CN116370404A - Injectable composite hydrogel for osteosarcoma diagnosis and treatment and preparation method thereof - Google Patents
Injectable composite hydrogel for osteosarcoma diagnosis and treatment and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an injectable composite hydrogel for osteosarcoma diagnosis and treatment integration and a preparation method thereof. The hydrogel is a double-network hydrogel of ion covalent double-crosslinked sodium alginate/polyacrylamide/carboxymethyl chitosan/liposome nano particles/magnesium particles, has excellent mechanical and injectable properties, can release nano medicines at body temperature after being implanted into a bone defect part by injection, can be used as a contrast agent to position a focus, and then generates hydroxyl free radicals by Fenton reaction so as to eliminate tumor cells; then, by in vitro ultrasonic heating, the magnesium particles react with water to generate hydrogen and magnesium ions, so that the anti-inflammatory and anti-tumor effects are realized, and finally, the differentiation of mesenchymal stem cells can be regulated to promote bone repair. Therefore, the invention realizes the integration of staged bone tumor diagnosis, treatment and repair and simultaneously expands the application of the hydrogel in the tumor treatment field.
Description
Technical Field
The invention belongs to the technical field of materials, and particularly relates to an injectable composite hydrogel for osteosarcoma diagnosis and treatment integration and a preparation method thereof.
Background
Osteosarcoma is the most common primary bone malignancy, and occurs clinically in the distal femur and proximal tibia, and the current treatment strategy of osteosarcoma mainly comprises the steps of surgical excision of the primary tumor and auxiliary radiotherapy and chemotherapy, and the further application of the primary tumor is limited by the serious side effects of cancer metastasis and chemotherapy drugs caused by surgical intervention. Notably, surgical resection of osteosarcoma often results in large bone defects and sacrifice of articular cartilage, in addition to the unavoidable problem of tumor recurrence and metastasis, which is difficult to self-heal after surgery. In the operation, the injectable filling material can better adapt to irregular defects, simplify operation, save time and improve the success rate of the operation. Furthermore, it is also important to monitor recurrence of osteosarcoma over time. In this case, achieving a diagnosis of tumor recurrence while reconstructing the bone defect and eliminating residual tumor cells is extremely necessary to achieve an effective treatment of osteosarcoma. Based on the above, in order to solve the problem of pathological changes from the source, the development of a biomedical material with the integration of injectability, diagnosis, treatment and repair becomes an effective strategy for clinical bone tumor treatment.
The tumor microenvironment is a special microenvironment of tumor tissues, and has the characteristics of subacidity, hypoxia and hydrogen peroxide overexpression and the like. The Fenton reaction is the conversion of hydrogen peroxide into hydroxyl radicals under acidic conditions by the catalysis of ferrous ions. In recent years, fenton's reaction has been widely explored in the field of cancer treatment. Compared with the traditional treatment mode, the Fenton reaction participates in the mechanism of tumor treatment and is tightly combined with the tumor microenvironment, so that the traditional treatment modes such as high selectivity, endogenous activation and the like have incomparable advantages. The 3D printing MnPSe-3 nano-sheet composite scaffold disclosed in patent CN 114939187A uses Fenton effect to generate hydroxyl free radicals, so that the purpose of treating tumors is achieved. Doxorubicin (DOX) and ferroferric oxide (Fe) as described in patent CN 111450267a 3 O 4 ) Nanoparticle co-supported microspheres synergistically treat tumors by DOX and fenton effect. Furthermore, fe 3 O 4 And the effect of nuclear magnetic imaging is achieved, and the focus can be found out rapidly. However, bone reconstruction after the elimination of the residual tumor is also important, bone tissue is difficult to reconstruct, and the Fenton effect can cause secondary damage to normal tissues.
The generation of hydrogen from magnesium as a reactant for the treatment of tumors is expected to solve the above-mentioned problems as an emerging therapeutic modality. Magnesium can react with water at a higher temperature (45 ℃) to generate hydrogen and magnesium ions, and the hydrogen can eliminate inflammation in tissues and has the effect of inhibiting tumors; and the magnesium ions can stimulate cell passages, promote stem cell bone differentiation and achieve the effect of bone regeneration. If the mechanisms can be combined, the diagnosis, treatment and repair of the bone tumor can be realized, which has great significance for completing the treatment of the bone tumor and has great application prospect in the field of the treatment and repair of the bone tumor.
Disclosure of Invention
Based on the above, the invention provides an injectable composite hydrogel for osteosarcoma diagnosis and treatment integration and a preparation method thereof. The composite hydrogel has excellent mechanical, anti-inflammatory, imaging and osteogenic performances, can realize early tumor positioning, treatment and later bone repair, and expands the application of the hydrogel in the tumor treatment field.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an injectable composite hydrogel for osteosarcoma diagnosis and treatment integration, which is specifically sodium alginate/polyacrylamide/carboxymethyl chitosan/liposome/magnesium particle double-network hydrogel with ion covalent double-crosslinking, wherein the liposome can generate Fenton effect and exert anti-tumor effect; the magnesium particles can generate hydrogen through chemical reaction, so that the effects of anti-inflammation and bone repair are exerted.
The preparation method of the injectable composite hydrogel comprises the following steps:
(1) Dipalmitoyl phosphatidylcholine (DPPC) and ferroferric oxide (Fe) 3 O 4 ) Mixing diphenyl azide phosphate (DPPA), 1, 2-bis (diphenyl phosphine) ethane (DPPE) and PEGylated phosphatidylethanolamine (DSPE-PEG-2000) in proportion, and adding chloroform (CHCl) 3 ) Performing ultrasonic treatment for 1-30 min after dissolution to obtain a solution S1;
(2) Removing the organic solution from the solution S1 by rotary evaporation, and adding deionized water to disperse to obtain a solution S2;
(3) Adding doxorubicin hydrochloride (DOX), propylene glycol block polyether (F-68) and Perfluorohexane (PFH) into the solution S2, and uniformly mixing to obtain a solution S3;
(4) Ultrasonic treatment is carried out on the solution S3 for 5-30 min by using a cell disruption instrument to obtain a solution S4;
(5) Adding distilled water into sodium alginate (Alg), acrylamide (AAm), carboxymethyl chitosan (CMC) and Hydroxyapatite (HA), and stirring uniformly to obtain a solution S5;
(6) Sequentially adding to the solution S5N,N'-Methylene Bisacrylamide (MBAA) and tetramethyl ethylenediamine (TEMED), stirring uniformly to obtain a solution S6;
(7) Ammonium Persulfate (APS), solution S4 and magnesium powder (Mg) are sequentially added into the solution S6 while stirring, and the mixture is stirred uniformly to obtain a prepolymerization solution S7;
(8) And polymerizing the prepolymerization solution S7 at room temperature to obtain the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration.
Further, DPPC, fe used in step (1) 3 O 4 The mass ratio of DPPA, DPPE, DSPE-PEG-2000 is (5-15): (3-8): (2-10): (2-10): (2-10), and the added CHCl 3 The amount of (2) is 0.1-0.2 mL/mg.
Further, the deionized water in the step (2) is added in an amount of 0.01-0.1. 0.1 mL per mg of the evaporated product.
Further, in the solution S3 in the step (3), the concentration of DOX is 0.002-0.080 g/mL, the concentration of F-68 is 0.002-0.070 mg/mL, and the concentration of PFH is 0.002-0.070 mg/mL.
Further, in the solution S5 in the step (5), the concentration of Alg is 0.015-0.050 g/mL, the concentration of AAm is 0.030-0.500 g/mL, the concentration of CMC is 0.025-0.090 g/mL, and the concentration of HA is 0.015-0.200 g/mL; the stirring time is 3-24 h.
Further, in the solution S6 of the step (6),MBAAthe concentration of (C) is 0.05-0.20 mg/mL, and the concentration of TEMED is 0.10-0.60 mg/mL.
Further, in the step (7), the addition amount of ammonium persulfate in the solution S6 is 1.50-2.00 mg/mL, and the addition amount of the solution S4 is 10-100 mu L/mL; the adding amount of the magnesium powder is 1-10 mg/mL; the stirring time is 1-12 h.
Further, the polymerization time in the step (8) is 1-10 min.
The prepared injectable composite hydrogel has excellent mechanical, anti-inflammatory, imaging and osteogenic properties and also has excellent anti-tumor properties, so that the injectable composite hydrogel can be used for diagnosis and treatment integration of osteosarcoma, and specifically:
(1) The ferroferric oxide nano particles contained in the composite hydrogel synthesized by the invention can be used as a contrast agent to strengthen nuclear magnetic imaging signals, thereby being used for positioning focus;
(2) The invention uses hydrogel as a carrier to load liposome containing DOX and ferroferric oxide, so that the synthesized composite hydrogel has excellent tumor elimination effect at body temperature, and can be used as a medicament for eliminating tumor cells;
(3) The composite hydrogel synthesized by the invention has excellent mechanical properties, can be used as a filler to be filled in a bone defect part, and provides mechanical support;
(4) The composite hydrogel synthesized by the invention has good anti-inflammatory effect and osteogenesis effect at 45 ℃, and can promote bone regeneration in the later period of repair.
The perfluorohexane in the liposome of the composite hydrogel system can generate phase change under the action of ultrasound, so that the encapsulated medicine can be accurately and controllably released, and the introduced doxorubicin and ferroferric oxide can generate Fenton effect at body temperature to generate hydroxyl free radicals so as to efficiently remove tumors; meanwhile, at a higher temperature (45 ℃), magnesium particles in the system can react with water to generate hydrogen and magnesium ions, so that the anti-inflammatory and bone repair capability is realized, and the outward migration of tumors can be prevented, and tumor recurrence can be prevented. Therefore, the composite hydrogel can realize the anti-inflammatory and efficient bone repair effects while realizing the elimination of tumor cells, realizes the integration of diagnosis, treatment and repair of bone tumors, and has wide application prospects in the field of bone tumor treatment.
Compared with the prior art, the invention has the following excellent effects:
(1) The composite hydrogel synthesized by the invention overcomes the existing defects of clinic, organically combines three functions of diagnosis, treatment and repair in one system, reduces the risk of secondary operation, has the injectable property, and improves the operation convenience and the treatment efficiency;
(2) The composite hydrogel synthesized by the invention can regulate and control the concentration of hydroxyl radicals in the system by regulating and controlling the temperature, thereby playing the role of treating inflammation in tissues, being an artificial controllable and intelligent integrated material and being applicable to different repairing environments;
(3) The composite hydrogel synthesized by the invention has excellent mechanical property and fatigue resistance, and can adapt to different defect conditions.
Drawings
FIG. 1 is a schematic diagram of the preparation flow chart (A) and the action mechanism (B) of the composite hydrogel.
Fig. 2 shows a projection electron microscope (a), a projection electron microscope (B) before and after ultrasound, an infrared spectrogram (C), an optical microscope (D) before and after ultrasound, zeta potential (E), a particle size distribution diagram (F, G) before and after ultrasound, a hysteresis curve (H), a relaxation curve (I) and an XPS (J) of the liposome prepared in example 1.
Fig. 3 is a scanning electron microscope (a), an average pore diameter and pore diameter analysis (B), an elemental analysis (C), an elemental scanning (D), an infrared spectrogram (E), a contact angle analysis (F) and a swelling ratio analysis (G) of the composite hydrogel prepared in example 1.
Fig. 4 is a cross-linking mechanism and adhesion mechanism diagram (a), adhesion physical diagram (B), adhesion quantitative test diagram (C), compression quantitative test diagram (D), tensile quantitative test diagram (E), compression displacement-stress diagram (F), tension displacement-stress diagram (G), compression 1000-time reciprocating displacement-stress diagram (H), tension 1000-time reciprocating displacement-stress diagram (I), compression, tension schematic diagram (J), dissipation energy quantitative diagram (K, L) in the reciprocating 1000 times, and amplitude test diagram (M) of the composite hydrogel prepared in example 1.
FIG. 5 is a graph of gel formation time and temperature change at different concentrations of APS (A, B), gel formation time at different temperatures (C), injectability evidence graph (D), gel formation rheological property analysis at different temperatures (E-G), self-healing property analysis graph (I-J), shape adaptability graph (K) and self-healing mechanism analysis graph (L) of the composite hydrogel prepared in example 1.
FIG. 6 is a graph (A, D) showing the mechanism of the composite hydrogel prepared in example 1 in influencing hydroxyl radical formation, a graph (B-H) showing the effect of liposomes, magnesium particles and both on hydroxyl radical levels at different temperatures, a graph (K) showing the biocompatibility characterization, and a graph (L) showing the dead-alive staining and macrophage differentiation.
Detailed Description
The technical scheme of the invention is specifically described below with reference to fig. 1.
The invention discloses an injectable composite hydrogel for osteosarcoma diagnosis and treatment integration, and a preparation method thereof comprises the following steps:
(1) DPPC, fe 3 O 4 Mixing DPPA, DPPE, DSPE-PEG-2000 with CHCl in the weight ratio of 5-15 to 3-8 to 2-10 and adding CHCl in the amount of 0.1-0.2 mL/mg 3 After dissolution, carrying out ultrasonic treatment for 1-30 min to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding deionized water into the obtained residue according to the amount of 0.01-0.1 mL/mg for dispersion to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 is obtained after uniform mixing; wherein, the concentration of DOX is 0.002-0.080 g/mL, the concentration of F-68 is 0.002-0.070 mg/mL, and the concentration of PFH is 0.002-0.070 mg/mL;
(4) Ultrasonic treatment is carried out on the solution S3 for 5-30 min by using a cell disruption instrument to obtain a solution S4;
(5) Adding Alg, AAm, CMC and HA into distilled water, stirring for 3-24 h to make them uniform to obtain solution S5; wherein, the concentration of Alg is 0.015-0.050 g/mL, the concentration of AAm is 0.030-0.500 g/mL, the concentration of CMC is 0.025-0.090 g/mL, and the concentration of HA is 0.015-0.200 g/mL;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6; wherein, the liquid crystal display device comprises a liquid crystal display device,MBAAthe concentration of TEMED is 0.05-0.20 mg/mL, and the concentration of TEMED is 0.10-0.60 mg/mL;
(7) Adding APS, solution S4 and magnesium powder into solution S6 in the amounts of 1.50-2.00 mg/mL, 10-100 mu L/mL and 1-10 mg/mL in sequence while stirring, and stirring 1-12 h to be uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 1-10 min to obtain the injectable composite hydrogel Alg/PAAm/CMC/Lip/Mg.
According to the invention, the proportion of Alg, AAm, HA, the liposome nano particles and the magnesium powder is optimized, so that the composite hydrogel has high mechanical properties, and simultaneously has the nuclear magnetic imaging capability and the capability of controlling the repair state of a system at different temperatures, and can play the roles of resisting inflammation and promoting bone repair, thereby realizing the staged rehabilitation of tissue diagnosis, cancer cell treatment and bone repair. Overall, the composite hydrogel synthesized by the invention not only has the Fe wrapping function 3 O 4 The nanoparticle and DOX liposome can treat tumor at body temperature (37deg.C), and mechanical, antiinflammatory and osteogenic properties at higher temperature (45deg.C) can realize focus search at early stage of treatment process, tumor elimination and late stage antiinflammatory and bone regeneration.
In order to further understand the present invention, the following examples are provided to illustrate an injectable diagnosis and treatment integrated composite hydrogel for osteosarcoma treatment and a preparation method thereof, and the scope of the present invention is not limited by the following examples.
Example 1
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 10:4:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.003 g/mL DOX, 0.003 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12 hours to be uniform, and a solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA is obtained;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.12 mg/mL MBAA and 0.40 mg/mL TEMED;
(7) Adding 1.60 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder into the solution S6 in sequence while stirring, and stirring for 2 hours to make the solution uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
FIG. 2 is a characterization map of the liposome prepared in example 1. From various characterization contents, the liposome which has uniform particle size, good dispersibility and nuclear magnetic imaging and paramagnetic properties is successfully prepared.
FIG. 3 is a basic characterization map of the composite hydrogel prepared in example 1. From various characterizations, it can be obtained that the double-network composite hydrogel is successfully prepared, and the composite hydrogel has higher porosity and hydrophilicity, which is beneficial to cell adhesion and proliferation.
FIG. 4 is a graph showing the mechanical properties of the composite hydrogel prepared in example 1. From various characterizations, the prepared composite hydrogel has better mechanical property and fatigue resistance, and can be used as bone defect filler.
FIG. 5 is a graph showing the functional properties of the composite hydrogel prepared in example 1. From various characterizations, it can be derived that the prepared composite hydrogel has the properties of injectability, self-healing, shape adaptation and the like, and can be used as an injectable bone defect filler.
FIG. 6 is a graph showing the chemical properties of the composite hydrogel prepared in example 1. The prepared composite hydrogel has the functions of increasing the hydroxyl radical level at the body temperature and reducing the hydroxyl radical level at the temperature of 45 ℃ and has better biocompatibility, and can be used as an injectable filling material for treating tumors, resisting inflammation and promoting repair.
Example 2
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 8:4:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.003 g/mL DOX, 0.003 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12h to be uniform, thus obtaining solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.12 mg/mL MBAA and 0.40 mg/mL TEMED;
(7) Adding 1.60 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder into the solution S6 in sequence while stirring, and stirring 2h to be uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
Example 3
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 8:4:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.005 g/mL DOX, 0.003 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12h to be uniform, thus obtaining solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.12 mg/mL MBAA and 0.40 mg/mL TEMED;
(7) Adding 1.60 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder into the solution S6 in sequence while stirring, and stirring 2h to be uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
Example 4
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 8:4:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.005 g/mL DOX, 0.004 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12h to be uniform, thus obtaining solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.12 mg/mL MBAA and 0.40 mg/mL TEMED;
(7) Adding 1.60 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder into the solution S6 in sequence while stirring, and stirring 2h to be uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
Example 5
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 8:4:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.005 g/mL DOX, 0.004 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12h to be uniform, thus obtaining solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.15 mg/mL MBAA and 0.40 mg/mL TEMED;
(7) Adding 1.60 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder into the solution S6 in sequence while stirring, and stirring 2h to be uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
Example 6
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 8:4:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.005 g/mL DOX, 0.004 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12h to be uniform, thus obtaining solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.15 mg/mL MBAA and 0.50 mg/mL TEMED;
(7) Adding 1.60 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder into the solution S6 in sequence while stirring, and stirring 2h to be uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
Example 7
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 8:4:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.005 g/mL DOX, 0.004 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12h to be uniform, thus obtaining solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.15 mg/mL MBAA and 0.50 mg/mL TEMED;
(7) Adding 1.60 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder into the solution S6 in sequence while stirring, and stirring 2h to be uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
Comparative example 1
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 10:10:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.003 g/mL DOX, 0.003 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12h to be uniform, thus obtaining solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.12 mg/mL MBAA and 0.40 mg/mL TEMED;
(7) Adding 1.60 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder into the solution S6 in sequence while stirring, and stirring 2h to be uniform to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
Comparative example 2
(1) DPPC, fe 3 O 4 DPPA, DPPE, DSPE-PEG-2000 is mixed according to the mass ratio of 8:4:3:3:3, and CHCl is added according to the amount of 0.1 mL/mg 3 Performing ultrasonic treatment for 20 min after dissolution to obtain a solution S1;
(2) Spin-evaporating the solution S1 to remove the organic solution, adding ion water into the obtained product according to the ratio of 0.02 mL/mg to disperse to obtain a solution S2;
(3) DOX, F-68 and PFH are added into the solution S2, and the solution S3 containing 0.003 g/mL DOX, 0.003 mg/mL F-68 and 0.004 mg/mL PFH is obtained after uniform mixing;
(4) Performing ultrasonic treatment on the solution S3 by using a cell disruption instrument for 20 min to obtain a solution S4;
(5) Alg, AAm, CMC and HA are added into distilled water and stirred for 12h to be uniform, thus obtaining solution S5 containing 0.0317 g/mL Alg, 0.333g/mL AAm, 0.00583 g/mL CMC and 0.0867 g/mL HA;
(6) Sequentially adding MBAA and TEMED into the solution S5, and uniformly stirring to obtain a solution S6 containing 0.12 mg/mL MBAA and 0.40 mg/mL TEMED;
(7) 3.0 mg/mL APS, 50 mu L/mL solution S4 and 2.5 mg/mL magnesium powder are sequentially added into the solution S6 while stirring, and 2h is stirred to be uniform, so as to obtain a prepolymerization solution S7;
(8) Polymerizing the prepolymerization solution S7 at room temperature for 3 min to obtain the injectable composite hydrogel for the diagnosis and treatment of osteosarcoma.
The composite hydrogels prepared in example 2 and comparative example 1 were tested for hydroxyl radical generating properties. The results show that when the concentration of other components is unchanged, the group with high ferroferric oxide concentration has stronger hydroxyl radical generating capability and better tumor removing effect. However, too high hydroxyl radicals can cause tissue inflammation to be too strong, and simultaneously, the generated hydroxyl radicals cannot be counteracted by the subsequently generated hydrogen, so that inflammation cannot be better eliminated, and bone repair is promoted.
The composite hydrogels prepared in example 2 and comparative example 2 were tested for gel formation. The result shows that when the concentration of other components is unchanged, increasing the concentration of APS accelerates the crosslinking degree of the system and enhances the mechanical property. But can result in excessive gelling temperatures and lower porosities that are detrimental to tissue growth.
The foregoing description is only of the preferred embodiments of the invention, and all changes and modifications that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (10)
1. The injectable composite hydrogel for osteosarcoma diagnosis and treatment integration is characterized in that the composite hydrogel is specifically an ionic covalent double-crosslinked sodium alginate/polyacrylamide/carboxymethyl chitosan/liposome/magnesium particle double-network hydrogel, wherein the liposome can generate Fenton effect and exert anti-tumor effect; the magnesium particles can generate hydrogen through chemical reaction, so that the effects of anti-inflammation and bone repair are exerted.
2. A method for preparing the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 1, comprising the steps of:
(1) Mixing dipalmitoyl phosphatidylcholine, ferroferric oxide, diphenyl azide phosphate, 1, 2-bis (diphenyl phosphine) ethane and pezited phosphatidylethanolamine in proportion, dissolving with chloroform, and performing ultrasonic treatment for 1-30 min to obtain a solution S1;
(2) Removing the organic solution from the solution S1 by rotary evaporation, and adding deionized water to disperse to obtain a solution S2;
(3) Adding doxorubicin hydrochloride, propylene glycol block polyether and perfluorohexane into the solution S2, and uniformly mixing to obtain a solution S3;
(4) Ultrasonic treatment is carried out on the solution S3 for 5-30 min by using a cell disruption instrument to obtain a solution S4;
(5) Adding sodium alginate, acrylamide, carboxymethyl chitosan and hydroxyapatite into distilled water, and uniformly stirring to obtain a solution S5;
(6) Sequentially adding to the solution S5N,N'-methylene bisacrylamide and tetramethyl ethylenediamine, and uniformly stirring to obtain a solution S6;
(7) Ammonium persulfate, a solution S4 and magnesium powder are sequentially added into the solution S6 while stirring, and the mixture is uniformly stirred to obtain a prepolymerized solution S7;
(8) And polymerizing the prepolymerization solution S7 at room temperature to obtain the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration.
3. The method for preparing the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 2, wherein the mass ratio of dipalmitoyl phosphatidylcholine, ferroferric oxide, diphenyl azide phosphate, 1, 2-bis (diphenylphosphine) ethane and cultivated phosphatidylethanolamine used in the step (1) is (5-15): (3-8): (2-10): (2-10): (2-10), and the amount of chloroform added is 0.1-0.2 mL/mg.
4. The method for preparing the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 2, wherein the deionized water in the step (2) is added in an amount of 0.01-0.1-mL per mg of the evaporated product.
5. The method for preparing the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 2, wherein in the solution S3 in the step (3), the concentration of doxorubicin hydrochloride is 0.002-0.080 g/mL, the concentration of propylene glycol block polyether is 0.002-0.070 mg/mL, and the concentration of perfluorohexane is 0.002-0.070 mg/mL.
6. The method for preparing the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 2, wherein in the solution S5 in the step (5), the concentration of sodium alginate is 0.015-0.050 g/mL, the concentration of acrylamide is 0.030-0.500 g/mL, the concentration of carboxymethyl chitosan is 0.025-0.090 g/mL, and the concentration of hydroxyapatite is 0.015-0.200 g/mL; the stirring time is 3-24 h.
7. The method for preparing an injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 2, wherein in the solution S6 of step (6),N,N'the concentration of methylene bisacrylamide is 0.05-0.20 mg/mL, and the concentration of tetramethyl ethylenediamine is 0.10-0.60 mg/mL.
8. The method for preparing an injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 2, wherein in the step (7), the addition amount of ammonium persulfate in the solution S6 is 1.50-2.00 mg/mL and the addition amount of the solution S4 is 10-100 μl/mL; the adding amount of the magnesium powder is 1-10 mg/mL; the stirring time is 1-12 h.
9. The method for preparing the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 2, wherein the polymerization time in the step (8) is 1-10 min.
10. The use of the injectable composite hydrogel for osteosarcoma diagnosis and treatment integration according to claim 1, wherein the composite hydrogel can be used as a contrast agent and can simultaneously exert anti-tumor and anti-inflammatory effects of implantation sites and promote bone repair.
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| CN117138058A (en) * | 2023-10-31 | 2023-12-01 | 吉林农业科技学院 | Liposome and hydrogel for repairing bone defect, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117138058A (en) * | 2023-10-31 | 2023-12-01 | 吉林农业科技学院 | Liposome and hydrogel for repairing bone defect, and preparation method and application thereof |
| CN117138058B (en) * | 2023-10-31 | 2024-02-06 | 吉林农业科技学院 | Liposome and hydrogel for repairing bone defect, and preparation method and application thereof |
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