Application of functional polymer in treatment of osteoporosis and / or osteosarcoma

Abstract

The invention provides an application of a functional polymer and / or a pharmaceutically acceptable salt thereof in preparation of a medicine for treating osteoporosis and / or osteosarcoma. Compared with the prior art, the functional polymer provided by the invention is divided into three parts, and the phospholipid part has the capability of being inserted into the surface of a cell membrane, so that the affinity of a drug and the cell membrane can be improved; the polyethylene glycol part can improve the water solubility of the whole material and the long circulation capability of the whole material in blood, prolong the retention period of the medicine in circulation and improve the utilization degree; the diphosphonate part has a bone targeting effect, so that the medicine can be preferentially positioned at the osteoporosis part, the osteoclast function is inhibited, a relatively good treatment effect on osteoporosis is achieved, and diphosphonate can also induce calcium ion deposition and form a physical barrier around osteosarcoma to inhibit osteosarcoma development.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer drugs, and in particular relates to the application of a functional polymer in the treatment of osteoporosis and / or osteosarcoma. Background Art

[0002] Osteoporosis is a systemic bone disease caused by various reasons. Its main characteristics are decreased bone density and bone quality, damage to bone microstructure, increased bone brittleness, and a state prone to fractures. Osteoporosis is mainly divided into primary and secondary types. Primary osteoporosis is further divided into postmenopausal osteoporosis, senile osteoporosis, and idiopathic osteoporosis. In addition, various diseases such as endocrine diseases, connective tissue diseases, chronic kidney disease, gastrointestinal diseases, and blood system diseases may cause osteoporosis. Symptoms of osteoporosis include pain, spinal deformity, and brittle fractures. These symptoms may lead to pain, functional impairment in daily life, or more serious complications, such as chest deformity that affects cardiopulmonary function.

[0003] Bisphosphonates are the first-line drugs for the clinical treatment of osteoporosis and are the most widely used. This type of drug can effectively inhibit bone resorption by osteoclasts and play an anti-osteoporosis role. Alendronate sodium is a commonly used bisphosphonate drug. There are currently two dosage forms: tablets and injections. At present, alendronate sodium tablets are the most widely used in clinical practice, but its oral requirements are high, its bioavailability is only 0.7%, and there are many side effects related to the digestive tract. Alendronate sodium injection is also seriously restricted in its clinical popularization due to the rapid metabolism of small molecule drugs, short plasma retention time, low effective drug utilization rate, and renal toxicity. Therefore, the development of a multifunctional polymer with high biosafety and good effect is of great significance for the treatment of osteoporosis.

[0004] Osteosarcoma is one of the most common malignant bone tumors, and its incidence ranks first among primary bone tumors. At present, neoadjuvant chemotherapy combined with surgery is the main treatment for osteosarcoma in the clinic. The application of neoadjuvant chemotherapy has increased the survival rate of osteosarcoma patients from 15% to 17% in surgical treatment alone to 70%. High-dose methotrexate, doxorubicin, platinum and ifosfamide are conventional drugs in osteosarcoma chemotherapy regimens, but due to their lack of tumor tissue targeting, they also produce strong toxic side effects while achieving therapeutic effects; in addition, chemotherapy has poor therapeutic effects on recurrent and metastatic osteosarcoma, and the overall five-year survival rate is about 20%. Therefore, designing and developing a new osteosarcoma treatment strategy that is targeted, has few toxic side effects, and can simultaneously inhibit the progression of primary lesions and lung metastases is a clinical problem that needs to be solved urgently. Summary of the invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide a functional polymer with high bioavailability, good biocompatibility and low toxicity and side effects for use in the treatment of osteoporosis and / or osteosarcoma.

[0006] The present invention provides a use of a functional polymer and / or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating osteoporosis and / or osteosarcoma; the functional polymer has a structure shown in formula (I):

[0007]

[0008] Wherein, R is a C10-C20 alkyl group or a C10-C20 alkenyl group;

[0009] n is the degree of polymerization, and n is an integer from 2 to 240;

[0010] m is an integer from 0 to 5.

[0011] Preferably, R is a C13-C17 alkyl group or a C13-C17 alkenyl group.

[0012] Preferably, m is 1, 2 or 4.

[0013] Preferably, the functional polymer has one or more structures shown in formula (I-1) to formula (I-4):

[0014]

[0015]

[0016] Preferably, the functional polymer is prepared according to the following method:

[0017] S1) reacting the compound represented by formula (II) and / or its salt compound with the polymer having the structure of formula (III) in an aqueous medium to obtain a functional polymer;

[0018]

[0019] Preferably, the aqueous medium is selected from boric acid-borax buffer; the pH value of the aqueous medium is 8-9.

[0020] Preferably, the reaction temperature is 15°C to 40°C; and the reaction time is 60 to 80 hours.

[0021] Preferably, the molar ratio of the compound represented by formula (II) and / or its salt compound to the polymer having the structure of formula (III) is (3-8):1.

[0022] Preferably, after the reaction, the product is dialyzed using a dialysis bag with a molecular weight cutoff of 1000 Da, and placed in a freeze dryer for freeze drying to obtain a functional polymer.

[0023] Preferably, the pharmaceutically acceptable salt is a sodium salt.

[0024] The present invention provides a functional polymer and / or its pharmaceutically acceptable salt for use in the preparation of osteoporosis and / or osteosarcoma therapeutic drugs; the functional polymer has a structure shown in formula (I). Compared with the prior art, the functional polymer provided by the present invention is divided into three parts, the phospholipid part has the ability to insert into the cell membrane surface; the polyethylene glycol part can increase the water solubility of the overall material and the long circulation ability in the blood, which can prolong the retention period of the drug in the circulation and improve the utilization; the bisphosphonate part has a targeting effect, and can also chelate calcium ions to induce its enrichment, so that the drug can be preferentially positioned in the osteoporotic site, and can inhibit the bone destruction caused by osteoclasts, and has a good therapeutic effect on osteoporosis. For the treatment of osteosarcoma, the mineralization-inducing polymer can be enriched in the tumor site, and then inserted into the cell membrane, inducing the continuous deposition of calcium ions, forming a biomineralization barrier around the tumor, hindering its material exchange with normal tissues, effectively inhibiting the progression and lung metastasis of osteosarcoma, and at the same time it can also inhibit the generation and differentiation of osteoclasts, and alleviate the bone destruction caused by osteosarcoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the H NMR spectrum of DSPE-polyethylene glycol-alendronic acid obtained in Example 1 of the present invention;

[0026] Figure 2 is the H NMR spectrum of DMPE-polyethylene glycol-alendronic acid obtained in Example 2 of the present invention;

[0027] Figure 3 is the H NMR spectrum of DPPE-polyethylene glycol-alendronic acid obtained in Example 3 of the present invention;

[0028] Figure 4 is the H NMR spectrum of DOPE-polyethylene glycol-alendronic acid obtained in Example 4 of the present invention;

[0029] Figure 5 This is a graph showing the bone density test results obtained in Example 5 of the present invention;

[0030] Figure 6 This is a result diagram of the microstructure-related indicators of the femur obtained in Example 5 of the present invention;

[0031] Figure 7 This is a result diagram of the microstructure-related indexes of the spine obtained in Example 5 of the present invention;

[0032] Figure 8 This is a result diagram of the microstructure-related indicators of the tibia obtained in Example 5 of the present invention;

[0033] Fig. 9 The three-point mechanical test photos and result diagrams obtained in Example 5 of the present invention;

[0034] Fig.10 This is a graph showing the change in mouse tumor volume obtained in Example 6 of the present invention;

[0035] Fig.11 This is a graph showing the change in the survival period of mice obtained in Example 6 of the present invention;

[0036] Fig.12 This is a graph showing the change in mouse tumor volume obtained from the combined administration with chemotherapeutic drugs treatment experiment in Example 6 of the present invention;

[0037] Fig.13 This is a graph showing the weight change results of mice obtained from the combined drug administration and chemotherapy drug treatment experiment in Example 6 of the present invention. DETAILED DESCRIPTION

[0038] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only 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 work are within the scope of protection of the present invention.

[0039] The present invention provides a use of a functional polymer and / or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating osteoporosis; the functional polymer has a structure shown in formula (I):

[0040]

[0041] Among them, R is a C10-C20 alkyl group or a C10-C20 alkenyl group, preferably a C12-C18 alkyl group or a C12-C18 alkenyl group, and more preferably a C13-C17 alkyl group or a C13-C17 alkenyl group; the number of double bonds in the alkenyl group is preferably 1 to 4, more preferably 1 to 3, further preferably 1 or 2, and most preferably 1.

[0042] n is a degree of polymerization, and n is an integer of 2 to 240, preferably an integer of 20 to 200, more preferably an integer of 20 to 150, further preferably an integer of 20 to 100, further preferably an integer of 20 to 80, further preferably an integer of 20 to 50, and most preferably an integer of 40 to 50.

[0043] m is an integer of 0 to 5, preferably an integer of 0 to 4; specifically, m can be 1, 2 or 4 in the present invention.

[0044] In a specific embodiment provided by the present invention, the functional polymer has one or more structures shown in formula (I-1) to formula (I-4):

[0045]

[0046]

[0047] In a specific embodiment provided by the present invention, the pharmaceutically acceptable salt is a sodium salt.

[0048] In a specific embodiment provided by the present invention, the functional polymer is prepared according to the following method: S1) reacting the compound represented by formula (II) and / or its salt compound with the polymer represented by formula (III) in an aqueous medium to obtain the functional polymer;

[0049]

[0050] According to the present invention, the compound represented by formula (II) and / or its salt compound is preferably first dissolved in an aqueous medium, and then added to the polymer with the structure of formula (III) for reaction; wherein the salt compound is preferably a sodium salt; specifically, the compound represented by formula (II) and / or its salt compound can be one or more of alendronate sodium, pamidronate disodium and neridronate sodium; the aqueous medium is preferably a boric acid-borax buffer; the pH value of the aqueous medium is preferably 8-9, more preferably 8.5; the molar ratio of the compound represented by formula (II) and / or its salt compound to the polymer with the structure of formula (III) is preferably (3-8):1, more preferably (4-6):1, and more preferably 5:1; the reaction temperature is preferably 15°C-40°C, more preferably 20°C-30°C, and more preferably 25°C; the reaction time is preferably 60-80h, more preferably 70-75h, and more preferably 72h.

[0051] After the reaction is completed, dialysis is preferably performed using a dialysis bag with a molecular weight cutoff of 1000Da, and freeze-dried to obtain a functional polymer; the dialysis time is preferably 1 to 3 days, more preferably 2 days; the dialysis is preferably performed using deionized water; during the dialysis process, the water is preferably changed every 3 to 4 hours.

[0052] The functional polymer provided by the present invention can be applied to the treatment of osteoporosis. The phospholipid group of the functional polymer has a similar chemical structure to the cell membrane, which improves the affinity of the drug to the cell membrane. The polyethylene glycol property prolongs the retention period of the drug in the circulation and improves the utilization rate. The active targeting effect of the bisphosphonate part can make the drug preferentially positioned at the osteoporotic site and can inhibit bone destruction caused by osteoclasts, thereby having a good therapeutic effect on osteoporosis.

[0053] The present invention also provides a use of a functional polymer and / or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating osteosarcoma; the functional polymer has a structure shown in formula (I):

[0054]

[0055] Wherein, R is a C10-C20 alkyl group or a C10-C20 alkenyl group;

[0056] n is the degree of polymerization, and n is an integer from 2 to 240;

[0057] m is an integer from 0 to 5.

[0058] The functional polymer is the same as described above and will not be described again here.

[0059] The functional polymer provided by the present invention can be applied to the treatment of osteosarcoma. Compared with traditional drugs, the functional polymer provided by the present invention has the ability of cell calcification, which can block the communication between tumor tissue and the outside, stabilize calcification, and inhibit the growth of cells in both the edge area and the center area, avoid drug resistance, and inhibit the occurrence of lung metastasis. Moreover, the functional polymer has good biocompatibility, and the polymer with physical tumor inhibition ability itself has low toxicity and little toxic and side effects on normal tissues.

[0060] The bisphosphonates contained in the functional polymer provided by the present invention are bone-targeted, so the mineralization-inducing polymer can be enriched at the tumor site, and then inserted into the cell membrane, inducing continuous deposition of calcium ions, establishing a physical barrier around the tumor tissue, inhibiting cell growth in the edge area, inducing cell death in the central area, and thus inhibiting tumor progression. The formation of a calcified layer can also effectively prevent the occurrence of lung metastasis. Compared with traditional drugs, this physical tumor inhibition ability can avoid the generation of drug resistance, and as a tumor blocking therapy, it also avoids the influence of tumor osmotic pressure that limits traditional chemotherapy drugs. It is a new strategy for the treatment of osteosarcoma that is targeted, has few toxic side effects, and can simultaneously inhibit the progression of primary lesions and lung metastasis.

[0061] The present invention also provides a pharmaceutical composition, comprising a functional polymer and / or a pharmaceutically acceptable salt thereof, cisplatin (CDDP) and doxorubicin (DOX); the functional polymer has a structure shown in formula (I).

[0062] In a specific embodiment provided by the present invention, based on the compound represented by formula (II) and / or its salt compound, the mass ratio of the functional polymer and / or its pharmaceutically acceptable salt, cisplatin (CDDP) and doxorubicin (DOX) is 70: (10-20): (20-30), more preferably 70: (12-18): (22-28), further preferably 70: (14-16): (24-26), and most preferably 70: 15: 25.

[0063] The functional polymer provided by the present invention can be used in combination with clinical chemotherapy drugs for osteosarcoma, has a better therapeutic effect on osteosarcoma, and has a good application prospect in the clinical treatment of osteosarcoma.

[0064] To further illustrate the present invention, the application of a functional polymer provided by the present invention in the treatment of osteoporosis and / or osteosarcoma is described in detail below in conjunction with examples.

[0065] The reagents used in the following examples are all commercially available.

[0066] Example 1: Preparation of distearoylphosphatidylethanolamine-polyethylene glycol-alendronate of formula (I-1)

[0067] Select a round-bottom flask of appropriate size, add 0.34g of sodium alendronate, add borax / boric acid buffer solution of pH 8.5 and stir to fully dissolve the sodium alendronate. Then add 0.75g of distearoylphosphatidyl acetamide-polyethylene glycol active ester (wherein the average molecular weight of polyethylene glycol is 2000), and stir and react for 72h at 25°C. The molar ratio of sodium alendronate and distearoylphosphatidyl acetamide-polyethylene glycol active ester is 5:1. After the reaction is completed, it is loaded into a dialysis bag with a molecular weight cutoff of 1000Da and dialyzed with water for 2 days, during which the water is changed every three to four hours on average. After the dialysis is completed, freeze-dry it with a freeze dryer to obtain the final product distearoylphosphatidylethanolamine-polyethylene glycol-alendronic acid, i.e. DSPE-polyethylene glycol-alendronic acid, with a yield of 90%.

[0068] The DSPE-polyethylene glycol-alendronic acid obtained in Example 1 was analyzed by a nuclear magnetic resonance spectrometer to obtain its hydrogen nuclear magnetic spectrum as shown in Figure 1 shown.

[0069] Example 2: Preparation of dimyristoylphosphatidylethanolamine-polyethylene glycol-alendronate of formula (I-2)

[0070] Select a round-bottom flask of appropriate size, add 0.34g of sodium alendronate, add borax / boric acid buffer solution of pH 8.5 and stir to fully dissolve the sodium alendronate. Then add 0.72g of dimyristoyl phosphatidylethanolamine-polyethylene glycol active ester (wherein the average molecular weight of polyethylene glycol is 2000), and stir and react for 72h at 25°C. The molar ratio of sodium alendronate to dimyristoyl phosphatidylethanolamine-polyethylene glycol active ester is 5:1. After the reaction is completed, it is loaded into a dialysis bag with a molecular weight cutoff of 1000Da and dialyzed with water for 2 days, during which the water is changed every three to four hours on average. After the dialysis is completed, freeze-dry it with a freeze dryer to obtain the final product dimyristoyl phosphatidylethanolamine-polyethylene glycol-alendronic acid, i.e. DMPE-polyethylene glycol-alendronic acid, with a yield of 90%.

[0071] The DMPE-polyethylene glycol-alendronic acid obtained in Example 2 was analyzed by nuclear magnetic resonance spectrometer to obtain its nuclear magnetic hydrogen spectrum as shown in Figure 2 shown.

[0072] Example 3: Preparation of dipalmitoylphosphatidylethanolamine-polyethylene glycol-alendronate of formula (I-3)

[0073] Select a round-bottom flask of appropriate size, add 0.34g of sodium alendronate, add borax / boric acid buffer solution of pH 8.5 and stir to fully dissolve the sodium alendronate. Then add 0.74g of dipalmitoylphosphatidyl acetamide-polyethylene glycol active ester (wherein the average molecular weight of polyethylene glycol is 2000), and stir and react for 72h at 25°C. The molar ratio of sodium alendronate and dipalmitoylphosphatidyl acetamide-polyethylene glycol active ester is 5:1. After the reaction is completed, it is loaded into a dialysis bag with a molecular weight cutoff of 1000Da and dialyzed with water for 2 days, during which the water is changed every three to four hours on average. After the dialysis is completed, freeze-dry it with a freeze dryer to obtain the final product dipalmitoylphosphatidylethanolamine-polyethylene glycol-alendronic acid, i.e. DPPE-polyethylene glycol-alendronic acid, with a yield of 90%.

[0074] The DPPE-polyethylene glycol-alendronic acid obtained in Example 3 was analyzed by nuclear magnetic resonance spectrometer to obtain its nuclear magnetic hydrogen spectrum as shown in Figure 3 shown.

[0075] Example 4: Preparation of dioleoylphosphatidylethanolamine-polyethylene glycol-alendronate of formula (I-4)

[0076] Select a round-bottom flask of appropriate size, add 0.34g of sodium alendronate, add borax / boric acid buffer solution of pH 8.5 and stir to fully dissolve the sodium alendronate. Then add 0.75g of dioleoylphosphatidyl acetamide-polyethylene glycol active ester (wherein the average molecular weight of polyethylene glycol is 2000), and stir and react for 72h at 25°C. The molar ratio of sodium alendronate and dioleoylphosphatidyl acetamide-polyethylene glycol active ester is 5:1. After the reaction is completed, it is loaded into a dialysis bag with a molecular weight cutoff of 1000Da and dialyzed with water for 2 days, during which the water is changed every three to four hours on average. After the dialysis is completed, freeze-dry it with a freeze dryer to obtain the final product dioleoylphosphatidylethanolamine-polyethylene glycol-alendronate, i.e. DOPE-polyethylene glycol-alendronate, with a yield of 90%.

[0077] The DOPE-polyethylene glycol-alendronic acid obtained in Example 4 was analyzed by a nuclear magnetic resonance spectrometer to obtain its hydrogen nuclear magnetic spectrum as shown in Figure 4 shown.

[0078] Example 5: Osteoporosis Treatment in Mice Animal Experiment

[0079] Osteoporosis modeling in mice. The mice were anesthetized, the backs were depilated, the back skin was cut open to expose the ovaries, the fallopian tubes were ligated at the upper and lower parts of the uterine horns, and the ovaries were removed and sutured. Twelve weeks after surgery, the osteoporosis model was successfully established when the bone density of the modeling group was less than 2.5 standard deviations of the average bone density of the sham operation group.

[0080] The animal experiments were divided into seven groups, namely, sham operation group, blank control group, alendronate sodium group and four material groups, with nine mice in each group. The treatment group was treated once a week at a dose of 3 μmol / kg, and the treatment method was injection into the tail vein of the mice.

[0081] After 12 weeks of treatment, the mice were tested for bone density (BMD) using a small animal dual-energy X-ray (DXA) bone density analyzer. The region of interest (ROI) was selected as the distal femur, spine, and proximal tibia. The bone density test results of the region of interest (ROI) are shown in the figure below. Figure 5 The results showed that compared with the control group, the bone density of mice in the four treatment groups given the four functional polymers was significantly improved, and the bone density of mice in the DMPE-polyethylene glycol-alendronate group and DSPE-polyethylene glycol-alendronate group was also higher than that in the alendronate sodium group.

[0082] After 12 weeks of treatment, the mice were sampled and their femurs, spines, and tibias were scanned, three-dimensionally reconstructed, and data analyzed using Micro-CT to detect the mouse bone microstructure-related indicators, including bone volume fraction (BV / TV), bone surface area and tissue volume ratio (BS / TV), trabecular number (Tb.N) and trabecular separation (Tb.Sp). The results of the femur microstructure-related indicators are shown in the figure below. Figure 6 As shown in the figure, the results of the microstructure related indicators of the spine are shown in Figure 7 As shown in the figure, the results of the microstructure related indicators of the tibia are shown in Figure 8 As shown. The results showed that the degree of bone microstructure destruction in the four treatment groups of mice given the four functional polymers was significantly improved compared with the control group, whether it was the femur, spine or tibia. The number of trabeculae, bone volume fraction, bone surface area and tissue volume ratio were significantly increased, and the degree of trabecular separation was significantly reduced. This shows that the four functional polymers can significantly inhibit bone loss in osteoporosis model mice, improve the degree of bone microstructure destruction, and increase the bone mass of osteoporotic mice. Among them, the DSPE-polyethylene glycol-alendronate group had the best results, which was better than the alendronate sodium group. This shows that DSPE-polyethylene glycol-alendronate is better than the clinical first-line drug alendronate sodium in the treatment of osteoporosis.

[0083] The femur of mice treated for 12 weeks was subjected to a three-point mechanical test. The separated bone tissue was subjected to a three-point mechanical test, with a span of 10 mm, a loading speed of 1 mm / min, and a uniform loading rate until the femur was destroyed. The photos and results of the three-point mechanical test are shown in the figure. Fig. 9 As shown. The results showed that compared with the control group, the maximum force of femoral destruction of mice in the four treatment groups given the four functional polymers was significantly increased, and all of them could improve the mechanical properties of the femur of osteoporotic mice. The results of the DSPE-polyethylene glycol-alendronate group were better than those of the alendronate sodium group, which shows that DSPE-polyethylene glycol-alendronate can better treat osteoporosis and prevent the occurrence of osteoporotic fractures.

[0084] Example 6: Osteosarcoma treatment mouse animal experiment

[0085] 6.1 Animal experiment on orthotopic osteosarcoma in mice

[0086] BALB / c nude mice were used to establish an orthotopic osteosarcoma model. 2.0×10 6 143B cells. When the average tumor volume reaches 160mm 3The mice were randomly divided into 6 groups, namely the control group, the alendronate sodium group and the four material treatment groups. The treatment was carried out on the 1st, 3rd, 5th, 7th, 9th, 11th, 13th and 15th days, with a dose of 10 mg / kg mouse (calculated as alendronate sodium). The tumor volume and survival period of the mice were recorded, and the results of the changes in the tumor volume of the mice were obtained as follows: Fig.10 The results of the changes in mouse survival time are shown in Fig.11 The results showed that the tumor volume of mice in the four material treatment groups was smaller than that in the control group and the alendronate sodium group, and the survival time of osteosarcoma model mice was also prolonged, which indicated that the four materials had a good therapeutic effect on osteosarcoma.

[0087] 6.2 Combined administration with chemotherapy drugs

[0088] DMPE-polyethylene glycol-alendronate was used in combination with cisplatin (CDDP) and doxorubicin (DOX), clinical chemotherapy drugs for osteosarcoma, to verify the therapeutic effect on osteosarcoma. BALB / c nude mice were selected and injected with 1.0×10 6 143B cells were used to establish an orthotopic osteosarcoma model. When the tumor volume reached 400 mm 3 Afterwards, they were randomly divided into three groups, namely the control group, CDDP+DOX group and DMPE-polyethylene glycol-alendronate+CDDP+DOX group. DMPE-polyethylene glycol-alendronate was administered via tail vein on days 1, 3, 5, 7, 9, 11, and 13, with a dose of 10 mg / kg mouse (calculated as alendronate sodium). CDDP+DOX was administered via tail vein on days 1, 4, 7, 10, and 13, with a dose of 5 mg / kg DOX and 3 mg / kg CDDP. The tumor volume and survival period of the mice were recorded. The tumor volume and survival period of the mice were recorded, and the results of the changes in the tumor volume of the mice were obtained as shown in the figure below. Fig.12 The mouse survival results were shown in Fig.13 As shown. The results showed that the tumor volume of mice in the treatment group was smaller than that in the control group, and the survival of osteosarcoma model mice was prolonged. The combined drug administration group had a significantly longer survival period than the CDDP+DOX group, and had a better therapeutic effect on osteosarcoma. This shows that DMPE-polyethylene glycol-alendronate has a good application prospect in the clinical treatment of osteosarcoma.

[0089] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Use of a functional polymer and / or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating osteoporosis and / or osteosarcoma; the functional polymer has a structure shown in formula (I): in, R is a C10-C20 alkyl group or a C10-C20 alkenyl group; n is the degree of polymerization, and n is an integer from 2 to 240; m is an integer from 0 to 5.

2. The use according to claim 1, characterized in that: The R is a C13-C17 alkyl group or a C13-C17 alkenyl group.

3. The use according to claim 1, characterized in that: The m is 1, 2 or 4.

4. The use according to claim 1, characterized in that: The functional polymer has one or more structures shown in formula (I-1) to formula (I-4):

5. The use according to claim 1, characterized in that: The functional polymer is prepared according to the following method: S1) reacting the compound represented by formula (II) and / or its salt compound with the polymer having the structure of formula (III) in an aqueous medium to obtain a functional polymer; 6. The use according to claim 5, characterized in that: The aqueous medium is selected from a boric acid-borax buffer; the pH value of the aqueous medium is 8 to 9; And / or, the reaction temperature is 15°C to 40°C; the reaction time is 60 to 80 hours.

7. The use according to claim 5, characterized in that: The molar ratio of the compound represented by formula (II) and / or its salt compound to the polymer having the structure of formula (III) is (3-8):

1.

8. The use according to claim 5, characterized in that: After the reaction, the product was dialyzed using a dialysis bag with a molecular weight cutoff of 1000 Da and placed in a freeze dryer for freeze drying to obtain a functional polymer.

9. The use according to claim 1, characterized in that: The pharmaceutically acceptable salt is a sodium salt.

10. A pharmaceutical composition, characterized in that It comprises a functional polymer and / or a pharmaceutically acceptable salt thereof, cisplatin and doxorubicin; the functional polymer has a structure shown in formula (I): Wherein, R is a C10-C20 alkyl group or a C10-C20 alkenyl group; n is the degree of polymerization, and n is an integer from 2 to 240; m is an integer from 0 to 5.

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