CN108524949B - Composite prodrug nano-carrier for reversing drug resistance of tumor drug and preparation method thereof - Google Patents
Composite prodrug nano-carrier for reversing drug resistance of tumor drug and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
- A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
- A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a composite prodrug nano carrier for reversing drug resistance of tumor drugs and a preparation method thereof, belonging to the fields of high polymer materials and medical engineering. The composite prodrug nano-carrier is formed by self-assembly of an amphiphilic pH sensitive type macromolecule prodrug and superparamagnetic nano-particles, has a typical core-shell structure, the inner core of the composite prodrug nano-carrier is formed by wrapping the superparamagnetic nano-particles through self-assembly of a hydrophobic chain segment of the amphiphilic pH sensitive type macromolecule prodrug coupled with a drug, and the outer shell of the composite prodrug nano-carrier is formed by a hydrophilic chain segment of the amphiphilic pH sensitive type macromolecule prodrug. Because the condition-responsive amphiphilic macromolecule prodrug is used for replacing the condition-responsive amphiphilic macromolecule in the composite prodrug nano carrier, the composite nano carrier has high-efficiency magnetic thermotherapy and targeted chemotherapy which is not interfered by the magnetic thermotherapy, so that the magnetic thermotherapy and the chemotherapy can be combined more efficiently and act on tumor tissues in a targeted manner, and the effective reversal of the drug resistance of the tumor is finally realized.
Description
Technical Field
The invention belongs to the fields of high polymer materials and medical engineering, particularly relates to a multifunctional nano-drug carrier, and particularly relates to a prodrug nano-carrier which is used for reversing drug resistance of tumor drugs and combines magnetic thermotherapy and pH-responsive chemotherapy.
Background
The treatment of tumor with chemotherapeutic medicine is the conventional means of tumor treatment at present, but clinical chemotherapy is often accompanied by the occurrence of tumor resistance, which is the most main reason known to cause the failure of tumor chemotherapy at present. Drug resistance of tumors can be classified into primary resistance and acquired resistance. The primary drug resistance means that the tumor cells are not sensitive to some chemotherapeutic drugs and show drug resistance after the first drug administration. Acquired resistance refers to resistance expressed by a decrease in the degree of sensitivity of the remaining tumor cells to chemotherapeutic drugs after a period of chemotherapy. Although the mechanism research aspect proves that the drug resistance of the tumor is the result of the combined action of a plurality of drug resistance mechanisms, the clinical manifestations are that the sensitivity of the tumor cells to the chemotherapeutic drugs is reduced or even insensitive, so that the improvement of the sensitivity of the tumor cells to the chemotherapeutic drugs is the key for reversing the drug resistance of the tumor.
The current research proves that the heat treatment can obviously increase the sensitivity of tumor cells to the chemotherapeutic drugs, so that the combination of the heat treatment and the chemotherapy, namely the heat chemotherapy, is an effective way for improving the curative effect of the chemotherapeutic drugs, reducing the drug concentration and relieving the side effects of the chemotherapeutic drugs, and is also a powerful means for effectively reversing the drug resistance of the tumors. In order to realize the high-efficiency synergistic effect of the thermotherapy and the chemotherapy, a simple and feasible idea is to load the nano thermotherapy medium and the chemotherapy medicament in the same medicament carrier, including the porous nano silicon spheres, the liposome, the condition-responsive medicament carrier and the like, so as to realize the synchronism of the thermotherapy and the chemotherapy in the action space and the action time. However, the drug carriers of the above-mentioned types, which basically carry the nano hyperthermia medium and the chemotherapeutic drug together by physical encapsulation or physical adsorption, generally have the following two problems:
1. the drug is easily released from the carrier by free diffusion. Because the physical wrapping or adsorption is a weak acting force, when the drug carrier circulates in the body, the drug carried in the drug carrier can slowly leak out through free diffusion, thereby weakening the synchronism of the thermotherapy and the chemotherapy.
2. Has higher risk of the synergistic effect of non-targeting heat treatment and chemotherapy, thereby increasing the side effect of the chemotherapy medicament. The thermotherapy can accelerate the free diffusion of the medicine, so that the medicine can leak out from the carrier at a higher speed under the action of the thermotherapy, and particularly, the medicine carrier made of the thermosensitive material can cause the instantaneous sudden release of the medicine in the local thermotherapy caused by the nano thermotherapy medium. Therefore, the drug carrier which carries the nano thermotherapy medium and the chemotherapy drug together by utilizing the physical encapsulation or physical adsorption effect has the action time and the action site of the chemotherapy controlled by the thermotherapy effect, but not the specific recognition of the tumor tissue. This requires a higher tumor targeting ability of drug carriers, but so far, the targeted identification and distribution of tumors is still a worldwide problem. This non-targeted chemotherapy can cause more serious side effects on normal tissues. Therefore, how to cooperate thermotherapy and chemotherapy to effectively and specifically act on tumor tissues is also a problem to be solved urgently by the current drug carrier loaded with nano thermotherapy media and chemotherapy drugs.
In order to solve the two problems, particularly high side effects caused by the non-targeting effect of the thermal chemotherapy, the invention uses the amphiphilic pH sensitive type macromolecular prodrug coupled with the drug to replace other types of drug carriers, and wraps superparamagnetic nano particles through hydrophobic interaction to construct a composite prodrug nano carrier with efficient synergy of the chemotherapy and the magnetic thermal therapy. Because the drug is connected to the amphiphilic macromolecules through covalent bonds sensitive to pH, the probability of drug leakage is greatly reduced, and the chemotherapeutic effect is only influenced by the pH value of the environment and is not interfered by the magnetocaloric effect. If the composite prodrug nano-carrier is distributed in normal tissues with physiological pH value environment, the introduction of an external magnetic field can only cause non-targeted thermotherapy, but can not cause drug release to cause non-targeted thermotherapy. When the composite prodrug nano-carrier is distributed at tumor tissues with lower pH values, the low pH value environment of the composite prodrug nano-carrier can cause the hydrolysis of pH-sensitive covalent bonds in the amphiphilic pH-sensitive macromolecular prodrug. The hydrolysis of the covalent bond can enable the chemotherapeutic drug to be separated from macromolecules and act on tumor cells. On the other hand, the amphiphilic macromolecular prodrug can be changed into a completely hydrophilic macromolecule, so that hydrophobic superparamagnetic nanoparticles can not be coated to form a micelle. With the disintegration of the micelles, the hydrophobic superparamagnetic nanoparticles aggregate and are dispersed in the tumor tissue. The nanometer thermotherapy medium and chemotherapy medicine are distributed in tumor tissue simultaneously, so that under the action of external magnetic field, the magnetic thermotherapy and chemotherapy can act on the tumor tissue synchronously, so that the composite prodrug nanometer carrier can realize the synergistic effect of targeted thermotherapy and chemotherapy on tumor tissue, especially on drug-resistant tumor tissue, and can realize the reversion of drug resistance of tumor.
Disclosure of Invention
The invention aims to provide a composite prodrug nano carrier with magnetic thermotherapy and targeted chemotherapy for reversing drug resistance of tumor drugs, namely, the composite prodrug nano carrier with efficient synergy of chemotherapy and magnetic thermotherapy is obtained by wrapping superparamagnetic nano particles through hydrophobic interaction by using an amphiphilic pH sensitive macromolecular prodrug coupled with drugs. The composite prodrug nano carrier has higher drug loading stability and targeting property, so that the release of the drug is not interfered by the action of magnetic heat, and the drug can be intensively distributed in tumor tissues with lower pH values. Meanwhile, the hydrophobic superparamagnetic nano-particles can be separated from the drug carrier along with the release of the drug and are synchronously dispersed in the tumor tissue with the drug. Therefore, the magnetic heat therapy-chemotherapy synergistic composite prodrug nano carrier constructed by the amphiphilic pH sensitive macromolecule prodrug can better act the heat chemotherapy targeting on tumor tissues, has great application potential in the aspects of realizing high-efficiency synergy of two therapies, improving the cytotoxicity of chemotherapy drugs and reducing the potential side effect of non-targeting heat chemotherapy, and is particularly suitable for treating and reversing drug-resistant tumors with higher requirements on the action dosage of the drugs and the cytotoxicity of the drugs.
In order to achieve the above object, the technical solution provided by the present invention is:
a composite prodrug nano carrier for reversing drug resistance of tumor drugs is characterized in that the composite prodrug nano carrier is formed by self-assembly of superparamagnetic nano particles and amphiphilic pH sensitive macromolecular prodrugs, has a typical core-shell structure, and has the particle size of 30-300 nm, wherein the amphiphilic pH sensitive macromolecular prodrugs are couples of fully hydrophilic two-block polymers and hydrophobic drugs which are bonded through pH sensitive chemical bonds, hydrophobic chain segments of the amphiphilic pH sensitive macromolecular prodrugs, which are coupled with the drugs, and the superparamagnetic nano particles form hydrophobic cores of the composite prodrug nano carrier through hydrophobic interaction, and hydrophilic shells of the composite prodrug nano carrier are formed by hydrophilic chain segments, which do not contain the drugs, in the amphiphilic pH sensitive macromolecular prodrugs.
The superparamagnetic nanoparticle comprises MnxZn1-xFe2O4Wherein x is between 0 and 1The particle size is between 5 and 20nm, the surface is stabilized by oleylamine or oleic acid, and the hydrophobic property is strong.
The amphiphilic pH-sensitive macromolecular prodrug is a coupling body formed by bonding a fully hydrophilic diblock polymer and a hydrophobic drug through a pH-sensitive chemical bond, wherein one block of the fully hydrophilic diblock polymer is polyethylene glycol with the molecular weight of 5000-20000, and the other block of the fully hydrophilic diblock polymer is composed of polymethacrylate or polyacrylamide polymers containing hydroxyl, including but not limited to polyhydroxypropylmethacrylate, polyhydroxyethylmethacrylate, poly N-hydroxymethyl acrylamide and poly N-hydroxyethyl acrylamide, the molecular weight of the amphiphilic pH-sensitive macromolecular prodrug is 2000-10000, and the molecular weight of the amphiphilic pH-sensitive macromolecular prodrug is 40-50% of that of the polyethylene glycol on the same fully hydrophilic diblock polymer.
The amphiphilic pH-sensitive macromolecular prodrug is a coupling body formed by bonding a fully hydrophilic diblock polymer and a hydrophobic drug through a chemical bond sensitive to pH, wherein the fully hydrophilic diblock polymer contains polymethacrylate or polyacrylamide polymers with hydroxyl, and the hydroxyl on the side chain of the fully hydrophilic diblock polymer can be modified into carboxyl or diamine through the reaction with anhydride or nitrobenzoyl chloride.
The amphipathic pH sensitive macromolecule prodrug disclosed by the invention is a hydrophobic antitumor drug containing carboxyl, hydroxyl, aldehyde or ketone groups coupled with polymethacrylate or polyacrylamide in a hydrophobic chain segment, or can be subjected to appropriate post-treatment to carry the hydrophobic antitumor drugs containing the carboxyl, hydroxyl, aldehyde or ketone groups, and comprises but is not limited to camptothecin, paclitaxel, curcumin, methotrexate, adriamycin, cisplatin and the like.
In the hydrophobic chain segment of the amphiphilic pH-sensitive macromolecular prodrug, a hydrophobic drug is coupled with polymethacrylate or polyacrylamide polymers through ester bonds or hydrazone bonds sensitive to the environmental pH, and the coupling rate is more than 80%.
The preparation method of the composite prodrug nano carrier for reversing tumor drug resistance is characterized by comprising the following steps:
dispersing superparamagnetic nano particles and amphiphilic pH sensitive macromolecular prodrug in an organic solvent according to a proper mass ratio, dispersing the superparamagnetic nano particles and the amphiphilic pH sensitive macromolecular prodrug in a water phase under the assistance of ultrasound, and removing the organic solvent to obtain the composite prodrug nano carrier.
In order to improve the magnetocaloric effect of the composite prodrug nanocarrier, the mass ratio of the superparamagnetic nanoparticles to the amphiphilic pH-sensitive macromolecule prodrug is 1: 0.1-10.
In order to ensure the formation of the composite prodrug nano-carrier, the ratio of the superparamagnetic nanoparticles to the amphiphilic pH sensitive macromolecule prodrug to the organic solvent is 0.1-5 mg: 0.1-10 mg: 1-5 mL, and the ratio of the organic solvent for dispersing the superparamagnetic nanoparticles and the amphiphilic pH sensitive macromolecule prodrug to the water phase is 1: 10-100.
In order to effectively control the particle size of the composite prodrug nano carrier, the organic solvent used for dispersing the superparamagnetic nano particles and the amphiphilic pH sensitive macromolecular prodrug in the preparation process is a single-component organic solvent or an organic solvent mixed according to a certain proportion, wherein the single-component organic solvent is NN-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran which can be mutually dissolved with water, the organic solvent mixed according to a certain proportion is tetrahydrofuran and NN-dimethylformamide or a mixture of tetrahydrofuran and dimethyl sulfoxide, and in the two mixed solvents, the volume ratio of tetrahydrofuran/NN-dimethylformamide to tetrahydrofuran/dimethyl sulfoxide is 1: 0.1-10.
Compared with the prior art, the invention has the following characteristics:
1. overcomes the defect that chemotherapy drugs are easy to leak through a nano drug carrier loaded with drugs through physical packaging or physical adsorption, thereby acting on normal tissues in a non-targeting way.
2. Overcomes the defect that the release of the chemotherapy medicament is easily interfered by the action of the thermotherapy in the nano medicament carrier with the combined action of the thermotherapy and the chemotherapy, so that the non-targeted thermotherapy often causes the non-targeted release of the chemotherapy medicament, thereby causing the non-targeted thermotherapy and causing serious side effects on normal tissues.
3. In the existing nano-drug carrier with combined effect of thermal therapy and chemotherapy, the in-vivo distribution of the chemotherapy drugs can be obviously influenced by the thermal therapy, but the in-vivo distribution of the nano-thermal therapy medium can not be influenced by the release of the chemotherapy drugs. The composite prodrug nano carrier is just opposite to the composite prodrug nano carrier, and the composite prodrug nano carrier is disintegrated due to the release of the drug, so that the distribution in the body of the hydrophobic nano thermotherapy medium is influenced.
4. Compared with the existing nano-drug carrier with combined action of thermal therapy and chemotherapy, the composite prodrug nano-carrier ensures that superparamagnetic nano-particles and chemotherapy drugs can be simultaneously and intensively distributed in tumor tissues through a unique cooperative targeting mechanism, so that the magnetic thermal therapy and the chemotherapy can be targeted and efficiently acted on the tumor tissues in a cooperative manner, and the reversal of tumor drug resistance is facilitated.
Drawings
FIG. 1 is a schematic view of the process of the present invention.
Detailed Description
The above-described scheme is further illustrated below with reference to specific examples. It should be understood that these examples are for illustrative purposes and are not intended to limit the scope of the present invention. The conditions used in the examples may be further adjusted according to the conditions of the particular manufacturer, and the conditions not specified are generally the conditions in routine experiments.
Example 1:
weighing 100mg of poly (hydroxypropyl methacrylate) -polyethylene glycol copolymer, and reacting with 20mg of carboxylated tetravalent platinum to obtain the macromolecular prodrug connected with tetravalent platinum through ester bond, poly (hydroxypropyl methacrylate-tetravalent platinum) -polyethylene glycol, wherein the coupling rate of the poly (hydroxypropyl methacrylate) and the carboxylated tetravalent platinum is 90%.
Taking 5mg of superparamagnetic nano-particle MnFe with the particle size of 8nm2O4And 5mg of platinum-containing macromolecular prodrug poly (hydroxypropyl methacrylate-tetravalent platinum) -polyethylene glycol dispersed in 2mL of tetrahydrofuran/NN-dimethylformamide (1/1), adding the mixed solution dropwise into 20 times of deionized water under the action of ultrasound, dialyzing in deionized water for 24 hours, and removing organic solvent to obtain the compound prodrugAqueous solution of drug nano-carrier. The composite prodrug nanocarrier was then lyophilized to obtain a powdered solid. (as shown in the process flow diagram of the invention in FIG. 1). The product is dispersed in water at a relatively low concentration (0.1mg/mL), and the composite prodrug nanocarrier has a particle size distribution of about 70nm as measured by dynamic laser light scattering, and has a polydispersity of 0.047. The TEM picture shows that the average particle size of the composite prodrug nano-carrier is 60nm, the composite prodrug nano-carrier is spherical and is uniformly dispersed.
Example 2:
weighing 80mg of poly-N-hydroxymethyl acrylamide-polyethylene glycol copolymer, modifying hydroxyl of poly-N-hydroxymethyl acrylamide into diamine, and then reacting with 20mg of doxorubicin hydrochloride to obtain a macromolecular prodrug connected with doxorubicin through a hydrazone bond, namely poly (N-hydroxyethyl methacrylate-doxorubicin) -polyethylene glycol, wherein the coupling rate of the modified poly-N-hydroxyethyl methacrylate and the doxorubicin is 86%.
Taking 2mg of superparamagnetic nano-particle Mn with the particle size of 15nm0.6Zn0.4Fe2O4And 5mg of macromolecular prodrug poly (N-hydroxymethyl acrylamide-adriamycin) -polyethylene glycol, adding the macromolecular prodrug poly (N-hydroxymethyl acrylamide-adriamycin) -polyethylene glycol into 5mL of mixed solution of tetrahydrofuran/dimethyl sulfoxide (1/1), dropwise adding the mixed solution into 10-time volume of deionized water under the action of ultrasound, dialyzing in the deionized water for 24 hours, and removing the organic solvent to obtain the aqueous solution of the composite prodrug nano carrier. The composite prodrug nanocarrier was then lyophilized to obtain a powdered solid. The product is dispersed in water at a relatively low concentration (0.1mg/mL), and the composite prodrug nanocarrier has a particle size distribution of about 132nm as measured by dynamic laser light scattering, and has a polydispersity of 0.056. The TEM picture shows that the average particle size of the composite prodrug nano-carrier is 115nm, the composite prodrug nano-carrier is spherical and is uniformly dispersed.
Example 3:
weighing 50mg of poly (hydroxyethyl methacrylate) -polyethylene glycol copolymer, and reacting the poly (hydroxyethyl methacrylate) -polyethylene glycol copolymer with 10mg of methotrexate to obtain the macromolecular prodrug connected with the methotrexate through ester bond, namely poly (hydroxypropyl methacrylate-methotrexate) -polyethylene glycol, wherein the coupling rate of the poly (hydroxyethyl methacrylate) and the methotrexate is 88%.
Taking 2mg of superparamagnetic nano-particle Mn with the particle size of 12nm0.4Zn0.6Fe2O4And 4mg of macromolecular prodrug poly (hydroxypropyl methacrylate-methotrexate) -polyethylene glycol, adding 4mL of mixed solution of tetrahydrofuran/NN-dimethylformamide (3/7), dropwise adding the mixed solution into deionized water with the volume 20 times that of the mixed solution under the action of ultrasound, dialyzing the mixture in the deionized water for 24 hours, and removing the organic solvent to obtain the aqueous solution of the composite prodrug nanocarrier. The composite prodrug nanocarrier was then lyophilized to obtain a powdered solid. The product was dispersed in water at a relatively low concentration (0.1mg/mL), and the composite prodrug nanocarrier had a particle size distribution of about 102nm, as measured by dynamic laser light scattering, and a polydispersity of 0.035. The TEM picture shows that the average particle size of the composite prodrug nano-carrier is 95nm, the composite prodrug nano-carrier is spherical and is uniformly dispersed.
Example 4:
100mg of poly-N-hydroxyethyl acrylamide-polyethylene glycol copolymer is weighed, hydroxyl in the poly-N-hydroxyethyl acrylamide is modified into carboxyl, and then the carboxyl reacts with 20mg of paclitaxel to obtain a macromolecular prodrug connected with paclitaxel through an ester bond, namely poly (N-hydroxyethyl acrylamide-paclitaxel) -polyethylene glycol, wherein the coupling rate of the modified poly-N-hydroxyethyl acrylamide and adriamycin is 84%.
Taking 1mg of superparamagnetic nano-particle ZnFe with the particle size of 20nm2O4And 5mg of macromolecular prodrug poly (N-hydroxyethyl acrylamide-paclitaxel) -polyethylene glycol is added into 5mL of mixed solution of tetrahydrofuran/dimethyl sulfoxide (8/2), then the mixed solution is dropwise added into deionized water with the volume 40 times that of the mixed solution under the action of ultrasound, then the deionized water is dialyzed for 24 hours, and the organic solvent is removed to obtain the aqueous solution of the composite prodrug nano carrier. The composite prodrug nanocarrier was then lyophilized to obtain a powdered solid. The product is dispersed in water at a relatively low concentration (0.1mg/mL), and the composite prodrug nanocarrier has a particle size distribution of about 149nm as measured by dynamic laser light scattering, and a polydispersity of 0.029. The TEM picture shows that the average particle size of the composite prodrug nano-carrier is 132nm, the composite prodrug nano-carrier is spherical and is uniformly dispersed.
Example 5: proliferation inhibition effect of composite prodrug nano-carrier on multiple drug-resistant tumor cell strains in vitro
Cisplatin was used as a model of chemotherapeutic drugs, and composite prodrug nanocarriers were prepared as in example 1. Selecting a plurality of drug-resistant cell strains: a549, A549/DDP, SKOV3 and SKOV3/DDP are used as in vitro drug resistance reversal models. The initial concentration of each cell line was 1X 106One cell/mL, after 24 hours of culture in a 96-well plate, each cell group was added with a concentration gradient of 5. mu.g/mL according to the drug, and the cells were cultured at 37 ℃ for 48 hours as a control. The experimental group adopts the composite prodrug nano-carrier, and the composite prodrug nano-carrier is firstly statically cultured for 24 hours, then cultured for 5 minutes under the action of a magnetic field and then cultured for 24 hours at 37 ℃. The apoptosis conditions of the control group and the experimental group are measured at the same time, and the apoptosis rate of the experimental group is calculated by taking the apoptosis rate of the control group as a reference, and the multiplication rate of the apoptosis rate of the experimental group compared with that of the control group is calculated.
Example 6: inhibition of drug-resistant tumors by composite prodrug nanocarriers in vivo
Nude mice 4-6 weeks old were used as subjects, and 1X 10 injections were subcutaneously injected into the abdomen6MCF-7/ADR until the tumor grows to 150mm3Size, random grouping, 12 in each group, as a drug-resistant tumor model. Corresponding adriamycin is selected as a drug model, and the related composite prodrug nano-carrier is prepared according to the embodiment 2.
The drug is administered by tail vein injection, physiological saline is selected as negative control, doxorubicin is selected as a positive control group 1, an in-situ magnetic-thermal temperature-sensitive targeted nano-drug carrier carrying the doxorubicin is selected as a positive control group 2, a composite prodrug nano-carrier is selected as a material group, and the dosage of the doxorubicin in each group is based on that of the doxorubicin in the positive control group 1. The medicine is taken once a day, 2 hours after injection, four groups all receive the magnetic field effect for 30 minutes, and the material group and the positive control group 2 can be heated under the magnetic field effect. Infrared shows that the material group and the positive control group 2 both cause the temperature rise of non-tumor parts, but the material group is more prone to the temperature rise of tumor parts, and invasive temperature measurement also shows that the thermotherapy temperature of the material group is higher than that of the positive control group 2. In addition, the research on the in vivo distribution of the drug shows that the concentration of the drug in the tumor part is higher in the compound prodrug nano-carrier mediated tumor thermal chemotherapy, and the distribution of the drug in other main organs is obviously less than that in the positive control groups 1 and 2. Tumor size changes, and survival of nude mice were determined at seven time points, day 0, day 3, day 6, day 10, day 15, day 20, and day 30 of dosing. The experimental results show that the tumor volumes of the material group and the positive control groups 1&2 are reduced, but the tumor volumes of the material group are reduced more obviously, while the tumor volumes of the negative control group are increased obviously. From day 6, the negative control group was statistically different from the positive control groups 1&2 and the material group, with P < 0.05; starting on day 10, the negative control group has a very significant statistical difference P < 0.01 compared with the positive control groups 1&2 and the material group; starting on day 15, the material group was statistically different from positive control group 1, with P < 0.05; starting on day 20, the material group and positive control group 2 had significant statistical differences, P < 0.05; by day 30, the material group and positive control group 2 had very significant statistical differences, P < 0.01.
The above examples are only for illustrating the technical idea and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered in the protection scope of the present invention.
Claims (1)
1. A composite prodrug nano-carrier for reversing drug resistance of tumor drugs is characterized by being prepared according to the following steps:
weighing 100mg of poly (hydroxypropyl methacrylate) -polyethylene glycol copolymer, and reacting the poly (hydroxypropyl methacrylate) -polyethylene glycol copolymer with 20mg of carboxylated tetravalent platinum to obtain a macromolecular prodrug connected with tetravalent platinum through an ester bond, namely poly (hydroxypropyl methacrylate-tetravalent platinum) -polyethylene glycol, wherein the coupling rate of the poly (hydroxypropyl methacrylate) and the carboxylated tetravalent platinum is 90%;
taking 5mg of superparamagnetic nano-particle MnFe with the particle size of 8nm2O4And 5mg of platinum macromolecule prodrug poly (hydroxypropyl methacrylate-tetravalent platinum) -polyethylene glycol is dispersed in 2mL of mixed solution of tetrahydrofuran/NN-dimethylformamide ═ 1/1, then the mixed solution is dripped into deionized water with 20 times of volume under the action of ultrasound, then the deionized water is dialyzed for 24 hours, and the organic solvent is removed to obtain the aqueous solution of the composite prodrug nano carrier; then, freeze-drying the composite prodrug nano carrier to obtain powdery solid; dispersing the product in water at a low concentration of 0.1mg/mL, and measuring the particle size distribution of the composite prodrug nano-carrier by using a dynamic laser light scattering instrument to be about 70nm, wherein the polydispersity is 0.047; the TEM picture shows that the average particle size of the composite prodrug nano-carrier is 60nm, the composite prodrug nano-carrier is spherical and is uniformly dispersed.
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