CN115232304B - Bisphosphonate-containing polyamino acid copolymer, bone material for resisting bone tumor and preparation thereof - Google Patents
Bisphosphonate-containing polyamino acid copolymer, bone material for resisting bone tumor and preparation thereof Download PDFInfo
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/42—Polyamides containing atoms other than carbon, hydrogen, oxygen, and nitrogen
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
Abstract
The invention particularly relates to a bisphosphonate-containing polyamino acid copolymer, an anti-bone tumor bone material and preparation thereof, belonging to the field of polymer synthesis and processing. The invention provides a copolymer containing bisphosphonic acid polyamino acid, the structural formula of the copolymer is shown as a formula I, wherein m is more than or equal to 30 and less than or equal to 100, n+p+r is more than or equal to 0 and less than or equal to 70, n is more than or equal to 0, r is more than 0, and p is more than or equal to 0. The invention prepares the bisphosphonate-containing polyamino acid copolymer and the bone tumor resisting composite material which can directly act on the bone defect part caused by tumors, realize no injection, controllable degradation, low toxicity, obvious inhibition effect on osteoclasts and continuous bone tumor resisting.
Description
Technical Field
The invention particularly relates to a bisphosphonate-containing polyamino acid copolymer, an anti-bone tumor bone material and preparation thereof, belonging to the field of polymer synthesis and processing.
Background
Bone tumors are one of the tumors which are difficult to treat nowadays, and the treatment of the bone tumors generally comprises methods such as surgery, chemotherapy, radiotherapy and the like at the present stage. In the course of chemotherapy, drugs that inhibit or kill tumor cells are generally used for treatment, typically by oral administration or by comprehensive intravenous injection. However, the antitumor drug small molecules, whether taken orally or injected, have the following problems:
1, the concentration of the medicine reaching the tumor part is small, the utilization rate of the medicine is low, the acting time of the medicine effect is short, and the medicine needs to be repeatedly used for a long time;
2, most of high-concentration medicines are required to be metabolized by livers, kidneys and the like, and have great side effects on organs such as livers, kidneys and the like.
Thus, the current research on bone tumor treatment generally takes medicine-carrying bone cement, medicine-carrying filler, nano microsphere medicine-carrying, polymer prodrug and the like as main materials. But the drug-loaded bone cement and the drug-loaded filler have lower mechanical properties in the later degradation period and do not have mechanical bearing properties; although the functional nano microsphere drug can be transmitted to the tumor part through the targeting effect, the drug loading rate of the microsphere drug is generally small, and the drug needs to be injected for multiple times, and the toxicity related to nanoparticle metabolism still needs to be verified; the polymer prodrug nano microsphere is also used by being prepared into nano particles, but the grafted medicine rate is low, and the related problems of metabolic toxicity and the like are also existed.
There are no reports in the prior art about bisphosphonate-containing polyamino acid copolymers that can be used for persistent anti-bone tumors and their use for preparing anti-bone tumor composites.
Disclosure of Invention
Aiming at the defects, the invention aims to prepare a bisphosphonate-containing polyamino acid copolymer and an anti-bone tumor composite material which directly act on a bone defect part caused by tumors, realize no injection, controllable degradation, low toxicity, obvious inhibition effect on osteoclasts and continuous anti-bone tumor; by regulating the content of each component, the composite material can be used as a filling degradation material or a supporting material for bone defects caused by bone tumors.
The technical scheme of the invention is as follows:
the first technical problem to be solved by the invention is to provide a bisphosphonate-containing polyamino acid copolymer, the structural formula of which is shown as formula I:
wherein m is more than or equal to 30 and less than 100, n+p+r is more than or equal to 0 and less than or equal to 70, n is more than or equal to 0 and less than r is more than or equal to 0 and less than p is more than or equal to 0;
R 1 selected from the following groups:
R 2 selected from the following groups:
r3 is selected from the following groups:
Furthermore, the bisphosphonate polyamino acid-containing copolymer shown in the formula I has the anti-bone tumor performance and has the inhibition effect on osteosarcoma, chondrosarcoma, ewing sarcoma and the like.
The second technical problem to be solved by the invention is to provide a preparation method of a polyamino acid copolymer shown in formula I, which comprises the following steps: under the protection of inert gas (such as nitrogen), 6-aminocaproic acid, other poly-amino acid, anti-tumor micromolecules and biphosphoric acid or salts thereof are added into water, the temperature is gradually increased to 160-190 ℃ for dehydration under stirring, then the temperature is increased to 190-260 ℃ for reaction for 2.5-5 h under the molten state, and the polyamino acid copolymer shown in the formula I is prepared. In the invention, the selected bisphosphonic acid or salt thereof and the antitumor small molecular substance can react with amino acid.
In the polyamino acid copolymer, the mole number of 6-aminocaproic acid is more than or equal to 30% and less than 100%, and the mole total number of 0 < polybasic amino acid, biphosphoric acid or salt thereof and anti-tumor micromolecules is more than or equal to 70%.
Further, the other polyamino acid is at least one of glycine, alanine, leucine, isoleucine, valine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, hydroxyproline, lysine, arginine or 4-aminobutyric acid.
Further, the biphosphoric acid or salt thereof is selected from: zoledronic acid:
ibandronic acid:
ibandronate sodium: />
Pamidronate:
pamidronate disodium: />
Alendronic acid: />
Alendronate sodium: />
Risedronic acid: />
Risedronate sodium: />
Etidronic acid: />
Etidronate sodium: />
Neridronic acid: />
Sodium neridronate: />
Olpatadine phosphate: />
Any one of them.
Further, the anti-tumor small molecule is selected from the group consisting of: cyclophosphamide:
ifosfamide: />
Methaemastra (L.) Diels>
Isoanti Oncoin->
Or anti-tumor amino acid->
Any one of them.
Further, the particle size of the bisphosphonate-containing polyamino acid copolymer is 0.3 mm-5 mm; if the particle size is too large to be implanted, the particle size is too small to be washed away by tissue fluid.
The third technical problem to be solved by the invention is to provide a composite material with anti-bone tumor performance, wherein the composite material is prepared by melt blending of a bisphosphonate-containing polyamino acid copolymer shown in a formula I and a calcium salt compound, and the mass of the calcium salt compound is 30-70% of the total mass of the composite material.
Further, the calcium salt compound is: at least one of hydroxyapatite, nano hydroxyapatite, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, calcium lactate, calcium citrate, calcium glycerophosphate, calcium gluconate or calcium ascorbate.
Further, the composite material with anti-bone tumor property has an inhibitory effect on osteosarcoma, chondrosarcoma, ewing sarcoma, etc.
The fourth technical problem to be solved by the invention is to provide a preparation method of the composite material with the anti-bone tumor performance, which comprises the following steps: uniformly mixing the bisphosphonate-containing polyamino acid copolymer shown in the formula I with a calcium salt compound, and then carrying out melt blending to obtain the bisphosphonate-containing polyamino acid copolymer/calcium salt composite material with bone tumor resistance.
Further, the melt blending temperature is 190 to 230 ℃.
The invention has the beneficial effects that:
1. the raw materials used in the invention are all medical grade raw materials, and the raw materials are easy to obtain.
2. The composite material is prepared by a two-step method, and has simple process, short period, simplicity and easy implementation.
3. The bisphosphonate-containing polyamino acid copolymer and the composite material thereof prepared by the invention can prepare micro-degradation and full-degradation composite material according to the regulation and control of the proportion components; the composite material can be used as a filling material or a supporting material for bone tumor defect.
4. After the composite material with the anti-bone tumor performance is soaked in SBF solution for 7 days, a large amount of hydroxyapatite is deposited on the surface, and the composite material shows excellent bioactivity.
5. The bisphosphonate-containing polyamino acid copolymer and the composite material thereof prepared by the invention directly act on defect parts caused by tumors, have inhibition effects on osteosarcoma, ewing sarcoma, chondrosarcoma and the like, and can be used as bone tumor drugs or medical instruments.
Detailed Description
The invention takes 6-aminocaproic acid, other multi-amino acid, biphosphoric acid capable of reacting with amino acid and salts thereof, and antitumor small molecules capable of reacting with amino acid as copolymerization monomers to prepare a novel antitumor copolymer containing biphosphoric polyamino acid, and the copolymer can be further prepared into corresponding composite materials with calcium salt through a melt blending mode. Compared with the existing antitumor micromolecule medicines such as biphosphate and antitumor micromolecule, the biphosphate-containing polyamino acid copolymer and the composite material thereof prepared by the invention can directly act on bone tumor sites, have small side effect and high medicine concentration at the tumor sites, and have extremely high bioactivity.
The present invention is described in detail below by way of examples, which are necessary to be pointed out herein for further illustration of the invention and are not to be construed as limiting the scope of the invention, which is to be construed as being limited only by the appended claims.
Example 1
0.93mol of 6-aminocaproic acid, 0.01mol of methotrexate, 0.01mol of zoledronic acid, 0.02mol of proline and 0.03mol of hydroxyproline are added into water, stirred and gradually heated to 190 ℃ for dehydration, heated to 230 ℃ for reaction for 3 hours in a molten state, and then heated to 260 ℃ for reaction for 1 hour. After the reaction is finished, the zoledronic acid-containing polyamino acid copolymer is prepared, and the yield is: 93%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
50 g of zoledronic acid-containing polyamino acid copolymer, 45 g of hydroxyapatite and 5 g of calcium sulfate are mixed, extruded at 220 ℃ in an extruder and crushed into a zoledronic acid-containing polyamino acid copolymer/hydroxyapatite/calcium sulfate composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 5 days, a large amount of apatite was deposited on the surface, showing good bioactivity. The degradation rate of the composite material in PBS solution is 4.5% after 1 month. The test shows that the bending strength of the composite material is 92MPa, and the compression strength is 120MPa. The zoledronic acid-containing polyamino acid copolymer/hydroxyapatite/calcium sulfate composite material has an inhibition effect on osteosarcoma.
Example 2
0.9mol of 6-aminocaproic acid, 0.01mol of ifosfamide, 0.005mol of zoledronic acid, 0.005mol of proline, 0.01mol of hydroxyproline, 0.02mol of phenylalanine, 0.03mol of glycine, 0.01mol of alanine and 0.01mol of leucine are added into water, stirred and gradually heated to 160 ℃ for dehydration under the protection of nitrogen atmosphere, heated to 190 ℃, reacted for 2 hours in a molten state, and then heated to 220 ℃ for reaction for 0.5 hours. After the reaction is finished, the faint yellow zoledronic acid-containing polyamino acid copolymer is prepared, and the yield is 94%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
70 g of the polyamino acid copolymer containing zoledronic acid and 30 g of hydroxyapatite are blended, extruded at 190 ℃ in an extruder, crushed into a polyamino acid copolymer containing zoledronic acid/hydroxyapatite composite material with the particle size of 0.3-5 mm, and injection-molded into standard bars. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, hydroxyapatite salt was deposited on the surface, showing good bioactivity. In PBS solution, the composite material had a 1 month weight loss rate of 5.4%. The mechanical test shows that the bending strength of the composite material is 88MPa, and the compression strength is 103MPa.
Example 3
0.9mol of 6-aminocaproic acid, 0.01mol of cyclophosphamide, 0.005mol of zoledronic acid, 0.025mol of valine, 0.02mol of proline, 0.01mol of threonine, 0.01mol of serine, 0.01mol of phenylalanine and 0.01mol of hydroxyproline are added into water, stirred and gradually heated to 190 ℃ for dehydration, heated to 200 ℃, reacted in a molten state for 3 hours, and then heated to 260 ℃ for 2 hours. After the reaction is finished, the faint yellow zoledronic acid-containing polyamino acid copolymer is prepared. The yield was 94%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
70 g of zoledronic acid-containing polyamino acid copolymer and 30 g of nano hydroxyapatite are mixed, extruded at 200 ℃ in an extruder, crushed into a zoledronic acid-containing polyamino acid copolymer/nano hydroxyapatite composite material with the particle size of 0.3-5 mm, and subjected to injection molding to form standard bars. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 5 days, a large amount of apatite was deposited on the surface, showing good bioactivity. The mechanical test shows that the bending strength of the composite material is 85MPa, and the compression strength is 105MPa.
Example 4
0.9mol of 6-aminocaproic acid, 0.005mol of methotrexate, 0.005mol of ibandronic acid, 0.02mol of proline, 0.02mol of hydroxyproline, 0.02mol of lysine, 0.02mol of arginine and 0.01mol of phenylalanine are added into water, stirred and gradually heated to 190 ℃ for dehydration, heated to 210 ℃ for reaction for 2 hours in a molten state, and then heated to 260 ℃ for reaction for 0.5 hour. After the reaction is finished, a pale yellow ibandronate-containing polyamino acid copolymer is prepared, and the yield is: 95%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
30 g of ibandronate containing polyamino acid copolymer and 70 g of calcium phosphate are mixed, extruded at 230 ℃ in an extruder and crushed into an ibandronate containing polyamino acid copolymer/calcium phosphate composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 5 days, a large amount of apatite was deposited on the surface, showing good bioactivity. The degradation rate of the composite material in PBS solution is 6.5% after 1 month. Through tests, the ibandronate containing polyamino acid copolymer and the ibandronate containing polyamino acid copolymer/calcium phosphate composite material have an inhibiting effect on osteosarcoma.
Example 5
0.3mol of 6-aminocaproic acid, 0.01mol of methotrexate, 0.005mol of zoledronic acid, 0.02mol of tyrosine, 0.03mol of tryptophan, 0.02mol of proline, 0.01mol of hydroxyproline, 0.005mol of phenylalanine and 0.6mol of 4-aminobutyric acid are added into water, stirred and gradually heated to 190 ℃ for dehydration, heated to 220 ℃ for reaction for 3 hours in a molten state, and then heated to 230 ℃ for reaction for 1 hour. After the reaction is finished, the faint yellow zoledronic acid-containing polyamino acid copolymer is prepared, and the yield is 95%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
40 g of zoledronic acid-containing polyamino acid copolymer is mixed with 50 g of calcium sulfate and 10g of calcium hydrophosphate, extruded at 230 ℃ in an extruder and crushed into a zoledronic acid-containing polyamino acid copolymer/calcium sulfate/calcium hydrophosphate composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a large amount of apatite was deposited on the surface, showing good bioactivity. The degradation rate of the composite material in PBS solution is 44.6 percent in one month. Through tests, the zoledronic acid-containing polyamino acid copolymer/calcium sulfate/calcium hydrophosphate composite material has an inhibitory effect on Ewing sarcoma.
Example 6
0.8mol of 6-aminocaproic acid, 0.05mol of methotrexate, 0.05mol of sodium ibandronate, 0.05mol of glycine, 0.03mol of alanine and 0.02mol of leucine are added into water, stirred and gradually heated to 160 ℃ for dehydration under the protection of nitrogen atmosphere, heated to 190 ℃, reacted for 2 hours in a molten state, and then heated to 220 ℃ for reaction for 0.5 hour. After the reaction is finished, the light yellow polyamino acid copolymer containing ibandronate sodium is prepared, and the yield is 94%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
40 g of the sodium ibandronate containing polyamino acid copolymer is blended with 55 g of calcium sulfate and 5 g of calcium hydrophosphate, and the mixture is extruded at 230 ℃ in an extruder and crushed into a sodium ibandronate containing polyamino acid copolymer/calcium hydrophosphate/calcium sulfate composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a large amount of apatite was deposited on the surface, showing good bioactivity. The degradation experiment result shows that the degradation rate of the composite material in PBS for 1 month is 28%. Through tests, the copolymer containing ibandronate sodium polyamino acid and the copolymer containing ibandronate sodium polyamino acid/calcium hydrophosphate/calcium sulfate compound have an inhibition effect on chondrosarcoma and osteosarcoma.
Example 7
0.9mol of 6-aminocaproic acid, 0.01mol of methotrexate, 0.01mol of pamidronate, 0.03mol of proline, 0.02mol of hydroxyproline and 0.03mol of lysine are added into water, stirred and gradually heated to 180 ℃ for dehydration under the protection of nitrogen atmosphere, heated to 200 ℃, reacted for 2 hours in a molten state, and then heated to 220 ℃ for reaction for 0.5 hours. After the reaction is finished, the light yellow pamidronate polyamino acid copolymer is prepared, and the yield is 96%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
40 g of the pamidronate-containing polyamino acid copolymer is blended with 55 g of calcium carbonate and 5 g of calcium hydrophosphate, extruded at 220 ℃ in an extruder and crushed into a pamidronate-containing polyamino acid copolymer/calcium carbonate/calcium hydrophosphate composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a large amount of apatite was deposited on the surface, showing good bioactivity. Through tests, the pamidronate-containing polyamino acid copolymer and the pamidronate-containing polyamino acid copolymer/calcium carbonate/calcium hydrophosphate composite material have an inhibitory effect on chondrosarcoma and osteosarcoma.
Example 8
0.6mol of 6-aminocaproic acid, 0.1mol of methotrexate, 0.1mol of pamidronate sodium, 0.1mol of hydroxyproline and 0.1mol of proline are added into water, stirred and gradually heated to 160 ℃ for dehydration, heated to 190 ℃, reacted for 2.5 hours in a molten state, and then heated to 260 ℃ for reaction for 1 hour. After the reaction is finished, the light yellow pamidronate polyamino acid copolymer is prepared, and the yield is 92%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
50 g of the pamidronate-containing polyamino acid copolymer is mixed with 48 g of calcium lactate and 2 g of calcium phosphate, extruded at 220 ℃ in an extruder and crushed into a compound material of the pamidronate-containing polyamino acid copolymer/calcium lactate/calcium phosphate with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a small amount of apatite was deposited on the surface, showing relatively good bioactivity. Through tests, the pamidronate-containing polyamino acid copolymer and the pamidronate-containing polyamino acid copolymer/calcium lactate/calcium phosphate composite material have an inhibitory effect on chondrosarcoma and osteosarcoma.
Example 9
0.9mol of 6-aminocaproic acid, 0.01mol of alendronic acid, 0.01mol of phenylalanine, 0.03mol of proline, 0.02mol of hydroxyproline and 0.03mol of cyclophosphamide are added into water, stirred and gradually heated to 180 ℃ for dehydration under the protection of nitrogen atmosphere, heated to 200 ℃, reacted for 2 hours in a molten state, and then heated to 220 ℃ for reaction for 0.5 hour. After the reaction is finished, the pale yellow copolymer containing the alendronate polyamino acid is prepared, and the yield is 95%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
40 g of the copolymer containing the alendronate polyamino acid, 55 g of calcium citrate and 5 g of calcium hydrophosphate are blended, extruded at 220 ℃ in an extruder and crushed into a composite material containing the copolymer containing the alendronate polyamino acid, the calcium citrate and the calcium hydrophosphate, wherein the particle size of the composite material is 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a large amount of apatite was deposited on the surface, showing good bioactivity. Through tests, the copolymer containing the alendronate polyamino acid and the copolymer containing the alendronate polyamino acid/calcium citrate/calcium hydrophosphate composite material have an inhibition effect on chondrosarcoma and osteosarcoma.
Example 10
0.9mol of 6-aminocaproic acid, 0.01mol of sodium alemtujopsis, 0.01mol of methotrexate, 0.03mol of proline, 0.02mol of hydroxyproline and 0.03mol of lysine are added into water, stirred and gradually heated to 180 ℃ for dehydration under the protection of nitrogen atmosphere, heated to 200 ℃, reacted for 2 hours in a molten state, and then heated to 220 ℃ for reaction for 0.5 hour. After the reaction is finished, the pale yellow polyamino acid copolymer containing the alendronate sodium is prepared, and the yield is 94%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
40 g of the copolymer containing the sodium alembic phosphate and 58 g of calcium glycerophosphate and 2 g of hydroxyapatite are mixed, extruded at 220 ℃ in an extruder and crushed into the copolymer containing the sodium alembic phosphate/calcium glycerophosphate/hydroxyapatite composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a few apatites were deposited on the surface, showing relatively good bioactivity. Through tests, the copolymer containing the alen sodium phosphate and the composite material containing the copolymer containing the alen sodium phosphate, the calcium glycerophosphate and the hydroxyapatite have the inhibition effect on chondrosarcoma and osteosarcoma.
Example 11
0.9mol of 6-aminocaproic acid, 0.01mol of risedronic acid, 0.01mol of phenylalanine, 0.03mol of proline, 0.02mol of hydroxyproline, 0.02mol of lysine and 0.01mol of methotrexate are added into water, stirred and gradually heated to 180 ℃ for dehydration under the protection of nitrogen atmosphere, heated to 200 ℃, reacted for 2 hours in a molten state, and then heated to 220 ℃ for reaction for 0.5 hour. After the reaction is finished, the pale yellow polyamino acid copolymer containing risedronate is prepared, and the yield is 92%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
40 g of risedronate-containing polyamino acid copolymer, 55 g of calcium gluconate and 5 g of hydroxyapatite are mixed, extruded at 220 ℃ in an extruder and crushed into a risedronate-containing polyamino acid copolymer/calcium gluconate/hydroxyapatite composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a small amount of hydroxyapatite was deposited on the surface, showing better bioactivity. Through tests, the risedronate-containing polyamino acid copolymer/calcium gluconate/hydroxyapatite composite material has an inhibition effect on chondrosarcoma, osteosarcoma and ewing sarcoma.
Comparative example 1
0.9mol of 6-aminocaproic acid, 0.01mol of proline, 0.01mol of hydroxyproline, 0.03mol of glycine, 0.03mol of alanine and 0.01mol of leucine are added into water, and the mixture is stirred and gradually heated to 160 ℃ for dehydration under the protection of nitrogen atmosphere, heated to 190 ℃, reacted for 2 hours in a molten state, and then heated to 220 ℃ for reaction for 0.5 hour. After the reaction is finished, the light yellow phosphorus-containing ester polyamino acid copolymer is prepared, and the yield is 95%. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
70 g of polyamino acid copolymer and 30 g of hydroxyapatite are mixed, extruded in an extruder at 190 ℃ and crushed into polyamino acid copolymer/hydroxyapatite composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a large amount of hydroxyapatite was deposited on the surface, showing good bioactivity. Through tests, the polyamino acid copolymer and polyamino acid copolymer/hydroxyapatite composite material have no inhibition effect on chondrosarcoma, osteosarcoma and ewing sarcoma.
Comparative example 2
0.3mol of 6-aminocaproic acid, 0.02mol of tyrosine, 0.03mol of tryptophan, 0.02mol of proline, 0.01mol of hydroxyproline, 0.02mol of phenylalanine and 0.6mol of 4-aminobutyric acid are added into water, stirred and gradually heated to 160 ℃ for dehydration, heated to 190 ℃, reacted in a molten state for 2.5 hours, and then heated to 260 ℃ for reaction for 1 hour. After the reaction, a pale yellow polyamino acid copolymer was obtained in 93% yield. Pulverizing into particles with the particle size of 0.3-5 mm for later use.
40 g of the amino acid copolymer and 50 g of calcium sulfate and 10g of calcium hydrophosphate are mixed, extruded at 230 ℃ in an extruder and crushed into an amino acid copolymer/calcium sulfate/calcium hydrophosphate composite material with the particle size of 0.3-5 mm. Soaking in absolute ethanol for 10 min, ultrasonic cleaning for 5 min, drying in vacuum oven at 40deg.C for 12 hr, and sterilizing with ethylene oxide.
The composite particles were immersed in simulated body fluid (SBF, ph=7.40) and after 7 days, a large amount of apatite was deposited on the surface, showing good bioactivity. The degradation rate of the composite material in PBS solution is 43.6 percent in one month. Through tests, the amino acid copolymer and the calcium sulfate/calcium hydrophosphate composite material have no inhibition effect on Ewing sarcoma.
Claims (9)
1. A preparation method of a bisphosphonate-containing polyamino acid copolymer, which is characterized by comprising the following steps: under the protection of inert gas, adding 6-aminocaproic acid, other amino acids, antitumor micromolecules, biphosphoric acid or salts thereof into water, gradually heating to 160-190 ℃ under stirring to dehydrate, heating to 190-260 ℃ and reacting for 2.5-5 h in a molten state to prepare the polyamino acid copolymer;
wherein the biphosphoric acid or salt thereof is selected from:
the anti-tumor small molecule is selected from the group consisting of:
/>
any one of them.
2. The method for producing a bisphosphonate polyamino acid copolymer according to claim 1, characterized in that the other amino acid is at least one of glycine, alanine, leucine, isoleucine, valine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, hydroxyproline, lysine, arginine or 4-aminobutyric acid.
3. The method for producing a bisphosphonate polyamino acid containing copolymer according to claim 1, characterized in that the particle size of the bisphosphonate polyamino acid containing copolymer is 0.3mm to 5mm.
4. A bisphosphonic acid-containing polyamino acid copolymer prepared by the preparation method according to any one of claims 1 to 3.
5. The bisphosphonate polyamino acid containing copolymer according to claim 4, wherein the bisphosphonate polyamino acid containing copolymer has anti-bone tumor properties, and the bone tumor is osteosarcoma, chondrosarcoma or ewing sarcoma.
6. The composite material with the bone tumor resistance is characterized in that the composite material is prepared by melt blending the bisphosphonate-containing polyamino acid copolymer according to claim 4 or 5 and a calcium salt compound, and the mass of the calcium salt compound is 30-70% of the total mass of the composite material.
7. The composite material with anti-bone tumor performance according to claim 6, wherein the calcium salt compound is: at least one of hydroxyapatite, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, calcium lactate, calcium citrate, calcium glycerophosphate, calcium gluconate, or calcium ascorbate.
8. The method for preparing the composite material with the anti-bone tumor performance according to claim 6 or 7, wherein the preparation method is as follows: uniformly mixing the bisphosphonate-containing polyamino acid copolymer with a calcium salt compound, and then carrying out melt blending to obtain the bisphosphonate-containing polyamino acid copolymer/calcium salt composite material with bone tumor resistance.
9. The method for preparing a composite material with anti-bone tumor property according to claim 8, wherein the temperature of the melt blending is 190-230 ℃.
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