Preparation method of ROS-responsive drug delivery system for dual-targeted treatment of diabetic nephropathy

Abstract

This invention discloses a method for preparing a ROS-responsive drug-loaded dual-targeted nanodelivery system for the treatment of diabetic nephropathy, belonging to the fields of nanomedicine and biomedicine. This invention uses FeCl3, Ce(NO3)3·6H2O, and tetrakis(4-carboxyphenyl)porphyrin (TCPP) as raw materials to prepare the metal complex TCPP-Fe. 3+ -Ce 3+ The nanocarrier TCPP-Fe was obtained by activating the carboxyl groups on the metal complex, grafting them with amino groups, and linking them with ROS-responsive diselenyl bonds. 3+ -Ce 3+ @Se-Se, using TCPP-Fe 3+ -Ce 3+ The amino group on @Se-Se binds to a specific peptide ligand targeting kidney tissue, and is then further loaded with drugs to obtain a reactive oxygen species-responsive drug delivery nanodelivery system for targeted therapy of diabetic nephropathy.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a method for preparing a ROS-responsive drug delivery system for dual-targeted treatment of diabetic nephropathy. Background Technology

[0002] Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes and an important cause of chronic kidney disease and end-stage renal disease. The progression of DKD is closely related to excessive production of mitochondrial reactive oxygen species (ROS), mitochondrial DNA mutations, mitochondrial abnormalities, excessive mitochondrial division caused by mitochondrial respiratory chain complex disorder, and mitochondrial dynamic disorders. Regulating mitochondrial homeostasis in DKD has been shown to alleviate lipid accumulation.

[0003] Since the 1990s, nanoparticles have served as drug delivery carriers for various diseases, including cancer and tumors. However, research on nanomedicines targeting kidney disease (DKD) remains limited. This is because the glomerular filtration barrier (GFB) is the primary obstacle for passively targeting nanomedicines into the kidneys. Besides designing the physicochemical properties of nanoparticles to passively target them into the kidneys, functionalization with targeting ligands can actively target and specifically identify the site of kidney disease, improving drug delivery for specific kidney conditions. Furthermore, the selection of nanomedicine carriers and the bioavailability of nanosystems are also major challenges that need to be addressed. The choice of nanocarrier affects drug release and the degradation cycle of the system. Therefore, there is an urgent need to develop a precise, safer, and more efficient DKD treatment strategy.

[0004] To effectively treat diabetic kidney disease (DKD), it is necessary to develop a drug delivery system that targets both the renal tubules and glomeruli, has good biocompatibility, sustained-release properties, and is biodegradable. Combining this system with key drugs to intervene in key targets can provide a foundation for further research and development of drugs for diabetic nephropathy. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing a ROS-responsive drug delivery system for dual-targeted treatment of diabetic nephropathy using nanoparticles. The metal complex TCPP-Fe is prepared using FeCl3, Ce(NO3)3·6H2O, and tetrakis(4-carboxyphenyl)porphyrin (TCPP) as raw materials. 3+ -Ce 3+ The nanocarrier TCPP-Fe was obtained by activating the carboxyl groups on the metal complex, grafting them with amino groups, and linking them with ROS-responsive diselenyl bonds. 3+ -Ce 3+ @Se-Se, utilizing TCPP-Fe 3+ -Ce 3+The amino group on @Se-Se binds to a specific peptide ligand targeting kidney tissue, and is then further loaded with drugs to obtain a reactive oxygen species-responsive drug delivery nanodelivery system for targeted therapy of diabetic nephropathy.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] The present invention provides a method for preparing a ROS-responsive drug-loaded dual-targeted nanodelivery system for the treatment of diabetic nephropathy, comprising the following steps:

[0008] Step 1: Preparation of Nanocarriers

[0009] Ferric chloride and cerium nitrate were dissolved in 5 mL of organic solvent, and TCPP was added and stirred for 1-3 h (600-1500 rpm) followed by sonication for 5-30 min. Then, polyvinylpyrrolidone (PVP) and glacial acetic acid were added, stirred for 1-3 h (600-1500 rpm), and sonicated for 5-30 min to form a homogeneous dispersion. This mixture was then added to a hydrothermal reactor and heated in a water bath at 50-100℃ for 10-48 h. After the reaction, the sample was collected, centrifuged for 5-30 min (10000-15000 rpm, 0-4℃), and the supernatant was dialyzed (MWCO: 3500 Da) for 12-48 h to obtain the product, denoted as TCPP-Fe. 3+ -Ce 3+ .

[0010] Step 2: Preparation of diselenylene bond-modified nanocarriers

[0011] Take the above dialysis product, add carbodiimide (EDC), adjust the pH to 4-6 with NaOH, activate for 0.5-2 h (600-1500 rpm), then add a crosslinking stabilizer and stir for 2-24 h (600-1500 rpm). The resulting product is denoted as TCPP-Fe. 3+ -Ce 3+ @Se-Se;

[0012] Step 3: Loading specific ligands

[0013] In TCPP-Fe 3+ -Ce 3+ A specific ligand was added to the Se-Se solution, followed by EDC and a crosslinking stabilizer. The mixture was stirred for 2-24 hours (600-1500 rpm) and then dialyzed (MWCO: 3500 Da) for 12-48 hours to obtain TCPP-Fe. 3+ -Ce 3+ @Se-Se@Pep.

[0014] Step 4: Drug Loading

[0015] Weigh out the drug and dissolve it in an organic solvent, vortex at high speed for 30-300 seconds, and add it to TCPP-Fe. 3+ -Ce 3+ In a solution of @Se-Se@Pep., stir for 2-12 h. Dialyze for 10-24 h (3500 Da) to obtain the final product TCPP-Fe. 3+ -Ce 3+ @Se-Se@Pep.@Dr.

[0016] The organic solvents in steps 1 and 4 are one or more of the original water-soluble organic solvents, such as dimethylformamide (DMF), dihydrolevoglucosenone, ethyl acetate, and methyl ethyl ketone (MEK).

[0017] In step 1, the molecular weight of PVP is 10,000-50,000 Mw, and the mass ratio of PVP to glacial acetic acid is 0-2:1.

[0018] The crosslinking stabilizers in steps 2 and 3 are one or more carbodiimide crosslinking stabilizers such as N-hydroxysuccinimide (NHS) and selenocysteine ​​dihydrochloride.

[0019] The specific ligand in step 3 is one or more of the following: Cyclo (RGDfC), PKNGSDP, and ELRGD (R / M)AX (W / L), which can target both glomerular podocytes and renal tubular interstitial endothelial cells.

[0020] The drug in step 4 is one or more of the following: potent antioxidants and anti-inflammatory agents, including triptolide, vitamin C, vitamin E, tea polyphenols, anthocyanins, coenzyme Q10, sulforaphane, lipoic acid, etc., or other drugs that can be used to treat diabetic nephropathy.

[0021] The beneficial technical effects of the present invention are as follows:

[0022] In this invention, we are dedicated to designing a drug delivery platform for diabetic nephropathy using nanopolymers with dual glomerular and tubular targeting properties and ROS responsiveness. By utilizing the high specificity of specific peptide ligands to target cells and the ROS responsiveness of nanocarriers, we aim to improve the bioavailability and efficacy of drug therapy for diabetic nephropathy.

[0023] In this invention, we coordinate organic polymer TCPP with metal particles and link diselenide bonds to form a ROS-responsive substrate. While ensuring that it can be grafted with peptides, it endows the system with higher cycling stability, drug accumulation capacity and oxidative stress response, providing a favorable guarantee for the treatment of diabetic nephropathy. Attached Figure Description

[0024] Figure 1 TCPP-Fe in Examples 1, 2, 3, and 4 3+ -Ce 3+ Transmission electron microscope (TEM) images. Examples 1(a), 2(b), 3(c), and 4(d).

[0025] Figure 2 TCPP-Fe in Examples 1, 2, 3, and 4 3+ -Ce 3+ XRD patterns of the samples. Examples 1(a), 2(b), 3(c), and 4(d).

[0026] Figure 3 TCPP-Fe in Examples 1, 2, 3, and 4 3+ -Ce 3+ Particle size distribution. Examples 1(a), 2(b), 3(c), and 4(d). Detailed Implementation

[0027] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0028] Furthermore, regarding the numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0029] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this invention.

[0030] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0031] Example 1

[0032] Step 1: Preparation of Nanocarriers

[0033] 7.66 mg ferric chloride and 20.52 mg cerium nitrate were dissolved in 5 mL of DMF organic solvent, and 5 mg TCPP was added. The mixture was stirred for 1 h (1000 rpm) and sonicated for 5 min. The mixture was then added to a hydrothermal reactor and heated in a 65 °C water bath for 10 h. After the reaction was complete, the sample was collected, centrifuged for 10 min (15000 rpm, 0 °C), and the supernatant was dialyzed (MWCO: 3500 Da) for 12 h to obtain the product, denoted as TCPP-Fe. 3+ -Ce 3+ .

[0034] Step 2: Preparation of diselenylene bond-modified nanocarriers

[0035] The dialysis product was taken, and 9.66 mg of carbodiimide (EDC) was added. The pH was adjusted to 4.5 with NaOH, and the mixture was activated for 2 h (1000 rpm). Subsequently, 58.01 mg of NHS and 1 mg of selenocysteine ​​dihydrochloride were added, and the mixture was stirred for 12 h (1000 rpm). The resulting product was designated TCPP-Fe. 3+ -Ce 3+ @Se-Se;

[0036] Step 3: Loading specific ligands

[0037] In TCPP-Fe 3+ -Ce 3+ 2.15 mg of the specific ligand polypeptide cyclo was added to the Se-Se solution, followed by 1.2 mg of EDC and 7.1 mg of NHS. The mixture was stirred for 8 h (1000 rpm) and then dialyzed (MWCO: 3500 Da) for 48 h to obtain TCPP-Fe. 3+ -Ce 3+ @Se-Se@Pep.

[0038] Step 4: Drug Loading

[0039] Weigh 3 mg of triptolide and dissolve it in DMF organic solvent, vortex at high speed for 30 seconds, and add it to TCPP-Fe. 3+ -Ce 3+ The solution was stirred for 8 hours in a Se-Se@Pep. solution. Dialysis was then performed for 12 hours (3500 Da) to obtain the final product TCPP-Fe. 3+ -Ce 3+ @Se-Se@Pep.@Dr.

[0040] Example 2

[0041] Step 1: Preparation of Nanocarriers

[0042] 7.66 mg ferric chloride and 20.52 mg cerium nitrate were dissolved in 5 mL of DMF organic solvent, and 5 mg TCPP was added. The mixture was stirred for 1 h (1000 rpm) and sonicated for 5 min. Then, 300 mg polyvinylpyrrolidone (PVP) (MW: 10000) and 200 μL glacial acetic acid were added, and the mixture was stirred for 1 h (600 rpm) and sonicated for 5 min to form a homogeneous dispersion. The mixture was then added to a hydrothermal reactor and heated in a 65°C water bath for 10 h. After the reaction, the sample was collected, centrifuged for 10 min (15000 rpm, 0°C), and the supernatant was dialyzed (MWCO: 3500 Da) for 12 h to obtain the product, denoted as TCPP-Fe. 3+ -Ce 3+ .

[0043] Step 2: Preparation of diselenylene bond-modified nanocarriers

[0044] The dialysis product was taken, and 9.66 mg of carbodiimide (EDC) was added. The pH was adjusted to 4.5 with NaOH, and the mixture was activated for 2 h (1000 rpm). Subsequently, 58.01 mg of NHS and 1 mg of selenocysteine ​​dihydrochloride were added, and the mixture was stirred for 12 h (1000 rpm). The resulting product was designated TCPP-Fe. 3+ -Ce 3+ @Se-Se;

[0045] Step 3: Loading specific ligands

[0046] In TCPP-Fe 3+ -Ce 3+ 2.15 mg of the specific ligand polypeptide cyclo was added to the Se-Se solution, followed by 1.2 mg of EDC and 7.1 mg of NHS. The mixture was stirred for 8 h (1000 rpm) and then dialyzed (MWCO: 3500 Da) for 48 h to obtain TCPP-Fe. 3+ -Ce 3+ @Se-Se@Pep.

[0047] Step 4: Drug Loading

[0048] Weigh out 3 mg of vitamin E and dissolve it in DMF organic solvent. Vortex at high speed for 30 seconds, then add it to TCPP-Fe. 3+ -Ce 3+ The solution was stirred for 8 hours in a Se-Se@Pep. solution. Dialysis was then performed for 12 hours (3500 Da) to obtain the final product. TCPP-Fe 3+ -Ce 3+ @Sa-Sa@ Pep.@Dr.

[0049] Example 3

[0050] Step 1: Preparation of Nanocarriers

[0051] 7.66 mg ferric chloride and 20.52 mg cerium nitrate were dissolved in 5 mL of DMF organic solvent, and 5 mg TCPP was added. The mixture was stirred for 1 h (1000 rpm) and sonicated for 5 min. Then, 300 mg polyvinylpyrrolidone (PVP) (MW: 40000) and 200 μL glacial acetic acid were added, and the mixture was stirred for 1 h (600 rpm) and sonicated for 5 min to form a homogeneous dispersion. The mixture was then added to a hydrothermal reactor and heated in a 65°C water bath for 10 h. After the reaction, the sample was collected, centrifuged for 10 min (15000 rpm, 0°C), and the supernatant was dialyzed (MWCO: 3500 Da) for 12 h to obtain the product, denoted as TCPP-Fe. 3+ -Ce 3+ .

[0052] Step 2: Preparation of diselenylene bond-modified nanocarriers

[0053] The dialysis product was taken, and 9.66 mg of carbodiimide (EDC) was added. The pH was adjusted to 4.5 with NaOH, and the mixture was activated for 2 h (1000 rpm). Subsequently, 58.01 mg of NHS and 1 mg of selenocysteine ​​dihydrochloride were added, and the mixture was stirred for 12 h (1000 rpm). The resulting product was designated TCPP-Fe. 3+ -Ce 3+ @Se-Se;

[0054] Step 3: Loading specific ligands

[0055] In TCPP-Fe 3+ -Ce 3+ 2.15 mg of the specific ligand polypeptide cyclo was added to the Se-Se solution, followed by 1.2 mg of EDC and 7.1 mg of NHS. The mixture was stirred for 8 h (1000 rpm) and then dialyzed (MWCO: 3500 Da) for 48 h to obtain TCPP-Fe. 3+ -Ce 3+ @Se-Se@Pep.

[0056] Step 4: Drug Loading

[0057] Weigh 3 mg of tea polyphenols and dissolve them in DMF organic solvent, vortex at high speed for 30 seconds, and then add them to TCPP-Fe. 3+ -Ce 3+ The solution was stirred for 8 hours in a Se-Se@Pep. solution. Dialysis was then performed for 12 hours (3500 Da) to obtain the final product TCPP-Fe. 3+ -Ce 3+ @Se-Se@Pep.@Dr.

[0058] Example 4

[0059] Step 1: Preparation of Nanocarriers

[0060] 7.66 mg ferric chloride and 20.52 mg cerium nitrate were dissolved in 5 mL of DMF organic solvent, and 5 mg TCPP was added. The mixture was stirred for 1 h (1000 rpm) and sonicated for 5 min. Then, 300 mg polyvinylpyrrolidone (PVP) (MW: 50000) and 200 μL glacial acetic acid were added, and the mixture was stirred for 1 h (600 rpm) and sonicated for 5 min to form a homogeneous dispersion. The mixture was then added to a hydrothermal reactor and heated in a 65°C water bath for 10 h. After the reaction, the sample was collected, centrifuged for 10 min (15000 rpm, 0°C), and the supernatant was dialyzed (MWCO: 3500 Da) for 12 h to obtain the product, denoted as TCPP-Fe. 3+ -Ce 3+ .

[0061] Step 2: Preparation of diselenylene bond-modified nanocarriers

[0062] The dialysis product was taken, and 9.66 mg of carbodiimide (EDC) was added. The pH was adjusted to 4.5 with NaOH, and the mixture was activated for 2 h (1000 rpm). Subsequently, 58.01 mg of NHS and 1 mg of selenocysteine ​​dihydrochloride were added, and the mixture was stirred for 12 h (1000 rpm). The resulting product was designated TCPP-Fe. 3+ -Ce 3+ @Se-Se;

[0063] Step 3: Loading specific ligands

[0064] In TCPP-Fe 3+ -Ce 3+ 2.15 mg of the specific ligand polypeptide cyclo was added to the Se-Se solution, followed by 1.2 mg of EDC and 7.1 mg of NHS. The mixture was stirred for 8 h (1000 rpm) and then dialyzed (MWCO: 3500 Da) for 48 h to obtain TCPP-Fe. 3+ -Ce 3+ @Se-Se@Pep.

[0065] Step 4: Drug Loading

[0066] Weigh 3 mg of triptolide and dissolve it in DMF organic solvent, vortex at high speed for 30 seconds, and add it to TCPP-Fe. 3+ -Ce 3+ The solution was stirred for 8 hours in a Se-Se@Pep. solution. Dialysis was then performed for 12 hours (3500 Da) to obtain the final product. TCPP-Fe 3+ -Ce 3+ @Sa-Sa@ Pep.@Dr.

[0067] Figure 1TCPP-Fe in Examples 1, 2, 3, and 4 3+ -Ce 3+ Transmission electron microscope (TEM) images. Examples 1(a), 2(b), 3(c), and 4(d). Figure 1 As shown, no PVP was added in Example 1, PVP (Mw10000) was added in Example 2, PVP (Mw40000) was added in Example 3, and PVP (Mw50000) was added in Example 4. Due to the different amounts and molecular weights of polyvinylpyrrolidone (PVP), different morphologies of TCPP-Fe nanocarriers were synthesized. 3+ -Ce 3+ .

[0068] Figure 2 TCPP-Fe in Examples 1, 2, 3, and 4 3+ -Ce 3+ The XRD patterns of the samples are shown in Examples 1(a), 2(b), 3(c), and 4(d). The XRD patterns show that the nanocarriers synthesized in all four examples exhibit TCPP diffraction peaks, indicating successful competitive coordination of the metal particles.

[0069] Figure 3 TCPP-Fe in Examples 1, 2, 3, and 4 3+ -Ce 3+ Particle size distribution. Examples 1(a), 2(b), 3(c), and 4(d). In Example 1, no PVP was added; in Example 2, PVP (Mw10000) was added; in Example 3, PVP (Mw40000) was added; and in Example 4, PVP (Mw50000) was added. Due to the different amounts and molecular weights of polyvinylpyrrolidone (PVP), nanocarriers with varying particle sizes (TCPP-Fe) were synthesized. 3+ -Ce 3+ .

[0070] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A preparation method of ROS-responsive drug-loaded dual-targeting nanosystem for treating diabetic nephropathy, characterized in that, It comprises the following steps: FeCl3, Ce(NO3)3·6H2O and tetra(4-carboxyphenyl)porphyrin as raw materials to prepare metal complex TCPP-Fe 3+ -Ce 3+ The specific steps are as follows: FeCl3 and Ce(NO3)3·6H2O are dissolved in 5 mL of an organic solvent, and tetra(4-carboxyphenyl)porphyrin is added and stirred for 1-3 h, and ultrasonic treatment is performed for 5-30 min; then polyvinylpyrrolidone and glacial acetic acid are added, stirred for 1-3 h, and ultrasonic treatment is performed for 5-30 min to form a uniform dispersion system; the above mixture is added to a hydrothermal reaction device, heated in a 50-100℃ water bath for 10-48 h; after the reaction is completed, the sample is collected and centrifuged at a centrifugal force of 10000-15000 rpm for 5-30 min, and the supernatant is taken, dialyzed with a dialysis membrane with a molecular weight cut-off of 3500 Da for 12-48 h to obtain the product, which is recorded as TCPP-Fe 3+ -Ce 3+ ; Subsequently, the carboxyl group on the metal complex is activated and grafted with amino group to link ROS-responsive diselenide bond to obtain nanocarrier TCPP-Fe 3+ -Ce 3+ @Se-Se, the specific steps are as follows: taking the dialysis product TCPP-Fe 3+ -Ce 3+ , adding carbodiimide, adjusting pH to 4-6 with NaOH, activating for 0.5-2 h; subsequently adding selenocystamine dihydrochloride and NHS, stirring at 600-1500 rpm for 2-24 h to obtain the product, denoted as TCPP-Fe 3+ -Ce 3+ @Se-Se; Then TCPP-Fe 3+ -Ce 3+ @Se-Se is obtained by combining the amino group on Se-Se with the specific peptide ligand targeting kidney tissue to obtain TCPP-Fe 3+ -Ce 3+ @Se-Se@Pep. The specific steps are as follows: adding the specific peptide ligand targeting kidney tissue to the TCPP-Fe 3+ -Ce 3+ @Se-Se solution, adding carbodiimide and cross-linking stabilizer, stirring at 600-1500 rpm for 2-24 h, and then dialyzing with a dialysis membrane with a molecular weight cut-off of 3500 Da for 12-48 h to obtain TCPP-Fe 3+ -Ce 3+ @Se-Se@Pep. Finally in TCPP-Fe 3+ -Ce 3+ @Se-Se@Pep. The drug was dissolved in organic solvent, and then added to the TCPP-Fe 3+ -Ce 3+ @Se-Se@Pep. solution, and stirred for 2-12 h; then dialyzed against a dialysis membrane with a molecular weight cut-off of 3500 Da for 10-24 h to obtain the final product TCPP-Fe 3+ -Ce 3+ @Se-Se@Pep.

2. The preparation method of ROS-responsive drug-loaded dual-targeted nanosystem for diabetic nephropathy treatment according to claim 1, characterized in that, The mass ratio of the tetra(4-carboxyphenyl)porphyrin, FeCl3 and Ce(NO3)3·6H2O is 1-5:0.1-3:0.1-3.

3. The method for preparing ROS-responsive drug-loaded dual-targeted nanodelivery system for diabetic nephropathy treatment according to claim 1, wherein, The organic solvent is one or several of dimethylformamide, dihydrolevoglucosenone, ethyl acetate and butanone.

4. The method for preparing ROS-responsive drug-loaded dual-targeted nanodelivery system for diabetic nephropathy treatment according to claim 1, wherein, The molecular weight of the polyvinylpyrrolidone is 10000-50000Mw, and the mass ratio of the polyvinylpyrrolidone to glacial acetic acid is 0-2:

1.

5. The method for preparing ROS-responsive drug-loaded dual-targeted nanodelivery system for diabetic nephropathy treatment according to claim 1, wherein, The crosslinking stabilizer is N-hydroxysuccinimide.

6. The method for preparing ROS-responsive drug-loaded dual-targeted nanodelivery system for diabetic nephropathy treatment according to claim 1, wherein, The specific ligand is one or several of polypeptides RGDfC, PKNGSDP and ELRGD(R / M)AX(W / L) which can be double-targeted to glomerular podocytes and renal tubular interstitial endothelial cells.

7. The method for preparing ROS-responsive drug-loaded dual-targeted nanodelivery system for diabetic nephropathy treatment according to claim 1, wherein, The drug is one or several of gossypipin, vitamin C, vitamin E, tea polyphenol, anthocyanin, coenzyme Q10, sulforaphane, thioctic acid or other drugs for treating diabetic nephropathy. 8.A ROS-responsive drug-loaded double-targeted nanodelivery system for treating diabetic nephropathy, prepared by the preparation method according to any one of claims 1-7. 9.Use of the ROS-responsive drug-loaded double-targeted nanodelivery system for treating diabetic nephropathy according to claim 8 in the preparation of a drug for treating diabetic nephropathy.

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