CN108283728B - PH-sensitive self-regulated drug release tumor embolization microsphere and preparation method thereof - Google Patents

PH-sensitive self-regulated drug release tumor embolization microsphere and preparation method thereof Download PDF

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CN108283728B
CN108283728B CN201810109478.6A CN201810109478A CN108283728B CN 108283728 B CN108283728 B CN 108283728B CN 201810109478 A CN201810109478 A CN 201810109478A CN 108283728 B CN108283728 B CN 108283728B
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drug release
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陶秀梅
冷鸿飞
陈鹏
徐小雨
刘培岩
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Beijing Nuokangda Pharmaceutical Technology Co ltd
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Abstract

The invention provides a pH-sensitive self-regulating drug-release tumor embolization microsphere and a preparation method thereof. The preparation method comprises the steps of preparing a prepolymer from a pH sensitive compound, mixing the prepolymer with a tumor microenvironment regulator, sodium alginate and a medicament, adding the mixture into liquid paraffin, and fully stirring to prepare the interpenetrating network polymer microspheres. The tumor embolization microsphere provided by the invention can realize pH-sensitive self-regulated drug release, and adjust the acidic environment around cancer tissue cells so as to inhibit the reproduction and metastasis of cancer cells, is beneficial to tumor treatment, and has wide application prospect in anti-tumor embolization chemotherapy.

Description

PH-sensitive self-regulated drug release tumor embolization microsphere and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, relates to a tumor embolization microsphere and a preparation method thereof, and particularly relates to a pH-sensitive self-regulating drug release tumor embolization microsphere and a preparation method thereof.
Background
According to the latest live report of the world health organization, the tumor is the second leading cause of death in the world, and 1000 ten thousand cancer patients are newly added every year at present, which seriously threatens the human health. Modern medicine usually treats tumor patients by means of tumor eradication surgery, chemotherapy, radiotherapy and the like, but the traditional treatment means has limited effect and obvious toxic and side effects.
The arterial embolization developed in recent years is an important interventional therapy technology, and is currently applied to preoperative embolization and palliative treatment of various solid tumors, organ bleeding, vascular malformation, internal organ resection and the like. Compared with traditional chemotherapy, TACE (transcatheter arterial chemoembolization) is safe, effective, obvious in effect and obvious in advantage, and becomes one of the most important technologies for tumor interventional therapy.
The drug-loaded embolism microsphere can block tumor blood supply, so that the tumor is lack of necessary nutrients, the lethality of the drug to the tumor can be enhanced, and the systemic toxicity of the drug can be reduced, such as DC bead, HepaSphere and the like in the market. In addition, in patent CN 105816920A, sodium alginate is modified to introduce sulfonic group as drug-carrying group; patent CN 101536986A discloses a preparation method of sodium alginate microspheres loaded with sorafenib. However, in the preparation technology of the sodium alginate and other polymer system embolism microspheres published at present, the loaded drugs are mostly loaded by negatively charged groups on the microspheres through electrostatic action or physically embedded. The medicine loaded by the embolism microsphere is gradually released at the embolism position along with the degradation or ion replacement of the microsphere, and the release of the medicine is uncontrollable; in addition, in order to increase drug loading, most of these embolizing materials contain acidic groups such as carboxyl groups and sulfonic acid groups, which further lower the pH of the embolized site at the same time as embolization, creating an environment in which cancer cells can easily proliferate, and thus not contributing to the recovery of the human body.
The pH value around normal cells of a human body is 7.35-7.45, the pH value around the normal cells is slightly basic, and the pH value around cancer cells is 6.85-6.95, and the pH value is slightly acidic, if the body fluid of the human body is in an acidic environment for a long time, the cancer is easily obtained, the lower the pH value of the body fluid is, the more suitable the body fluid is for the survival and development of the cancer cells, and the lower the pH value of the body fluid of a tissue organ, the cancer cells are easily transferred to the organ, meanwhile, the cancer cells can release a toxin named L50, which is a strong acid substance and can destroy the acid-base balance of the body fluid and attack immune cells in vivo.
Patent CN 104758945 a discloses a method for preparing pH-responsive thrombolytic drug targeted nanogel, which is prepared by covalently linking thrombolytic drug and oxidized dextran through pH-sensitive imine bond, but the system can only be used as thrombolytic drug carrier for protein or peptide drug delivery, and is limited to plasminogen activator drugs of lysine amino residue. Patent 104208704 a discloses a preparation method of a pH-sensitive carbon nanotube targeted drug delivery system, which transfers drugs to tumor cells by the dual actions of chitosan modification and RGD targeted guidance, and promotes the release of drugs in a low pH tumor cell environment. However, the carbon nanotubes cannot be degraded and remain in the body, which increases the burden on the patient.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention introduces the pH sensitive material to realize the pH sensitive self-regulating release of the embolism microsphere, intelligently releases the drug aiming at the tumor cell area and avoids or reduces the damage to the normal tissue; meanwhile, the addition of the tumor microenvironment regulator is beneficial to neutralizing strong acid substances around the cancer tissues and released by the cancer tissues and regulating the acid environment around the cancer tissue cells so as to inhibit the reproduction and metastasis of the cancer cells, and has bright application prospect in the field of tumor treatment by an interventional method.
The invention provides a pH-sensitive self-regulating drug-release tumor embolization microsphere, which comprises a pH-sensitive compound and a tumor microenvironment regulator.
Further, the tumor embolization microsphere comprises 30-50 parts by weight of pH sensitive compound and 0.5-6 parts by weight of tumor microenvironment regulator.
Still further, the pH sensitive compound is selected from one or both of N, N-dimethylaminoethyl methacrylate or N, N-diethylaminoethyl methacrylate.
The tumor microenvironment regulator is selected from arginine, lysine, histidine, chitosan, β -TCP, NaHCO3One or more of (a).
Furthermore, the tumor embolization microsphere also comprises 35-60 parts by weight of sodium alginate, 50-300 parts by weight of antitumor drug, 8-16 parts by weight of cross-linking agent and 5.501-15.05 parts by weight of other auxiliary agents.
Further, the viscosity of the sodium alginate is 100-600 mpa-s.
The cross-linking agent is selected from one or more of calcium chloride, magnesium chloride and barium chloride, and is preferably calcium chloride.
The anti-tumor drug is selected from: doxorubicin, irinotecan, topotecan, hydroxycamptothecin, epirubicin, cisplatin, carboplatin, platinum oxalate, oxaliplatin, mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, melphalan, thiotepa, carmustine, semustine, busulfan, mitomycin, methotrexate, pemetrexed, 5-FU, FT-207, capecitabine, 6-mercaptopurine, 6-TG, hydroxyurea, cytarabine, gemcitabine, actinomycin D, daunorubicin, epirubicin, aclarubicin, mithramycin, paclitaxel, docetaxel, vinblastine, catharanthine, podophylline, homoharringtonine, asparaginase, tamoxifen, toremifene, exemestane, diphenoxylate, fosetyl-ethyl-piperidone, letrozole, anastrozole, megestrol, methyltestosterone, one or more of testosterone propionate, diethylstilbestrol, flutamide, goserelin and leuprorelin acetate.
Still further, the antitumor drug is selected from one or more of adriamycin, cyclophosphamide and exemestane.
Further, the other auxiliary agents include: 5-10 parts of polymerization degree regulator, 0.5-5 parts of acrylic acid crosslinking agent and 0.001-0.05 part of catalyst.
Still further, the polymerization degree regulator is selected from one or two of hydroxyethyl methacrylate and acrylamide.
The acrylic crosslinking agent is selected from: one or more of N, N '-methylene bisacrylamide, 1, 4-butanediol diacrylate, ethylene glycol dimethacrylate and triallyl cyanurate, preferably N, N' -methylene bisacrylamide.
The catalyst is at least one selected from ammonium persulfate-sodium bisulfite and potassium persulfate-tetramethylethylenediamine, and preferably ammonium sulfate-sodium bisulfite.
Further, the preparation method of the pH-sensitive self-regulated drug release tumor embolization microsphere adopts the following steps:
(1) dissolving sodium alginate in deionized water to obtain a sodium alginate solution;
(2) dissolving a pH sensitive compound, a polymerization degree regulator and an acrylic acid crosslinking agent in water, and initiating by a catalyst to prepare a prepolymer;
(3) dissolving the prepolymer and the tumor microenvironment regulator in deionized water to form a solution, and adding a sodium alginate solution and an anti-tumor drug to mix uniformly;
(4) preparing a W/O system (water-in-oil system) by an emulsification method, adding a sodium alginate cross-linking agent, and freeze-drying to prepare the pH-sensitive self-regulating drug release embolism microsphere.
The invention has the beneficial effects that:
1. the pH sensitive material is introduced during the preparation of the embolism microsphere, so that the amino group of the polymer gel is not dissociated at a high pH value of the microsphere, the gel is relatively compact and does not swell, and the medicine is wrapped in the gel. Along with the reduction of pH, the dissociation of amino groups, the increase of charge density and the swelling of the polymer release the medicine encapsulated in the microsphere, thereby realizing the pH value-sensitive self-regulating medicine release of the embolism microsphere.
2. The invention introduces the tumor microenvironment regulator, can neutralize the surrounding of cancer tissues and strong acid substances released by the cancer tissues, can inhibit the reproduction and the transfer of cancer cells by regulating the acid environment surrounding the cancer tissue cells under the dual actions of embolism and drug treatment, effectively improves the influence of acid groups of an embolism material on the pH value of an embolism position, and is beneficial to the recovery of a patient.
3. The construction of the interpenetrating network system of the acrylate and the sodium alginate improves the strength of the embolization microsphere, increases the elasticity of the microsphere, and avoids the defects of low strength and the like of the microsphere prepared by singly using the sodium alginate.
Drawings
FIG. 1 is liver tumor tissue under optical microscope after treatment of tumor-bearing rabbit 7d with tumor embolization microspheres prepared in example 3
FIG. 2 is liver tumor tissue under optical microscope after 7d treatment of tumor-bearing rabbit with tumor embolization microspheres prepared in comparative example 2
Detailed Description
EXAMPLE 1pH sensitive self-releasing tumor embolizing microspheres
The pH-sensitive self-release tumor embolization microsphere comprises the following components: 30 parts of N, N-dimethylaminoethyl methacrylate, 5 parts of hydroxyethyl methacrylate, 1 part of N, N' -methylene bisacrylamide, 0.05 part of ammonium persulfate-sodium bisulfite, 50 parts of sodium alginate, 1 part of lysine, 60 parts of azithromycin and 12 parts of calcium chloride.
The specific preparation method of the pH-sensitive self-regulated release tumor embolism microsphere comprises the following steps:
(1) preparation of pH sensitive prepolymers
Dissolving 30 parts of N, N-dimethylaminoethyl methacrylate and 5 parts of hydroxyethyl methacrylate in 300ml of deionized water, adding 1 part of N, N' -methylene bisacrylamide as a crosslinking reagent, adding 0.05 part of ammonium persulfate-sodium bisulfite, stirring, dissolving and uniformly mixing, heating in a water bath to 40 ℃, reacting for 5 hours to form viscous-flow prepolymer, dripping the prepolymer solution into methyl tertiary ether solution for precipitation, repeatedly dissolving and re-precipitating, and finally drying in vacuum to obtain the pure polymer.
(2) Preparation of Sodium Alginate (SA) solution
50 parts of sodium alginate having a viscosity of 400 mPa.s are dissolved in 1L deionized water and mechanically stirred until a homogeneous solution is formed.
(3) Preparation of Polymer blend solutions
Dissolving the acrylate prepolymer and 1 part of lysine in deionized water to form a 1.5 wt% solution, mixing the prepolymer solution, the SA solution and 60 parts of adriamycin solution, and stirring for 3 hours to fully and uniformly mix the components.
(4) Preparation of interpenetrating network Polymer microspheres
Adding 1 wt% span-80 serving as an emulsifier into 2000 parts of liquid paraffin, stirring at a high speed of 500r/min for 10min, then adding a blending solution of the acrylate prepolymer and SA into the liquid paraffin, stirring at 50r/min for 1 hour to form a stable W/O system, then slowly dripping a calcium chloride solution (12 parts of calcium chloride dissolved in 35 parts of water) into the W/O system, stirring for crosslinking reaction for 2h to prepare microspheres, centrifugally separating at 1000r/min, washing for several times, and freeze-drying to prepare the pH-sensitive self-release embolic microspheres.
EXAMPLE 2 pH sensitive self-releasing tumor embolizing microspheres
The pH-sensitive self-release tumor embolization microsphere comprises the following components: 50 parts of N, N-dimethylaminoethyl methacrylate, 7 parts of hydroxyethyl methacrylate, 0.5 part of N, N' -methylene bisacrylamide, 0.001 part of ammonium persulfate-sodium bisulfite, 60 parts of sodium alginate, 6 parts of chitosan, 200 parts of carmustine and 16 parts of calcium chloride.
The specific preparation method of the pH-sensitive self-regulated release tumor embolism microsphere comprises the following steps:
(1) preparation of pH sensitive prepolymers
Dissolving 50 parts of N, N-dimethylaminoethyl methacrylate and 7 parts of hydroxyethyl methacrylate in 350ml of deionized water, adding 0.5 part of N, N' -methylene bisacrylamide as a crosslinking reagent, adding 0.001 part of ammonium persulfate-sodium bisulfite, stirring, dissolving and uniformly mixing, heating in a water bath to 40 ℃, reacting for 4 hours to form viscous-flow prepolymer, dripping the prepolymer solution into methyl tert-ether solution for precipitation, repeatedly dissolving and re-precipitating, and finally drying in vacuum to obtain the pure polymer.
(2) Preparation of Sodium Alginate (SA) solution
60 parts of sodium alginate having a viscosity of 200 mPa.s are dissolved in 1L deionized water and mechanically stirred until a homogeneous solution is formed.
(3) Preparation of Polymer blend solutions
Dissolving the acrylate prepolymer and 6 parts of chitosan in deionized water to form a 3 wt% solution, mixing the prepolymer solution, the SA solution and 200 parts of carmustine, and stirring for 3 hours to fully and uniformly mix the components.
(4) Preparation of interpenetrating network Polymer microspheres
Adding 2 wt% span-80 serving as an emulsifier into 3000 parts of liquid paraffin, stirring at a high speed of 2000r/min for 10min, then adding a blending solution of the acrylate prepolymer and SA into the liquid paraffin, stirring at 100r/min for 2 hours to form a stable W/O system, then slowly dripping a calcium chloride solution (16 parts of calcium chloride are dissolved in 50 parts of water) into the W/O system, stirring for crosslinking reaction for 0.5h to prepare microspheres, washing for a plurality of times after centrifugal separation at 2000r/min, and freeze-drying to prepare the pH-sensitive self-release embolic microspheres.
EXAMPLE 3 pH sensitive self-releasing tumor embolizing microspheres
The pH-sensitive self-release tumor embolization microsphere comprises the following components: 45 parts of N, N-dimethylaminoethyl methacrylate, 10 parts of hydroxyethyl methacrylate, 5 parts of N, N' -methylene bisacrylamide, 0.008 part of ammonium persulfate-sodium bisulfite, 35 parts of sodium alginate and NaHCO30.5 part, 50 parts of cyclophosphamide and 8 parts of calcium chloride.
The specific preparation method of the pH-sensitive self-regulated release tumor embolism microsphere comprises the following steps:
(1) preparation of pH sensitive prepolymer:
dissolving 45 parts of N, N-dimethylaminoethyl methacrylate and 10 parts of hydroxyethyl methacrylate in 500ml of deionized water, adding 5 parts of N, N' -methylene bisacrylamide as a crosslinking reagent, adding 0.008 part of ammonium persulfate-sodium bisulfite, stirring, dissolving and uniformly mixing, heating in a water bath to 40 ℃, reacting for 5 hours to form viscous-flow prepolymer, dropping the prepolymer solution into methyl tert-ether solution for precipitation, repeatedly dissolving and re-precipitating, and finally drying in vacuum to obtain the pure polymer.
(2) Preparation of sodium alginate solution
35 parts of sodium alginate having a viscosity of 600 mPa.s are dissolved in 700ml of deionized water and mechanically stirred until a homogeneous solution is formed.
(3) Preparation of Polymer blend solutions
The acrylate prepolymer and 0.5 part NaHCO were mixed3Dissolving the mixture in deionized water to form a 3 wt% solution, mixing the prepolymer solution, the SA solution and 50 parts of cyclophosphamide, and stirring for 5 hours to fully and uniformly mix the components.
(4) Preparation of interpenetrating network Polymer microspheres
Adding 1 wt% span-80 serving as an emulsifier into 3600 parts of liquid paraffin, stirring at a high speed of 1000r/min for 10min, then adding a blending solution of an acrylate prepolymer and SA into the liquid paraffin, stirring at 300r/min for 2 hours to form a stable W/O system, then slowly dripping a calcium chloride solution (8 parts of calcium chloride is dissolved in 25 parts of water) into the W/O system, stirring for crosslinking reaction for 1h to prepare microspheres, centrifuging at 1000r/min, washing for a plurality of times, and freeze-drying to prepare the pH-sensitive self-release embolic microspheres.
EXAMPLE 4 pH sensitive self-regulating Release of tumor embolic microspheres
The pH-sensitive self-release tumor embolization microsphere comprises 40 parts of N, N-diethylaminoethyl methacrylate, 8 parts of acrylamide, 2 parts of 1, 4-butanediol diacrylate, 0.01 part of ammonium persulfate-sodium bisulfite, 50 parts of sodium alginate, β -TCP3 parts, 300 parts of exemestane and 13 parts of barium chloride.
The specific preparation method of the pH-sensitive self-regulated release tumor embolism microsphere comprises the following steps:
(1) preparation of pH sensitive prepolymer:
dissolving 40 parts of N, N-diethylaminoethyl methacrylate and 8 parts of acrylamide in 500ml of deionized water, adding 2 parts of 1, 4-butanediol diacrylate as a crosslinking reagent, adding 0.01 part of ammonium persulfate-sodium bisulfite, stirring, dissolving and uniformly mixing, heating in a water bath to 40 ℃, reacting for 5 hours to form viscous-flow prepolymer, dripping the prepolymer solution into the methyl tertiary ether solution for precipitation, repeatedly dissolving and re-precipitating, and finally drying in vacuum to obtain the pure polymer.
(2) Preparation of sodium alginate solution
50 parts of sodium alginate having a viscosity of 100 mPa.s are dissolved in 700ml of deionized water and mechanically stirred until a homogeneous solution is formed.
(3) Preparation of Polymer blend solutions
Dissolving the acrylate prepolymer and 3 parts of β -TCP in deionized water to form a 3 wt% solution, mixing the prepolymer solution, the SA solution and 300 parts of exemestane, and stirring for 5 hours to fully and uniformly mix the components.
(4) Preparation of interpenetrating network Polymer microspheres
Adding 2 wt% span-80 serving as an emulsifier into 4800 parts of liquid paraffin, stirring at a high speed of 1500r/min for 10min, adding a blending solution of an acrylate prepolymer and SA into the liquid paraffin, stirring at 300r/min for 2 hours to form a stable W/O system, slowly dripping a barium chloride solution (13 parts of barium chloride dissolved in 80 parts of water) into the W/O system, stirring for crosslinking reaction for 1 hour to prepare microspheres, centrifuging at 1000r/min, washing for several times, and freeze-drying to prepare the pH-sensitive self-release embolic microspheres.
Comparative example 1
5 parts of hydroxyethyl methacrylate, 1 part of N, N' -methylene bisacrylamide, 0.05 part of ammonium persulfate-sodium bisulfite, 50 parts of sodium alginate, 1 part of lysine, 60 parts of azithromycin and 13 parts of calcium chloride.
The preparation method comprises the following steps:
(1) preparation of pH sensitive prepolymers
Dissolving 5 parts of hydroxyethyl methacrylate in 300ml of deionized water, adding 1 part of N, N' -methylene bisacrylamide as a crosslinking reagent, adding 0.05 part of ammonium persulfate-sodium bisulfite, stirring, dissolving and uniformly mixing, heating in a water bath to 40 ℃, reacting for 5 hours to form viscous-flow prepolymer, dripping the prepolymer solution into methyl tertiary ether solution for precipitation, repeatedly dissolving and re-precipitating, and finally drying in vacuum to obtain the pure polymer.
(2) Preparation of Sodium Alginate (SA) solution
50 parts of sodium alginate having a viscosity of 400 mPa.s are dissolved in 1L deionized water and mechanically stirred until a homogeneous solution is formed.
(3) Preparation of Polymer blend solutions
Dissolving the acrylate prepolymer and 1 part of lysine in deionized water to form a 1.5 wt% solution, mixing the prepolymer solution, the SA solution and 60 parts of adriamycin, and stirring for 3 hours to fully and uniformly mix the components.
(4) Preparation of interpenetrating network Polymer microspheres
Adding 1 wt% span-80 serving as an emulsifier into 2000 parts of liquid paraffin, stirring at a high speed of 500r/min for 10min, then adding a blending solution of the acrylate prepolymer and SA into the liquid paraffin, stirring at 50r/min for 1 hour to form a stable W/O system, then slowly dripping a calcium chloride solution (13 parts of calcium chloride dissolved in 40 parts of water) into the W/O system, stirring for crosslinking reaction for 2h to prepare microspheres, centrifugally separating at 1000r/min, washing for several times, and freeze-drying to prepare the pH-sensitive self-release embolic microspheres.
Comparative example 2
10 parts of hydroxyethyl methacrylate, 5 parts of N, N' -methylene bisacrylamide, 0.008 part of ammonium persulfate-sodium bisulfite, 35 parts of sodium alginate, 50 parts of cyclophosphamide and 8 parts of calcium chloride.
The preparation method comprises the following steps:
(1) preparation of pH sensitive prepolymers
Dissolving 10 parts of hydroxyethyl methacrylate in 500ml of deionized water, adding 5 parts of N, N' -methylene bisacrylamide as a crosslinking reagent, adding 0.008 part of ammonium persulfate-sodium bisulfite, stirring, dissolving and uniformly mixing, heating in a water bath to 40 ℃, reacting for 5 hours to form viscous-flow prepolymer, dripping the prepolymer solution into methyl tert-ether solution for precipitation, repeatedly dissolving and re-precipitating, and finally drying in vacuum to obtain the pure polymer.
(2) Preparation of sodium alginate solution
35 parts of sodium alginate having a viscosity of 600 mPa.s are dissolved in 700ml of deionized water and mechanically stirred until a homogeneous solution is formed.
(3) Preparation of Polymer blend solutions
Dissolving the acrylate prepolymer in deionized water to form a 3 wt% solution, mixing the prepolymer solution, the SA solution and 50 parts of cyclophosphamide, and stirring for 5 hours to fully and uniformly mix the components.
(4) Preparation of interpenetrating network Polymer microspheres
Adding 1 wt% span-80 serving as an emulsifier into 3600 parts of liquid paraffin, stirring at a high speed of 1000r/min for 10min, then adding a blending solution of an acrylate prepolymer and SA into the liquid paraffin, stirring at 300r/min for 2 hours to form a stable W/O system, then slowly dripping a calcium chloride solution (8 parts of calcium chloride is dissolved in 25 parts of water) into the W/O system, stirring for crosslinking reaction for 1h to prepare microspheres, centrifuging at 1000r/min, washing for a plurality of times, and freeze-drying to prepare the pH-sensitive self-release embolic microspheres.
Example 5 pH responsive Release study of pH sensitive self-modulating Release tumor embolic microspheres
10mg of the drug-loaded microspheres prepared in examples 1-4 and comparative examples 1 and 2 are precisely weighed and respectively placed in 1m L PBS buffer solution with pH6.85 and PBS buffer solution with pH 7.35 for carrying out an anti-tumor drug release test at 37 ℃, a sample lm L is taken at 72h, and the anti-tumor drug release rate of the microspheres for 72h is tested by high performance liquid chromatography (HP L C).
The pH response release results of the microspheres are shown in Table 1, and the results show that at pH6.85, the drug release rate of the pH-sensitive self-release tumor embolization microspheres provided by the invention is more than 4%, while the drug release rate of the ordinary microspheres without the pH-sensitive material is obviously lower than that of the microspheres provided by the invention, which indicates that the microspheres provided by the invention have higher release rate near the tumor. At pH 7.35, the maximum drug release rate of the pH-sensitive self-release tumor embolization microsphere provided by the invention is only 0.05%, and the drug release rate of the ordinary microsphere without the pH-sensitive material is obviously higher than that of the microsphere provided by the invention, which shows that the microsphere provided by the invention releases few drugs under the condition of higher pH of a normal human body and can realize pH-sensitive self-release.
Table 1pH responsive release results of microspheres
Figure BDA0001568756770000081
Figure BDA0001568756770000091
EXAMPLE 6 clinical therapeutic Effect of pH sensitive self-regulated Release tumor embolic microspheres
6.1 establishment of VX-2 liver cancer animal model
(1) Subjecting the rabbit with VX-2 tumor to ear vein general anesthesia with 30mg/kg sodium pentobarbital, peeling off tumor under aseptic condition, cutting into fish tissue blocks with vigorous growth at the edge of the wrapped block, repeatedly cleaning in physiological saline, and cutting into pieces of 1 × 1 × 1mm3The tumor tissue blocks were placed in 50m L normal saline containing gentamicin (containing 2 ten thousand IU of gentamicin) for use.
(2) Passage of tumor-bearing rabbits: after the New Zealand rabbit is completely numbed with 30mg/kg sodium pentobarbital through the marginal ear vein, the inner side skin of the hind leg is disinfected, each incision with the length of about 1.5cm is made, and 1mm of the incision is placed3The 2 tumor masses are placed in the muscle, the hemostasis and the suture are performed, and the penicillin powder is scattered and coated on the incision. Penicillin was intramuscularly administered for 4 consecutive days after the operation, 40 ten thousand IU.
(3) Intrahepatic planting of VX-2 tumor masses: new Zealand rabbits are planted and are fasted within 12 hours before operation without drinking. After 30mg/kg of sodium pentobarbital is used for complete anesthesia of the marginal ear vein, under the condition of a conventional aseptic operation, an incision is made at a position about 1cm below the xiphoid process, the liver is separated layer by layer until the liver is exposed, the left central lobe of the liver is slightly pulled out of the abdominal cavity, 1-2 spare tumor tissue blocks are taken and implanted into the liver, the bleeding is stopped, and the liver is brought back into the abdominal cavity. Then the other set of sterile equipment is replaced, and the peritoneum, the muscle and the skin are sutured layer by layer. After the suture, the suture is disinfected by iodophor, coated with penicillin powder, bandaged by blocking the waist, and injected with 40 ten thousand IU penicillin for four days after the operation.
6.2 tumor embolization microspheres for treating VX-2 liver cancer rabbits
The successfully molded experimental rabbits were divided into 2 groups of 5 rabbits each, and the experimental group for interventional therapy with the tumor embolization microspheres prepared in example 3 and the control group for interventional therapy with comparative example 2 were respectively used.
Each group of tumor-bearing rabbits was anesthetized with 3% sodium pentobarbital by ear vein, and then was covered with a conventional disinfectant in the inguinal region. The skin is incised along the longitudinal line of the femoral artery, subcutaneous tissues and muscle tissues are separated, the femoral artery sheath is exposed, the femoral artery sheath is cut, the length of the femoral artery is about 1.5-2 cm, and operation sutures are respectively threaded at the near end and the far end for later use. And (3) lifting the proximal suture, temporarily blocking blood flow, introducing the short guide wire after successful puncture, withdrawing the puncture needle sheath, and inserting the 3F catheter sheath along the guide wire into the proximal end of the femoral artery. After the experiment rabbit proved to be tumorous by B ultrasonic is introduced into a 4F Cobra catheter through a sheath tube and finds the celiac artery, celiac artery radiography is carried out to confirm the hepatic artery, a 3F catheter is coaxially introduced and is super-selected to the hepatic artery, and tumor development is proved by radiography. The experimental rabbits were injected with the drugs in different groups. The catheters were flushed with 0.5ml heparin saline after the interventional procedure. After the operation, the catheter and the sheath are removed, simultaneously, the proximal end and the distal end of the femoral artery are ligated, the suture layer by layer is sewed, penicillin powder is spread and the incision is bound, and green vegetables and special rabbit feed are fed.
(1) Tumor growth rate
Before treatment, tumor volume change was monitored 7 days after treatment by B-ultrasonic, and tumor major diameter (a) and minimum diameter (B) were measured using formula V ═ ab2The tumor volume was calculated 2. Tumor growth rates were calculated from the tumor volume ratio before and after treatment, and expressed as the mean value of each group, and the results are shown in Table 2.
TABLE 2 growth rate of tumor-bearing rabbit liver tumor
Experimental group Control group
Growth rate (%) 1.12 3.38
After 7, the experimental group treats the tumor-bearing rabbits, the liver tumor growth rate of the experimental group is the lowest, and the obvious difference is realized between the experimental group and the control group, which shows that the pH sensitive self-release tumor embolism microsphere provided by the invention has good tumor inhibition effect.
(2) Pathological examination
After 7 days of treatment, each group of tumor tissues was observed by an optical microscope, and the results are shown in the attached figures 1-2.
The gross pathological appearance of the liver segment embolised by each group of experimental rabbits is wedge-shaped, and the boundary between the liver segment embolised and the normal tissues is clear. Different ranges and degrees of necrosis can be seen in each group of experimental rabbits through downward section observation by a light microscope, different degrees of vascular endothelial damage can be seen in the experimental group (figure 1), the continuity of vascular walls disappears, the cells of surrounding tissues shrink and necrose, and a large amount of inflammatory cell infiltration can be seen. Large plaques of necrosis and infiltration of peripheral inflammatory cells were also seen in the control group (fig. 2), but the wall of the embolized vessels was intact and continuous, with slight edema of the peripheral liver tissue. The tumor embolization microsphere provided by the invention can effectively destroy the vascular wall of tumor tissue, thereby causing the necrosis of tumor cells.
(3) Determination of pH at tumor tissue
After 7 days of treatment, the pH of the tumor tissue was determined and the results are shown in Table 3
TABLE 3 pH of tumor tissue 7 days after tumor-bearing rabbits
pH value of tumor tissue after 7 days of embolism treatment
Experimental group 7.23
Control group 6.75
As can be seen from Table 3, the pH value of the tumor tissue in the experimental group is significantly higher than that of the control group, which indicates that the pH-sensitive self-release tumor embolization microsphere provided by the invention can significantly adjust the acid environment around the tumor tissue due to the tumor microenvironment regulator, thereby being beneficial to the treatment of tumors.
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.

Claims (11)

1. A pH-sensitive self-regulated drug release tumor embolization microsphere is characterized in that the tumor embolization microsphere comprises a pH-sensitive compound and a tumor microenvironment regulator;
the pH sensitive compound is selected from one or two of N, N-dimethylaminoethyl methacrylate or N, N-diethylaminoethyl methacrylate;
the tumor embolism microsphere also comprises 35-60 parts by weight of sodium alginate, 50-300 parts by weight of anti-tumor drug, 8-16 parts by weight of cross-linking agent and 5.501-15.05 parts by weight of other auxiliary agents;
the tumor microenvironment regulator is selected from arginine, lysine, histidine, chitosan, β -TCP, NaHCO3One or more of (a).
2. The pH-sensitive self-regulated drug release tumor embolization microsphere according to claim 1, wherein the weight ratio of the pH-sensitive compound to the tumor microenvironment regulator is 30-50: 0.5-6.
3. The pH-sensitive self-regulated drug release tumor embolization microsphere according to claim 1, wherein the viscosity of sodium alginate is 100-600 MPa-s; the cross-linking agent is selected from one or more of calcium chloride, magnesium chloride and barium chloride.
4. The pH-sensitive self-modulating drug-releasing tumor embolization microsphere of claim 3, wherein the cross-linking agent is calcium chloride.
5. The pH-sensitive self-regulated drug release tumor embolization microsphere according to claim 1, wherein the antitumor drug is selected from: doxorubicin, irinotecan, topotecan, hydroxycamptothecin, epirubicin, cisplatin, carboplatin, platinum oxalate, oxaliplatin, mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, melphalan, thiotepa, carmustine, semustine, busulfan, mitomycin, methotrexate, pemetrexed, 5-FU, FT-207, capecitabine, 6-mercaptopurine, 6-TG, hydroxyurea, cytarabine, gemcitabine, actinomycin D, daunorubicin, epirubicin, aclarubicin, mithramycin, paclitaxel, docetaxel, vinblastine, catharanthine, podophylline, homoharringtonine, asparaginase, tamoxifen, toremifene, exemestane, diphenoxylate, fosetyl-ethyl-piperidone, letrozole, anastrozole, megestrol, methyltestosterone, one or more of testosterone propionate, diethylstilbestrol, flutamide, goserelin and leuprorelin acetate.
6. The pH-sensitive self-regulated drug release tumor embolization microsphere according to claim 5, wherein the antitumor drug is one or more of adriamycin, cyclophosphamide and exemestane.
7. The pH-sensitive self-modulating drug-releasing tumor embolization microsphere according to claim 1, wherein the other auxiliary agents comprise: 5-10 parts of polymerization degree regulator, 0.5-5 parts of acrylic acid crosslinking agent and 0.001-0.05 part of catalyst.
8. The pH-sensitive self-regulated drug release tumor embolization microsphere according to claim 7, wherein the polymerization degree regulator is selected from one or two of hydroxyethyl methacrylate and acrylamide;
the acrylic crosslinking agent is selected from: one or more of N, N' -methylene bisacrylamide, 1, 4-butanediol diacrylate, ethylene glycol dimethacrylate and triallyl cyanurate;
the catalyst is selected from at least one of ammonium persulfate-sodium bisulfite and potassium persulfate-tetramethylethylenediamine.
9. The pH-sensitive self-modulating drug release tumor embolization microsphere of claim 8, wherein the acrylic acid cross-linking agent is N, N' -methylenebisacrylamide.
10. The pH-sensitive self-modulating drug release tumor embolization microsphere of claim 8, wherein the catalyst is ammonium sulfate-sodium bisulfite.
11. The preparation method of the pH-sensitive self-releasing tumor embolization microsphere according to any one of claims 7 to 10, wherein the pH-sensitive self-releasing tumor embolization microsphere is prepared by the following steps:
(1) dissolving sodium alginate in deionized water to obtain a sodium alginate solution;
(2) dissolving a pH sensitive compound, a polymerization degree regulator and an acrylic acid crosslinking agent in water, and initiating by a catalyst to prepare a prepolymer;
(3) dissolving the prepolymer and the tumor microenvironment regulator in deionized water to form a solution, and adding a sodium alginate solution and an anti-tumor drug to mix uniformly;
(4) preparing a W/O system by an emulsification method, adding a sodium alginate cross-linking agent, and freeze-drying to prepare the pH-sensitive self-regulating drug release embolism microsphere.
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