LPS-induced inflammatory conditions in Example 1 of the present invention;

[0034] Figure 7This is a diagram showing the effect of polycyclodextrin / dimethoxyoxylglycine composite nanoparticles in regulating the expression level of inflammatory factors in Example 1 of the present invention under a high concentration SP environment. DETAILED DESCRIPTION

[0035] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0036] Example 1

[0037] A method for preparing polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles, such as Figure 1 As shown, the steps include:

[0038] Weigh 0.2 g of poly(isobutylene-maleic anhydride) with a molecular weight of 6 kDa, 0.22 g of R1-R2 substituted β-cyclodextrin (R1 is -CH2NH2, R2 is -OH), and 1 mL of N,N-diisopropylethylamine (DIPEA) and place them in a 25 mL round-bottom flask, add 15 mL of N,N-dimethylformamide, heat at 50 ° C for 16 h, and remove the solvent by rotary evaporation. The remaining solid is dissolved in deionized water, dialyzed in a dialysis bag with MWCO3500 for 2-3 days, and freeze-dried to obtain a white product (labeled as PCD).

[0039] According to the grafting ratio of CD in the NMR results, the molecular weight of the polymer grafted with a single cyclodextrin (CD) was calculated. A deionized water solution with a molar ratio of polycyclodextrin to DMOG of 1:5 was prepared and stirred for 12 hours to mix evenly to prepare a D / PCD solution.

[0040] Example 2

[0041] Weigh 0.2 g of poly(isobutylene-maleic anhydride) with a molecular weight of 6 kDa, 0.22 g of R1-R2 substituted β-cyclodextrin (R1 is -CH2NHCH2CH2CH2NH2, R2 is -OH), and 1 mL of N,N-diisopropylethylamine (DIPEA) and place them in a 25 mL round-bottom flask, add 15 mL of dimethyl sulfoxide, heat at 50 ° C for 16 h, and remove the solvent by rotary evaporation. The remaining solid is dissolved in deionized water, dialyzed in a dialysis bag with MWCO3500 for 2-3 days, and freeze-dried to obtain a white product PCD1.

[0042] According to the grafting ratio of CD in the NMR results, the molecular weight of the polymer grafted with a single CD was calculated. A deionized water solution with a molar ratio of 1:1 of mono-polycyclodextrin and DMOG was prepared, stirred for 12 hours and mixed evenly to prepare a D / PCD1 solution.

[0043] Example 3

[0044] Weigh 0.2 g of poly(isobutylene-maleic anhydride) with a molecular weight of 6 kDa and 0.22 g of R1-R2 substituted β-cyclodextrin (R1 is -CH2OH, R2 is -NH2), add 0.57 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 0.34 g of N-hydroxysulfosuccinimide (NHS), place in a 25 mL round-bottom flask, add 15 mL of acetonitrile, heat at 50 ° C for 16 h, remove the solvent acetonitrile by rotary evaporation, dissolve the remaining solid in deionized water, dialyze in a dialysis bag of MWCO3500 for 2-3 days, and freeze-dry to obtain a white product PCD2.

[0045] According to the grafting ratio of CD in the NMR results, the molecular weight of the polymer grafted with a single CD was calculated. A deionized water solution with a molar ratio of 1:1 of mono-polycyclodextrin and DMOG was prepared, stirred for 12 hours to mix evenly, and a D / PCD2 solution was prepared.

[0046] Performance Testing

[0047] (1) Particle size distribution of polycyclodextrin and polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles

[0048] Figure 2 The particle size distribution diagram of polycyclodextrin and polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles in Example 1 of the present invention; PCD is polycyclodextrin, and D / PCD is polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles. Figure 2 It can be seen that after forming composite nanoparticles with dimethoxyoxalylglycine, the particle size of D / PCD increased significantly, proving that polycyclodextrin and dimethoxyoxalylglycine formed a host-guest inclusion complex.

[0049] (2) Polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles 1 H- 1 H NOESY spectrum

[0050] 600 μL of 2 mM D / PCD (the molar ratio of D to PCD was 1:1) was prepared with deuterated water and obtained by 2D NMR scanning. 1 H- 1 H NOESY spectrum.

[0051] Figure 3 This is the 1H-1HNOESY spectrum of the polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles of Example 1 of the present invention; wherein the positions of the peaks marked with a, b, and c are the corresponding proton peaks at the positions a, b, and c in the DMOG compound. Figure 3It can be seen that the a, b, c proton peaks in PCD and DMOG have cross peaks above and below the diagonal of the spectrum, confirming the host-guest interaction between PCD and DMOG. In addition, some other marks in the figure are data from the NMR data, which will not affect the data even if they are not clear.

[0052] (3) Effect of dimethoxyoxalylglycine on stability and delaying hydrolysis

[0053] PBS was used to prepare 3 mL of 0.1 mM D solution, 3 mL of 0.1 mM D / PCD2 (the molar ratio of D to PCD2 was 1:1) solution, and 3 mL of 0.1 mM D / PCD (the molar ratio of D to PCD was 1:1) solution, respectively. A UV-visible spectrophotometer was used to monitor the hydrolysis efficiency of D, D / PCD2, and D / PCD at different times. The UV-visible absorption spectra of D+0.5 mM NaOH, D / PCD2+0.5 mM NaOH solution, and D / PCD+0.5 mM NaOH solution were used as standards for complete hydrolysis, and the hydrolysis ratio was determined based on the absorbance value of each group at 224 nm.

[0054] Figure 4 The effect diagram of the composite nanoparticles D / PCD in Example 1 and D / PCD2 in Example 3 of the present invention on improving the stability of dimethoxyoxalylglycine and delaying hydrolysis; wherein D is dimethoxyoxalylglycine, and D / PCD is polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles. Figure 4 It can be seen that within 30 minutes, the hydrolysis rates of drug molecules in the D group, D / PCD2 group and D / PCD group were 39.9%, 52.6% and 57.6%, respectively, indicating that the D / PCD composite nanoparticles significantly enhanced the stability of the drug and delayed the hydrolysis process, and the effect was better than that of the D / PCD2 composite nanoparticles. This is because the steric hindrance of cyclodextrin is greater during the preparation of PCD2, so the cyclodextrin grafting rate of the prepared PCD2 is lower, so the encapsulation effect of DMOG is slightly worse.

[0055] (4) Role of LPS in clearing intracellular ROS in an inflammatory environment

[0056] ROS detection kit was used to detect the level of ROS in NIH3T3 cells under high concentration polyamine stimulation. NIH3T3 cells were cultured at 2.5×10 4 The cells were seeded at a density of 100 μg / well in a 48-well plate and co-cultured with D / PCD. After incubation with 5 μg / mL LPS for 24 h, the cells were treated with D, PCD and D / PCD for 24 h, respectively. The excess nanomaterials were removed, the cells were washed with PBS, and co-cultured with the DCFH-DA probe for 30 min. The intracellular ROS content of each group was observed using a fluorescence microscope (Leica, Wetzlar, Germany).

[0057] Figure 5 This is a diagram showing the effect of D / PCD composite nanoparticles in removing intracellular ROS in Example 1 of the present invention; wherein Con is a blank control group, LPS is a lipopolysaccharide stimulation-simulated inflammation group, D is an experimental group in which dimethoxyoxylic acid is added to cells after LPS stimulation, PCD is an experimental group in which polycyclodextrin is added to cells after LPS stimulation, and D / PCD is an experimental group in which polycyclodextrin / dimethoxyoxylic acid composite nanoparticles are added to cells after LPS stimulation; Merged is a fusion state, DCFH Channel is a DCFH fluorescent probe signal channel, and Bright Field is a bright field image. Figure 5 It can be seen that the fluorescence intensity of the D and PCD groups was slightly reduced compared with the LPS group, but there was no statistically significant difference between the D and PCD groups. The addition of D / PCD composite nanoparticles led to a significant decrease in fluorescence intensity, indicating that D / PCD composite nanoparticles enhanced the ROS scavenging ability through the synergistic effect of anti-inflammatory drug release and polyamine binding.

[0058] (5) The role of LPS in clearing intracellular polyamines in the context of LPS-induced inflammation

[0059] The total polyamine detection kit (Abcam, ab239728) was used to measure the intracellular polyamine concentration. NIH3T3 cells were cultured at 2×10 5 The cells were seeded at a density of 100 cells / well in a 6-well plate, and then 5 μg / mL LPS was added and incubated for 24 h. The cells were further treated with D, PCD, and D / PCD for 24 h. Finally, according to the operating steps in the manual, including the preparation of samples and reaction mixtures, incubation of samples and reaction mixtures, and fluorescence measurement, the intracellular polyamine concentrations of different groups were obtained.

[0060] Figure 6 This is a diagram showing the effect of polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles in clearing intracellular polyamines under LPS-induced inflammatory conditions in Example 1 of the present invention; wherein Con is a blank control group, LPS is a lipopolysaccharide-stimulated inflammation group, D is an experimental group in which dimethoxyoxalylglycine is added after LPS stimulation of cells, PCD is an experimental group in which polycyclodextrin is added after LPS stimulation of cells, and D / PCD is an experimental group in which polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles are added after LPS stimulation of cells. Figure 6 It can be seen that Figure 5The results depicted in the D / PCD group showed that LPS stimulation led to a significant increase in intracellular polyamine content (2-fold increase compared to the control group). Both the D and PCD groups showed a slight decrease in intracellular polyamine content, which was attributed to the anti-inflammatory properties of D and the polyamine binding properties of PCD. The polyamine levels of D / PCD composite nanoparticles decreased significantly after 24 hours of co-culture, which was the result of the synergistic effect of anti-inflammatory drug release and PCD binding to polyamines.

[0061] (6) Effect of regulating the expression level of inflammatory factors under high concentration SP environment

[0062] NIH3T3 cells were cultured at 2×10 5 The cells were seeded at a density of 100 μM spermine (SP) per well in a 6-well plate, and then 10 μM spermine (SP) was added and incubated for 24 h. The cells were further treated with D, PCD and D / PCD for 24 h. Total RNA of NIH3T3 cells was extracted using Trizol reagent. The RNA extraction process generally includes phase separation, RNA separation and washing. The RNA concentration was determined using NanoDrop OneC ultra-micro UV spectrophotometer (Thermo Fisher, USA). qRT-PCR analysis was performed using 2×SYBR Green qPCR Mix (SparkJade, Shandong, China) and SPARKscript1st Strand cDNASynthesis Kit (SparkJade, Shandong, China). The reaction was then measured using a Roche LightCycler 480IIPCR instrument (Basel, Switzerland). -ΔΔCT Methods The mRNA expression of the detected genes in each experimental group was normalized with that of GAPDH. Each experiment was repeated at least 3 times.

[0063] Figure 7 This is a diagram showing the effect of polycyclodextrin / dimethoxyglycine composite nanoparticles in regulating the expression level of inflammatory factors in Example 1 of the present invention under a 10 μM SP environment; wherein Con is a blank control group, LPS is a lipopolysaccharide-stimulated inflammation group, D is an experimental group in which dimethoxyglycine is added after LPS stimulation of cells, PCD is an experimental group in which polycyclodextrin is added after LPS stimulation of cells, and D / PCD is an experimental group in which polycyclodextrin / dimethoxyglycine composite nanoparticles are added after LPS stimulation of cells. Figure 7It can be seen that in the inflammatory microenvironment, excessive accumulation of SP induces oxidative stress, leading to overexpression of inflammatory factors. The expression levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were detected by qRT-PCR to evaluate the anti-inflammatory effect of D / PCD composite nanoparticles. Compared with the control group, SP stimulation significantly increased the relative mRNA expression levels of TNF-α and IL-1β. Compared with the SP group, the expression of the above genes in the D / PCD group was significantly reduced, while the reduction in the D and PCD groups was less. These results indicate that the addition of D / PCD composite nanoparticles can regulate the inflammatory microenvironment by downregulating the expression of pro-inflammatory genes, thereby effectively attenuating the SP-induced inflammatory response.

[0064] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A polycyclodextrin / dimethoxyoxalylglycine composite nanoparticle, characterized in that: The composite nanoparticles consist of a polycyclodextrin carrier and a dimethoxyoxalylglycine inhibitor, wherein the polycyclodextrin is polymerized from poly(isobutylene-maleic anhydride) and beta-cyclodextrin containing a substituent.

2. The polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to claim 1, characterized in that: The structural formula of the substituted β-cyclodextrin is as shown in Formula I: R1 is selected from -CH2OH, -CH2NH2, -CH2NH(CH2)3NH2, -CH2NH(CH2CH2NH)2CH2CH2NH2 and -CH2NH(CH2CH2NH)3CH2CH2NH2; R2 is selected from -NH2 and -OH; wherein R1 and R2 are not simultaneously substituents containing amino groups and hydroxyl groups; 3. The polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to claim 1, characterized in that: The molar ratio of the polycyclodextrin to dimethoxyoxalylglycine is 1:(5-25).

4. The polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to claim 1, characterized in that: The molecular weight of the poly(isobutylene-maleic anhydride) is 3-10 kDa; the molar ratio of the poly(isobutylene-maleic anhydride) to the substituted beta-cyclodextrin is 1:(6-10).

5. A method for preparing the polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) adding poly(isobutylene-maleic anhydride), substituted β-cyclodextrin and a catalyst into a solvent for heating reaction, dialyzing and freeze-drying to obtain polycyclodextrin; (2) Adding polycyclodextrin and dimethoxyoxalylglycine into an inorganic solvent and mixing them, and drying them to obtain polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles.

6. The method for preparing polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to claim 5, characterized in that: In step (1), the catalyst is selected from N,N-diisopropylethylamine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide; The molar ratio of the added amount of the catalyst to the substituted beta-cyclodextrin is 1:(10-30).

7. The method for preparing polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to claim 5, characterized in that: In step (1), the solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and deionized water; and the amount of the solvent added is 5-20 mL.

8. The method for preparing polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to claim 5, characterized in that: In step (1), the conditions of the heating reaction are: the heating temperature is 30-70° C., and the heating time is 6-20 h; Alternatively, the dialysis is performed using a dialysis bag for 2-3 days.

9. The method for preparing polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to claim 5, characterized in that: In step (2), the inorganic solvent is water and phosphate buffered saline solution; the mixing is stirring or ultrasonic time is 12h-24h; Alternatively, the drying is freeze-drying.

10. Use of the polycyclodextrin / dimethoxyoxalylglycine composite nanoparticles according to any one of claims 1 to 4 in preparing anti-inflammatory drugs.

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