A polymer nanoparticle with bone targeting, neutralizing acidic environment and antioxidant properties and a preparation method thereof

Abstract

The present application relates to the field of high polymer material and medical engineering, and particularly relates to a high polymer nanoparticle with bone targeting, neutralizing acidic environment and antioxidant properties and a preparation method thereof. The preparation raw material of the high polymer nanoparticle comprises a zoledronic acid modified polycaprolactone-polypeptide copolymer, and a chemical structural formula of the copolymer is shown as follows: The high polymer nanoparticle prepared by using the zoledronic acid modified polycaprolactone-polypeptide copolymer as the raw material has the bone targeting, excellent antioxidant property and the ability of neutralizing acidic environment. The high polymer nanoparticle can exert the significant therapeutic effect (antioxidant, neutralizing acidic environment) of osteoporosis only by relying on the inherent activity of the material itself, so that a series of toxicity problems possibly caused by traditional drugs are fundamentally and greatly reduced, and a new scheme is provided for the treatment of osteoporosis.

Description

Technical Field

[0001] The present invention relates to the fields of polymer materials and medical engineering, and in particular to polymer nanoparticles with bone targeting, acidic environment neutralization and antioxidant properties and a preparation method thereof. Background Art

[0002] Osteoporosis is a common systemic bone disease, the main characteristics of which are decreased bone mass and damage to the microstructure of bone tissue, which leads to increased bone brittleness and makes patients very susceptible to fractures. The disease is particularly prevalent in postmenopausal women and elderly men. With the advent of an aging society, the incidence of osteoporosis has increased year by year and has become one of the global health problems. At present, traditional drugs (such as estrogen, statins, etc.) are usually used to treat osteoporosis patients, but due to the special properties of bone tissue such as hardness and complex structure, these drugs are difficult to reach the target site accurately, lack of bone targeting, and increase the difficulty of treatment.

[0003] In addition, during the occurrence of osteoporosis, abnormal activation of osteoclasts is considered to be the core of the pathological mechanism. During their activation process, osteoclasts secrete a large amount of acidic substances, causing the pH value of the bone tissue microenvironment to drop to an acidic environment of about 4.0. Studies have shown that an acidic environment is a key initiating factor for osteoclasts to destroy bone tissue and a necessary prerequisite for the occurrence and development of osteoporosis. Therefore, regulating the acidic environment of bone tissue to restore it to a normal pH level (neutral) has become the key to treating osteoporosis.

[0004] In recent years, the application of nanotechnology in medicine has provided new insights into the treatment of osteoporosis. Nanomaterials, due to their excellent biocompatibility, stability, and targeted properties, hold great potential for treating bone-related diseases. However, existing nanomaterials often suffer from insufficient antioxidant properties. The occurrence and progression of osteoporosis are closely linked to oxidative stress, which limits their application in osteoporosis treatment.

[0005] Therefore, how to develop nanomaterials with bone targeting, excellent antioxidant properties and the ability to neutralize acidic environments is a technical problem that needs to be urgently solved in this field. Summary of the Invention

[0006] The present invention provides a polymer nanoparticle with bone targeting, acidic environment neutralization and antioxidant properties. The polymer nanoparticle is prepared from raw materials including a polycaprolactone-polypolypeptide copolymer modified with zoledronic acid. The polymer nanoparticle has bone targeting, excellent antioxidant properties and the ability to neutralize acidic environments.

[0007] The present invention also provides a method for preparing polymeric nanoparticles that combine bone targeting, acid neutralization, and antioxidant properties. This method can produce polymeric nanoparticles that possess bone targeting, excellent antioxidant properties, and the ability to neutralize acidic environments. This method is simple, has a short production cycle, and is suitable for widespread application.

[0008] The present invention also provides a bone-targeting polymer, which is the above-mentioned zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. The bone-targeting polymer can be used to prepare high-molecular nanoparticles with bone targeting, excellent antioxidant properties and the ability to neutralize acidic environments.

[0009] The first aspect of the present invention provides a polymer nanoparticle with bone targeting, acid neutralization and antioxidant properties. The raw materials for preparing the polymer nanoparticle include zoledronic acid-modified polycaprolactone-polypeptide copolymer.

[0010] The chemical structure of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer is shown in formula (1):

[0011]

[0012] The polymer nanoparticles having the properties of bone targeting, neutralizing acidic environment and anti-oxidation as described above, the preparation raw materials also include polycaprolactone-polyethylene oxide.

[0013] As described above, the polymer nanoparticles have bone targeting, acid neutralization and antioxidant properties, wherein the mass ratio of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer to polycaprolactone-polyethylene oxide is (1-3): (0-1).

[0014] A second aspect of the present invention provides a method for preparing the polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties, comprising the following steps:

[0015] Preparation of zoledronic acid modified polycaprolactone-polypeptide copolymer:

[0016] dissolving a first raw material system comprising polycaprolactone, tyrosine cyclic anhydride, and Nε-benzyloxycarbonyl-L-lysine cyclic anhydride in a first organic solvent, performing a first reaction under vacuum, and precipitating a first product after the first reaction using a second organic solvent to obtain a polycaprolactone-polypeptide copolymer;

[0017] dissolving the polycaprolactone-polypolypeptide copolymer in a third organic solvent to perform a second reaction, and sequentially performing a neutralization treatment and a first dialysis treatment on a second product after the second reaction to obtain a polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed;

[0018] dissolving the polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed in a fourth organic solvent, adding zoledronic acid activated with N,N'-carbonyldiimidazole, and performing a third reaction; and performing a second dialysis treatment on the third product after the third reaction to obtain the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer;

[0019] Preparation of polymer nanoparticles:

[0020] A third raw material system including the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide is dissolved in a fifth organic solvent to obtain a solution containing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. Under vigorous stirring, first deionized water is added to the solution containing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer to perform a third dialysis treatment to obtain the polymer nanoparticles.

[0021] As described above, the method for preparing polymer nanoparticles having bone targeting, neutralization of acidic environment and antioxidant properties, the molar ratio of the polycaprolactone, the tyrosine cyclic anhydride and the Nε-benzyloxycarbonyl-L-lysine cyclic anhydride is 1: (0.1-30): (0.1-15).

[0022] In the method for preparing the polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties, the molar ratio of the polycaprolactone to the N,N'-carbonyldiimidazole-activated zoledronic acid is 1:(0.1-10).

[0023] The method for preparing polymer nanoparticles having bone targeting, acidic environment neutralization and antioxidant properties as described above, wherein the second product after the second reaction is subjected to a neutralization treatment and a first dialysis treatment in sequence, comprises: neutralizing the second product after the second reaction using a sixth organic solvent, and then performing a first dialysis treatment on the neutralized second product using a second deionized water for 4 hours to 100 hours, wherein the sixth organic solvent is at least one of n-hexane, triethylamine, acetone, ether, and ethyl acetate.

[0024] The method for preparing the polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties as described above, wherein the third product after the third reaction is subjected to a second dialysis treatment, comprises: using a third deionized water to perform a second dialysis treatment on the third product after the third reaction for 4 to 100 hours.

[0025] The method for preparing the polymer nanoparticles having bone targeting, neutralization of acidic environment and antioxidant properties as described above, wherein the volume ratio of the fifth organic solvent to the first deionized water is 1:(1-5);

[0026] And / or, the third dialysis treatment lasts for 4 hours to 100 hours.

[0027] The third aspect of the present invention provides a bone-targeting polymer, which is the above-mentioned zoledronic acid-modified polycaprolactone-polypolypeptide copolymer.

[0028] The present invention provides polymer nanoparticles that combine bone targeting, acid neutralization, and antioxidant properties. The raw materials for preparing the polymer nanoparticles include a zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. The polymer nanoparticles prepared using the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer have bone targeting, excellent antioxidant properties, and the ability to neutralize acidic environments. Firstly, the zoledronic acid in the polymer nanoparticles can bind to hydroxyapatite (the main component of bone) to achieve bone targeting; secondly, the polytyrosine segments in the polymer nanoparticles can effectively scavenge reactive oxygen species, thereby exhibiting excellent antioxidant properties; and thirdly, the polylysine segments (which are alkaline) in the polymer nanoparticles can neutralize acidic environments, thereby exhibiting the ability to neutralize acidic environments. In addition, the polymer nanoparticles can exert significant therapeutic effects in treating osteoporosis (anti-oxidation, neutralization of acidic environment) solely by relying on the intrinsic activity of their own materials, thereby fundamentally and significantly reducing a series of toxicity problems that may be caused by traditional drugs, and providing a new solution for the treatment of osteoporosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of polycaprolactone-polyethylene oxide in Example 1 of the present invention;

[0031] Figure 2 This is a hydrogen nuclear magnetic resonance spectrum of the polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed in Example 1 of the present invention;

[0032] Figure 3 This is the H NMR spectrum of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer in Example 1 of the present invention;

[0033] Figure 4 This is the nuclear magnetic resonance phosphorus spectrum of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer in Example 1 of the present invention;

[0034] Figure 5Graph showing the relationship between particle size and particle size distribution (PDI) of polymer nanoparticles in Examples 1-4 and Comparative Examples 1-2 of the present invention;

[0035] Figure 6 1 is a transmission electron microscope (TEM) test result diagram of the polymer nanoparticles in Example 1, Example 2 and Comparative Example 2 of the present invention;

[0036] Figure 7 Graphs showing the results of the neutralization ability test of the polymer nanoparticles in Examples 1 to 4 and Comparative Examples 1 to 2 in the present invention;

[0037] Figure 8 Graphs showing the results of testing the binding efficiency of polymer nanoparticles with hydroxyapatite in Examples 1 to 4 and Comparative Examples 1 and 2, respectively;

[0038] Figure 9 The results of the antioxidant effect test of the polymer nanoparticles in Examples 1 to 4 and Comparative Examples 1 to 2 are shown in FIG. Figure 9 A is the test result of ABTS removal efficiency. Figure 9 Figure B is the test result of superoxide anion removal efficiency. Figure 9 C is the test result diagram of hydroxyl radical scavenging efficiency;

[0039] Figure 10 Graph showing the relationship between particle size and particle size distribution (PDI) of the polymer nanoparticles after being diluted 20 times with deionized water in Examples 1-4 of the present invention and Comparative Examples 1-2;

[0040] Figure 11 The relationship between the particle size and particle size distribution (PDI) and the polydispersity coefficient of the polymer nanoparticles in Examples 1-4 and Comparative Examples 1-2 of the present invention at pH = 4 is shown in FIG. Figure 11 A is a relationship diagram between the particle size and particle size distribution (PDI) of the polymer nanoparticles in Examples 1-4 of the present invention and Comparative Examples 1-2 under a pH = 4 environment, Figure 11 B is the polydispersity coefficient of the polymer nanoparticles in Examples 1-4 of the present invention and Comparative Examples 1-2 under a pH of 4;

[0041] Figure 12 The relationship between the particle size and particle size distribution (PDI) of the polymer nanoparticles in Examples 1-4 and Comparative Examples 1-2 of the present invention in an environment with a mass fraction of 10% fetal bovine serum is shown in FIG. Figure 12 A is a relationship diagram between the particle size and particle size distribution (PDI) of the polymer nanoparticles in Examples 1-4 and Comparative Examples 1-2 of the present invention in an environment with a mass fraction of 10% fetal bovine serum, Figure 12B is the polydispersity coefficient of the polymer nanoparticles in Examples 1-4 of the present invention and Comparative Examples 1-2 in an environment with a mass fraction of 10% fetal bovine serum. DETAILED DESCRIPTION

[0042] To make the objectives, technical solutions, and advantages of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0043] If no specific techniques or conditions are specified in the examples of the present invention, the techniques or conditions described in the literature in the field or the product instructions shall be followed. If the manufacturer of the raw materials, reagents or instruments is not specified, they are all commercially available conventional products.

[0044] It should be noted that the descriptions of “first”, “second”, “third”, “fourth”, “fifth”, “sixth”, etc. in the present invention are used to distinguish similar objects, and are not used to describe a specific order or sequence, and therefore cannot be understood as a limitation of the present invention.

[0045] The first aspect of the present invention provides a polymer nanoparticle with bone targeting, acid neutralization and antioxidant properties. The raw materials for preparing the polymer nanoparticle include zoledronic acid-modified polycaprolactone-polypeptide copolymer;

[0046] The chemical structure of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer is shown in formula (1):

[0047]

[0048] The zoledronic acid-modified polycaprolactone-polypolypeptide copolymer of the present invention is prepared by the following process: reacting a raw material system including polycaprolactone, tyrosine cyclic anhydride and Nε-benzyloxycarbonyl-L-lysine cyclic anhydride, and then performing zoledronic acid modification on the reaction product using zoledronic acid activated by N,N'-carbonyldiimidazole to form the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer.

[0049] The polymer nanoparticles provided by the present invention are prepared from raw materials including the above-mentioned zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. The polymer nanoparticles have bone targeting and excellent antioxidant properties. In addition, the polymer nanoparticles have the ability to neutralize acidic environments, which can neutralize acidic environments to neutral, maintaining a normal pH level. The inventors analyzed this and believe that the reason may be that the zoledronic acid in the polymer nanoparticles can bind to hydroxyapatite (the main component of bone) to achieve bone targeting, while the polylysine segments (which are alkaline) in the polymer nanoparticles can neutralize the acidic environment, and the polytyrosine segments in the polymer nanoparticles can effectively scavenge reactive oxygen species. Therefore, the polymer nanoparticles have bone targeting, excellent antioxidant properties, and the ability to neutralize acidic environments.

[0050] In another specific embodiment, the raw materials for preparing the polymer nanoparticles include zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide.

[0051] The polymer nanoparticles provided by the present invention can also be prepared from raw materials including the above-mentioned zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide. The polymer nanoparticles also have bone targeting, excellent antioxidant properties and the ability to neutralize acidic environments.

[0052] In some embodiments, the preparation method of the polycaprolactone-polyethylene oxide comprises the following steps:

[0053] dissolving polyethylene glycol monomethyl ether and ε-caprolactone in toluene to obtain a mixture solution;

[0054] The mixture solution is heated to 130° C. to 140° C. to obtain a reaction liquid; the temperature of the reaction liquid is lowered from 140° C. to room temperature, and then stannous zincate is added, and then heated to 105° C. to 120° C. to react for 24 h to 50 h, and then cooled to room temperature to obtain a reaction product; the reaction product is sequentially precipitated, filtered and dried to obtain polycaprolactone-polyethylene oxide.

[0055] In a specific embodiment, in the polymer nanoparticles, the mass ratio of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer to the polycaprolactone-polyethylene oxide is (1-3): (0-1).

[0056] When the mass ratio of zoledronic acid-modified polycaprolactone-polypolypeptide copolymer to polycaprolactone-polyethylene oxide in the polymer nanoparticles is within the above range, polymer nanoparticles with bone targeting, excellent antioxidant properties and the ability to neutralize acidic environments can be prepared.

[0057] For example, in the polymer nanoparticles, the mass ratio of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer to the polycaprolactone-polyethylene oxide can be any one of 1:0, 1:1, 2:0, 2:1, 3:0, 3:1, or any two of them.

[0058] A second aspect of the present invention provides a method for preparing the polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties, comprising the following steps:

[0059] Preparation of zoledronic acid modified polycaprolactone-polypeptide copolymer:

[0060] dissolving a first raw material system comprising polycaprolactone, tyrosine cyclic anhydride, and Nε-benzyloxycarbonyl-L-lysine cyclic anhydride in a first organic solvent, performing a first reaction under vacuum, and precipitating a first product after the first reaction using a second organic solvent to obtain a polycaprolactone-polypeptide copolymer;

[0061] dissolving the polycaprolactone-polypolypeptide copolymer in a third organic solvent for a second reaction, and sequentially performing a neutralization treatment and a first dialysis treatment on the second product after the second reaction to obtain the polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed;

[0062] The polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed is dissolved in a fourth organic solvent, and then zoledronic acid activated with N,N'-carbonyldiimidazole is added to perform a third reaction, and the third product after the third reaction is subjected to a second dialysis treatment to obtain a zoledronic acid-modified polycaprolactone-polypolypeptide copolymer;

[0063] Preparation of polymer nanoparticles:

[0064] A third raw material system including zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide is dissolved in a fifth organic solvent to obtain a solution containing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. The first deionized water is added to the solution containing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer under vigorous stirring, and a third dialysis treatment is performed to obtain polymer nanoparticles.

[0065] Specifically, the present invention first dissolves a first raw material system including polycaprolactone, tyrosine cyclic anhydride and Nε-benzyloxycarbonyl-L-lysine cyclic anhydride in a first organic solvent, performs a first reaction under vacuum to obtain a first product, and then uses a second organic solvent to precipitate the first product to obtain a polycaprolactone-polypolypeptide copolymer. The precipitation treatment is to effectively separate the polycaprolactone-polypolypeptide copolymer from the organic solvent; then the polycaprolactone-polypolypeptide copolymer is dissolved in a third organic solvent for a second reaction to obtain a second product, and then the second product is neutralized to obtain a neutralized second product. The second reaction is to remove the benzyloxycarbonyl group to facilitate subsequent modification of zoledronic acid. The neutralized second product is then subjected to a first dialysis treatment to obtain a polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed. The first dialysis treatment is to remove the organic solvent from the neutralized second product; the polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed is dissolved in a fourth organic solvent, and then N,N'-carbonyldiimidazole-activated zoledronic acid is added. The third product is subjected to a second dialysis treatment to obtain a zoledronic acid-modified polycaprolactone-polypolypeptide copolymer, and the second dialysis treatment is to remove the organic solvent in the third product; the third raw material system including the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide is dissolved in a fifth organic solvent to obtain a mixed solution containing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and the polycaprolactone-polyethylene oxide, and the first deionized water is added to the mixture containing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer under vigorous stirring. A third dialysis treatment is performed on a mixed solution of zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide to prepare polymer nanoparticles with bone targeting, excellent antioxidant properties and the ability to neutralize acidic environments. The third dialysis treatment is to remove the organic solvent in the nanoparticle dispersion assembled from the mixed solution of zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide to obtain polymer nanoparticles with bone targeting, excellent antioxidant properties and the ability to neutralize acidic environments.

[0066] In the present invention, N,N'-carbonyldiimidazole activated zoledronic acid is prepared by the following process:

[0067] Zoledronic acid is dissolved in anhydrous dimethyl sulfoxide, and triethylamine is then added to obtain a mixture; the mixture is degassed with nitrogen, and then N,N'-carbonyldiimidazole is added under nitrogen protection to react; the product obtained after the reaction is completed is precipitated in acetone, the supernatant is removed by centrifugation, and the mixture is dried under vacuum to obtain N,N'-carbonyldiimidazole-activated zoledronic acid.

[0068] The present invention does not particularly limit the specific sources of the above raw materials, and they can be purchased from commercial channels.

[0069] The present invention does not impose any particular limitation on the specific usage of the above-mentioned organic solvents, and the usage can be selected according to specific needs.

[0070] The present invention can prepare high-molecular-weight nanoparticles with bone targeting, excellent antioxidant properties, and the ability to neutralize acidic environments through the above-mentioned preparation method. The preparation method is simple and convenient, with a short preparation cycle, and can be widely promoted and applied.

[0071] In a specific embodiment, the molar ratio of the polycaprolactone, tyrosine cyclic anhydride and Nε-benzyloxycarbonyl-L-lysine cyclic anhydride is 1:(0.1-30):(0.1-15).

[0072] When the molar ratio of polycaprolactone, tyrosine cyclic anhydride and Nε-benzyloxycarbonyl-L-lysine cyclic anhydride is within the above range, the first reaction can be fully carried out, which is conducive to the preparation of polycaprolactone-polypolypeptide copolymer.

[0073] In a specific embodiment, the molar ratio of the polycaprolactone to the N,N'-carbonyldiimidazole-activated zoledronic acid is 1:(0.1-10).

[0074] When the molar ratio of polycaprolactone to N,N'-carbonyldiimidazole-activated zoledronic acid is within the above range, the third reaction can be fully carried out, which is beneficial for preparing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer.

[0075] In a specific embodiment, the second product after the second reaction is subjected to the neutralization treatment and the first dialysis treatment in sequence, including: neutralizing the second product after the second reaction with a sixth organic solvent, and then performing a first dialysis treatment on the neutralized second product with a second deionized water for 4 hours to 100 hours, wherein the sixth organic solvent is at least one of n-hexane, triethylamine, acetone, ether, and ethyl acetate.

[0076] The present invention does not impose any particular limitation on the specific usage of the sixth organic solvent and the second deionized water, and they can be selected according to needs.

[0077] The present invention uses the sixth organic solvent to neutralize the second product after the second reaction, thereby more effectively removing the benzyloxycarbonyl group to facilitate subsequent modification of zoledronic acid. The second product after the neutralization treatment is then subjected to a first dialysis treatment using a second deionized water to remove the organic solvent from the second product after the neutralization treatment, thereby preparing a polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed, which is beneficial for the subsequent preparation of polymer nanoparticles with bone targeting, excellent antioxidant properties, and the ability to neutralize acidic environments.

[0078] In an embodiment, the second dialysis treatment of the third product after the third reaction includes: using the third deionized water to perform the second dialysis treatment on the third product after the third reaction for 4-100 hours.

[0079] The specific amount of the third deionized water is not particularly limited in the present application, and can be selected as needed.

[0080] The present application can remove the organic solvent in the third product by using the third deionized water to perform the second dialysis treatment on the third product after the third reaction, so as to prepare the zoledronic acid modified polycaprolactone-polypeptide copolymer, which is beneficial to the subsequent preparation of the high molecular nano-particle with bone targeting, excellent antioxidant performance and the ability to neutralize the acidic environment.

[0081] In an embodiment, the volume ratio of the fifth organic solvent to the first deionized water is 1:(1-5), which can be preferably 1:2.

[0082] When the volume ratio of the fifth organic solvent to the first deionized water is 1:2, the nano-particle with the optimal particle size can be assembled.

[0083] In an embodiment, the third dialysis treatment is performed for 4-100 hours.

[0084] When the third dialysis treatment is performed for 4-100 hours, the organic solvent in the solution containing the zoledronic acid modified polycaprolactone-polypeptide copolymer can be effectively removed, so as to prepare the high molecular nano-particle with bone targeting, excellent antioxidant performance and the ability to neutralize the acidic environment.

[0085] In some embodiments, the first reaction is performed for 4-100 hours.

[0086] When the first reaction is performed for 4-100 hours, the first reaction can be sufficiently performed, so as to prepare the polycaprolactone-polypeptide copolymer.

[0087] In some embodiments, the second reaction is performed at a temperature of 20-30°C for 1-5 hours.

[0088] When the temperature and time of the second reaction are in the above range, the second reaction can be sufficiently performed, so as to prepare the polycaprolactone-polypeptide copolymer with the removal of the benzyloxy carbonyl group.

[0089] In some embodiments, the third reaction is performed for 1-15 hours.

[0090] When the third reaction is performed for 1-15 hours, the third reaction can be sufficiently performed, so as to prepare the zoledronic acid modified polycaprolactone-polypeptide copolymer.

[0091] In some embodiments, the first organic solvent is at least one of dimethyl sulfoxide, N,N-dimethylformamide, hydrobromic acid, trifluoroacetic acid, tetrahydrofuran, and dichloromethane; the second organic solvent is at least one of n-hexane, triethylamine, acetone, ether, and ethyl acetate; the third organic solvent is at least one of dimethyl sulfoxide, N,N-dimethylformamide, hydrobromic acid, trifluoroacetic acid, tetrahydrofuran, and dichloromethane; the fourth organic solvent is at least one of dimethyl sulfoxide, N,N-dimethylformamide, hydrobromic acid, trifluoroacetic acid, tetrahydrofuran, and dichloromethane; and the fifth organic solvent is at least one of dimethyl sulfoxide, N,N-dimethylformamide, hydrobromic acid, trifluoroacetic acid, tetrahydrofuran, and dichloromethane.

[0092] The present invention does not particularly limit the specific sources of the above-mentioned organic solvents, and they can be purchased from commercial channels.

[0093] The third aspect of the present invention provides a bone-targeting polymer, which is the aforementioned zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. The present invention utilizes the bone-targeting polymer to prepare polymer nanoparticles that have bone targeting, excellent antioxidant properties, and the ability to neutralize acidic environments.

[0094] The present invention is further described below through specific examples.

[0095] The tyrosine anhydride used in the following examples was synthesized according to the method in the reference (Antioxidant and Immunomodulatory Polymer Vesicles for Effective Diabetic Wound Treatment through Ros Scavenging and Immune Modulating. Nano Letters 2024, 24, 9494-9504).

[0096] Example 1

[0097] In this embodiment, polymer nanoparticles are obtained by the following preparation method:

[0098] Preparation of zoledronic acid modified polycaprolactone-polypeptide copolymer:

[0099] (1) 1.164 g of polycaprolactone and 2 g of tyrosine cyclic anhydride were dissolved in 6 mL of ultra-dry N,N-dimethylformamide and reacted under vacuum for 24 h, followed by adding 1.267 g of Nε-benzyloxycarbonyl-L-lysine cyclic anhydride and continuing the reaction for 24 h to obtain a first product, which was precipitated with diethyl ether to obtain a polycaprolactone-polypeptide copolymer;

[0100] (2) 1 g of the polycaprolactone-polypeptide copolymer was dissolved in 30 mL of trifluoroacetic acid, then 10 mL of hydrobromic acid acetic acid solution was added to obtain a mixture, and the mixture was reacted at 25°C for 4 h to obtain a second product. The second product was neutralized by 40 mL of triethylamine to obtain a neutralized second product, and the neutralized second product was dialyzed with deionized water for 48 h to obtain a benzyl oxycarbonyl-removed polycaprolactone-polypeptide copolymer. The chemical structural formula of the benzyl oxycarbonyl-removed polycaprolactone-polypeptide copolymer is as follows:

[0101]

[0102] (3) 100 mg of zoledronic acid was dissolved in 50 mL of anhydrous dimethyl sulfoxide, then 2 mL of triethylamine was added to obtain a mixture; the mixture was degassed with nitrogen for 30 min, then N,N'-carbonyldiimidazole was added under nitrogen protection, and reacted at 60°C for 24 h, then the product obtained after the reaction was completed was precipitated in acetone three times, the supernatant was removed by centrifugation, and dried under vacuum for 24 h to obtain N,N'-carbonyldiimidazole-activated zoledronic acid;

[0103] (4) 0.23 g of the benzyl oxycarbonyl-removed polycaprolactone-polypeptide copolymer was dissolved in 2 mL of super-dry dimethyl sulfoxide, then 0.23 mL of triethylamine was added to obtain a mixture solution, the mixture solution was purged with nitrogen for 30 min, then 0.07 g of N,N'-carbonyldiimidazole-activated zoledronic acid was added to the mixture solution, and the mixture was placed in a sealed reactor and reacted for 12 h to obtain a third product. The third product was dialyzed with deionized water for 48 h to obtain a zoledronic acid-modified polycaprolactone-polypeptide copolymer. The chemical structural formula of the zoledronic acid-modified polycaprolactone-polypeptide copolymer is as follows:

[0104]

[0105] Preparation of the high-molecular nanoparticle:

[0106] (1) 5 mg of the zoledronic acid-modified polycaprolactone-polypeptide copolymer was dissolved in 4 mL of dimethyl sulfoxide to obtain a solution containing the zoledronic acid-modified polycaprolactone-polypeptide copolymer. Under vigorous stirring, 8 mL of deionized water was added dropwise to the solution containing the zoledronic acid-modified polycaprolactone-polypeptide copolymer at a rate of 20 d / min (drops / min) for dialysis treatment for 48 h to remove dimethyl sulfoxide, thereby obtaining a high-molecular nanoparticle.

[0107] Example 2

[0108] The preparation method of the high-molecular nanoparticle provided in this example is basically the same as that of Example 1, except that:

[0109] Preparation of polymer nanoparticles:

[0110] (1) Preparation of polycaprolactone-polyethylene oxide:

[0111] 1.00 g of polyethylene glycol monomethyl ether (CAS: 9004-74-4) and 4.56 g of ε-caprolactone were dissolved in 75 mL of toluene to obtain a mixture solution, and the mixture solution was heated to 140° C. for azeotropic dehydration until the toluene in the mixture solution was 12 mL to obtain a reaction solution; the temperature of the reaction solution was lowered from 140° C. to room temperature, argon was introduced into the reaction solution for 30 minutes to deoxygenate, and then 0.0094 g of stannous zincate was added with a pipette under argon protection, and argon was further introduced for 15 minutes, and then heated to 110° C. for reaction for 48 hours, and then cooled to room temperature to obtain a reaction product; the reaction product was repeatedly precipitated in n-hexane three times, and a white powder was obtained after filtration. The white powder was placed in a vacuum oven at 30° C. for drying for 48 hours to finally obtain white powdery polycaprolactone-polyethylene oxide (NMR hydrogen spectrum as shown in FIG. Figure 1 The chemical structure of polycaprolactone-polyethylene oxide is shown below:

[0112]

[0113] (2) 1 mg of zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and 1 mg of polycaprolactone-polyethylene oxide were dissolved in 4 mL of dimethyl sulfoxide to obtain a solution containing zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. Under vigorous stirring, 8 mL of deionized water was added dropwise at a rate of 20 d / min (drops / minute) to the solution containing zoledronic acid-modified polycaprolactone-polypolypeptide copolymer, and the solution was dialyzed for 48 h to remove dimethyl sulfoxide to obtain polymer nanoparticles.

[0114] Example 3

[0115] The preparation method of the polymer nanoparticles provided in this embodiment is basically the same as that in Example 2, except that:

[0116] Preparation of polymer nanoparticles:

[0117] (2) 1 mg of zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and 0.5 mg of polycaprolactone-polyethylene oxide were dissolved in 4 mL of dimethyl sulfoxide to obtain a solution containing zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. Under vigorous stirring, 8 mL of deionized water was added dropwise at a rate of 20 d / min (drops / minute) to the solution containing zoledronic acid-modified polycaprolactone-polypolypeptide copolymer, and the solution was dialyzed for 48 h to remove dimethyl sulfoxide to obtain polymer nanoparticles.

[0118] Example 4

[0119] The preparation method of the polymer nanoparticles provided in this embodiment is basically the same as that in Example 2, except that:

[0120] Preparation of polymer nanoparticles:

[0121] (2) 1.2 mg of zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and 0.4 mg of polycaprolactone-polyethylene oxide were dissolved in 4 mL of dimethyl sulfoxide to obtain a solution containing zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. Under vigorous stirring, 8 mL of deionized water was added dropwise at a rate of 20 d / min (drops / minute) to the solution containing zoledronic acid-modified polycaprolactone-polypolypeptide copolymer, and the solution was dialyzed for 48 h to remove dimethyl sulfoxide to obtain polymer nanoparticles.

[0122] Comparative Example 1

[0123] The preparation method of the polymer nanoparticles provided in this comparative example is basically the same as that in Example 2, except that:

[0124] Preparation of polymer nanoparticles:

[0125] (2) 0.5 mg of zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and 1 mg of polycaprolactone-polyethylene oxide were dissolved in 4 mL of dimethyl sulfoxide to obtain a solution containing zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. Under vigorous stirring, 8 mL of deionized water was added dropwise at a rate of 20 d / min (drops / minute) to the solution containing zoledronic acid-modified polycaprolactone-polypolypeptide copolymer, and the solution was dialyzed for 48 h to remove dimethyl sulfoxide to obtain polymer nanoparticles.

[0126] Comparative Example 2

[0127] This comparative example obtains polymer nanoparticles by the following preparation method:

[0128] 1 mg of polycaprolactone-polyethylene oxide (polycaprolactone-polyethylene oxide was prepared according to the method in Example 2) was dissolved in 4 mL of dimethyl sulfoxide to obtain a solution containing polycaprolactone-polyethylene oxide. Under vigorous stirring, 8 mL of deionized water was added dropwise to the solution containing polycaprolactone-polyethylene oxide at a rate of 20 d / min (drops / minute), and the solution was dialyzed for 48 h to remove dimethyl sulfoxide to obtain polymer nanoparticles.

[0129] Performance Testing

[0130] 1. Nuclear magnetic resonance hydrogen spectrum test

[0131] The polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group was removed in Example 1 of the present invention was subjected to a nuclear magnetic resonance hydrogen spectrum test, and the polycaprolactone-polypolypeptide copolymer modified with zoledronic acid in Example 1 of the present invention was subjected to nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance phosphorus spectrum tests, respectively. Figure 2 This is a hydrogen nuclear magnetic resonance spectrum of the polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed in Example 1 of the present invention; Figure 3 This is the H NMR spectrum of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer in Example 1 of the present invention; Figure 4 This is the nuclear magnetic resonance phosphorus spectrum of the polycaprolactone-polypolypeptide copolymer modified with zoledronic acid in Example 1 of the present invention.

[0132] Depend on Figures 2-4 It can be seen that compared with the nuclear magnetic resonance hydrogen spectrum of the polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group was removed, the nuclear magnetic resonance hydrogen spectrum of the polycaprolactone-polypolypeptide copolymer modified with zoledronic acid shows a characteristic peak of zoledronic acid at 4.5-5.0 ppm, and the characteristic peak of zoledronic acid also appears in the nuclear magnetic resonance phosphorus spectrum of the polycaprolactone-polypolypeptide copolymer modified with zoledronic acid, confirming that zoledronic acid (ZOL) was successfully modified onto the polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group was removed.

[0133] 2. Particle size and particle size distribution (PDI) test

[0134] Figure 5 Graph showing the relationship between particle size and particle size distribution (PDI) of polymer nanoparticles in Examples 1-4 of the present invention and Comparative Examples 1-2.

[0135] Depend on Figure 5 It can be seen that the particle size of the polymer nanoparticles in Example 1 of the present invention is 185 nm, and the particle size distribution is narrow; the particle size of the polymer nanoparticles in Example 2 is 180 nm, and the particle size distribution is narrow; the particle size of the polymer nanoparticles in Example 3 is 168 nm, and the particle size distribution is narrow; the particle size of the polymer nanoparticles in Example 4 is 157 nm, and the particle size distribution is narrow; the particle size of the polymer nanoparticles in Comparative Example 1 is 200 nm, and the particle size distribution is narrow; the particle size of the polymer nanoparticles in Comparative Example 2 is 266 nm, and the particle size distribution is narrow.

[0136] 3. Transmission electron microscopy (TEM) test

[0137] Figure 6 1 and 2. These are transmission electron microscopy (TEM) test results of the polymer nanoparticles in Example 1, Example 2, and Comparative Example 2 of the present invention.

[0138] Depend on Figure 6 It can be seen that the polymer nanoparticles in Example 2 of the present invention have a clear structure and are evenly dispersed. The vesicle structure helps to improve the stability of the nanomaterial, facilitates circulation in the body and improves bioavailability.

[0139] 4. Test the ability of polymer nanoparticles to neutralize acidic environments

[0140] The ability of the polymer nanoparticles in Examples 1 to 4 and Comparative Examples 1 to 2 to neutralize acidic environments was tested, and the test results are as follows: Figure 7 shown.

[0141] Depend on Figure 7 It can be seen that the polymer nanoparticles in Examples 1 to 4 of the present invention can effectively neutralize the hydrochloric acid aqueous solution in vitro and maintain the pH value at a level of 7.0-7.4.

[0142] 5. Test the binding efficiency of polymer nanoparticles and hydroxyapatite

[0143] The binding rate of the polymer nanoparticles in Examples 1 to 4 and Comparative Examples 1 to 2 was tested respectively. The test results are shown in FIG. Figure 8 and as shown in Table 1;

[0144] Binding rate: 5 mg of fluorescein isothiocyanate (FITC) powder was dissolved in 5 mL of deionized water to obtain FITC solution, and then the FITC solution was assembled with polymer nanoparticles to obtain polymer vesicles loaded with FITC. The initial fluorescence intensity was measured using a fluorescence spectrometer (excitation wavelength = 480 nm, emission wavelength = 560 nm, operating voltage = 700 V). t0 Then, hydroxyapatite powder (25.0 mg) was added to 4.00 mL of FITC-labeled polymer vesicles, stirred at 37 ° C for 3 h, and then centrifuged to obtain the supernatant. The fluorescence intensity of the supernatant was measured as I t The formula for calculating the binding rate between vesicles and hydroxyapatite (HAbinding rate) is as follows:

[0145] Binding rate = (I t0 -I t ) / I t0 ×100%.

[0146] Table 1 Test results

[0147] Item Binding efficiency (%) Example 1 77.63 Example 2 75.34 Example 3 58.57 Example 4 71.55 Comparative Example 1 52.54 Comparative Example 2 47.23

[0148] Depend on Figure 8As shown in Table 1, the vesicles of the polymer nanoparticles in Example 1 of the present invention showed the best binding performance, with a binding rate of 77.63%. The vesicles of the polymer nanoparticles in Example 2 showed a higher binding rate of 75.34%, indicating that a mass ratio of 1:1 of zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide was sufficient to achieve bone targeting, and the addition of polycaprolactone-polyethylene oxide did not significantly affect the bone targeting ability of the mixed crown vesicles. In contrast, the binding rate of the vesicles of the polymer nanoparticles in Comparative Example 2 to hydroxyapatite was 47.2%, which was attributed to the nonspecific adsorption of hydroxyapatite to the vesicles. This inefficient binding does not represent true bone targeting. The binding of zoledronic acid (ZOL) to hydroxyapatite (HA) is mainly attributed to the strong affinity of ZOL for calcium ions in HA crystals. This interaction is further enhanced due to the structural similarity of ZOL to the phosphate groups in hydroxyapatite, resulting in its preferential adsorption on the HA surface.

[0149] 6. Test the antioxidant properties of polymer nanoparticles

[0150] The polymer nanoparticles in Examples 1 to 4 and Comparative Examples 1 to 2 were tested for ABTS scavenging efficiency (%), superoxide anion scavenging efficiency (%), and hydroxyl radical scavenging efficiency (%). The test results are as follows: Figure 9 and as shown in Table 2;

[0151] Table 2 Test results

[0152]

[0153]

[0154] Depend on Figure 9 As shown in Table 2, the ABTS scavenging efficiency, superoxide anion scavenging efficiency and hydroxyl radical scavenging efficiency of the polymer nanoparticles in Examples 1 to 4 of the present invention are higher than those in Comparative Example 1 and Comparative Example 2, indicating that the polymer nanoparticles provided by the embodiments of the present invention have excellent antioxidant properties.

[0155] 7. Test the stability of polymer nanoparticles

[0156] Figure 10 Graph showing the relationship between particle size and particle size distribution (PDI) of the polymer nanoparticles after being diluted 20 times with deionized water in Examples 1-4 of the present invention and Comparative Examples 1-2; Figure 11 The relationship between the particle size and particle size distribution (PDI) and the polydispersity coefficient of the polymer nanoparticles in Examples 1-4 and Comparative Examples 1-2 of the present invention at pH = 4 is shown in FIG. Figure 11A is a relationship diagram between the particle size and particle size distribution (PDI) of the polymer nanoparticles in Examples 1-4 of the present invention and Comparative Examples 1-2 under a pH = 4 environment, Figure 11 B is the polydispersity coefficient of the polymer nanoparticles in Examples 1-4 of the present invention and Comparative Examples 1-2 under a pH of 4; Figure 12 The relationship between the particle size and particle size distribution (PDI) of the polymer nanoparticles in Examples 1-4 and Comparative Examples 1-2 of the present invention in an environment with a mass fraction of 10% fetal bovine serum is shown in FIG. Figure 12 A is a relationship diagram between the particle size and particle size distribution (PDI) of the polymer nanoparticles in Examples 1-4 and Comparative Examples 1-2 of the present invention in an environment with a mass fraction of 10% fetal bovine serum, Figure 12 B is the polydispersity coefficient of the polymer nanoparticles in Examples 1-4 of the present invention and Comparative Examples 1-2 in an environment with a mass fraction of 10% fetal bovine serum.

[0157] Depend on Figures 10-12 It can be seen that the polymer nanoparticles provided by the present invention have good water solubility and dispersibility, and have good stability at pH = 4 and in serum storage, have a long storage time and are evenly dispersed and not easy to agglomerate, thereby ensuring the safety of in vivo application.

[0158] In summary, the polymer nanoparticles prepared in the embodiments of the present invention have bone targeting, excellent antioxidant properties and the ability to neutralize acidic environments.

[0159] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A polymer nanoparticle with bone targeting, acid neutralization and antioxidant properties, characterized in that: The raw materials for preparing the polymer nanoparticles include zoledronic acid-modified polycaprolactone-polypeptide copolymer; The zoledronic acid-modified polycaprolactone-polypolypeptide copolymer is obtained by a preparation method comprising the following steps: dissolving a first raw material system comprising polycaprolactone, tyrosine cyclic anhydride, and Nε-benzyloxycarbonyl-L-lysine cyclic anhydride in a first organic solvent, performing a first reaction under vacuum, and precipitating a first product after the first reaction using a second organic solvent to obtain a polycaprolactone-polypeptide copolymer; dissolving the polycaprolactone-polypolypeptide copolymer in a third organic solvent to perform a second reaction, and sequentially performing a neutralization treatment and a first dialysis treatment on a second product after the second reaction to obtain a polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed; The polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed is dissolved in a fourth organic solvent, and then zoledronic acid activated with N,N'-carbonyldiimidazole is added to carry out a third reaction. The third product after the third reaction is subjected to a second dialysis treatment to obtain the polycaprolactone-polypolypeptide copolymer modified with zoledronic acid. The chemical structure of the polycaprolactone-polypolypeptide copolymer modified with zoledronic acid is shown in Formula (1): Formula (1).

2. The polymer nanoparticles according to claim 1, which have bone targeting, acid neutralization and antioxidant properties, are characterized in that: The preparation raw materials also include polycaprolactone-polyethylene oxide.

3. The polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties according to claim 2, characterized in that: In the polymer nanoparticles, the mass ratio of the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer to polycaprolactone-polyethylene oxide is (1-3): (0-1).

4. A method for preparing polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties according to any one of claims 1 to 3, characterized in that: The following steps are involved: Preparation of zoledronic acid modified polycaprolactone-polypeptide copolymer: dissolving a first raw material system comprising polycaprolactone, tyrosine cyclic anhydride, and Nε-benzyloxycarbonyl-L-lysine cyclic anhydride in a first organic solvent, performing a first reaction under vacuum, and precipitating a first product after the first reaction using a second organic solvent to obtain a polycaprolactone-polypeptide copolymer; dissolving the polycaprolactone-polypolypeptide copolymer in a third organic solvent to perform a second reaction, and sequentially performing a neutralization treatment and a first dialysis treatment on a second product after the second reaction to obtain a polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed; dissolving the polycaprolactone-polypolypeptide copolymer from which the benzyloxycarbonyl group has been removed in a fourth organic solvent, adding zoledronic acid activated with N,N'-carbonyldiimidazole, and performing a third reaction; and performing a second dialysis treatment on the third product after the third reaction to obtain the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer; Preparation of polymer nanoparticles: A third raw material system including the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer and polycaprolactone-polyethylene oxide is dissolved in a fifth organic solvent to obtain a solution containing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer. Under vigorous stirring, first deionized water is added to the solution containing the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer to perform a third dialysis treatment to obtain the polymer nanoparticles.

5. The method for preparing polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties according to claim 4, characterized in that: The molar ratio of the polycaprolactone, the tyrosine cyclic anhydride and the Nε-benzyloxycarbonyl-L-lysine cyclic anhydride is 1:(0.1-30):(0.1-15).

6. The method for preparing polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties according to claim 4, characterized in that: The molar ratio of the polycaprolactone to the N,N'-carbonyldiimidazole-activated zoledronic acid is 1:(0.1-10).

7. The method for preparing polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties according to claim 4, characterized in that: The second product after the second reaction is subjected to a neutralization treatment and a first dialysis treatment in sequence, including: neutralizing the second product after the second reaction with a sixth organic solvent, and then performing a first dialysis treatment on the neutralized second product with a second deionized water for 4 hours to 100 hours, wherein the sixth organic solvent is at least one of n-hexane, triethylamine, acetone, ether, and ethyl acetate.

8. The method for preparing polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties according to claim 4, characterized in that: The third product after the third reaction is subjected to a second dialysis treatment, comprising: using a third deionized water to perform a second dialysis treatment on the third product after the third reaction for 4 hours to 100 hours.

9. The method for preparing polymer nanoparticles having bone targeting, acid neutralization and antioxidant properties according to claim 4, characterized in that: The volume ratio of the fifth organic solvent to the first deionized water is 1:(1-5); And / or, the third dialysis treatment lasts for 4 hours to 100 hours.

10. A bone-targeting polymer, characterized in that The bone-targeting polymer is the zoledronic acid-modified polycaprolactone-polypolypeptide copolymer according to claim 1.

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