CN105168230A - Tumor targeted prodrug having endosome escaping function as well as nano preparation and preparation method of tumor targeted prodrug - Google Patents
Tumor targeted prodrug having endosome escaping function as well as nano preparation and preparation method of tumor targeted prodrug Download PDFInfo
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Abstract
The invention provides a tumor targeted prodrug having an endosome escaping function; the tumor targeted prodrug is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA), wherein POEGMA is a water-soluble polymer having a long circulation function, BUF is chemotherapeutic bufalin having an antineoplastic activity, cRGD is polypeptide capable of targeting tumor tissues actively and P (DEA-co-BMA) is a polymer having an endosome escaping function. The invention also provides a method for preparing the tumor targeted prodrug, as well as a nano preparation and a preparation method of the tumor targeted prodrug having the endosome escaping function. The nano preparation can be used for effectively killing cancer cells with a relatively low dosage; and an effect of killing various cancer cells is obviously better than that of a free bufalin medicine.
Description
Technical field
The present invention relates to cancer target to send and Atrigel technical field, particularly relate to a kind of cancer target prodrug with endosome escape function, the preparation method of this prodrug, and the nanometer formulation of this prodrug and the preparation method of this nanometer formulation.
Background technology
Cancer morbidity, in ascendant trend year by year, has become at present and has threatened one of disease that human health is the most serious (SiegelR.L.etal, 2015, CACancerJClin, 2015,65:5-29).Chemotherapy is used widely in worldwide as a kind of important treatment means outside operation and radiotherapy.But there is the critical defects such as the low and toxic and side effects of poorly water-soluble, uncontrollable release, bioavailability is large in most of chemotherapeutics (as amycin, paclitaxel, camptothecine etc.).And a kind of development of new type anticancer medicine often has and has a big risk, invests the unfavorable factors such as large and cycle of opening is long.Therefore, how for the deficiency of existing cancer therapy drug, design, exploitation novel form become one of the important front edge and focus of biomedical sector research gradually with the deficiency improving existing dosage form.Nano medication preparation method based on polymer micelle is various, chemical modification is simple, develops, application aspect shows the technical advantage of becoming stronger day by day at the novel form of anticarcinogen.
Existing Nano medication adopts physically trapping, absorption or covalent modified mode that antitumor drug is prepared into Nano medication usually, and on its surface further chemical modification tumor targeted molecular to promote its enrichment and then reach the object improving curative effect near tumor tissues.A series ofly be developed (as Langeretal. based on micellar nanoparticles, liposome, inorganic nano-particle (golden nanometer particle, quantum dot, Graphene, CNT etc.) and the Nano medication of hybrid nanoparticle, NatNanotechnol., 2007,2 (12): 751-60; Chenetal., Adv.Mater.2014,65 (1): 104-120).It is worthy of note that most Nano medication enters cell in the mode of cell endocytic and discharge medicine in endosome/lysosome.Regrettably, medicine needs to escape out from endosome/lysosome competence exertion antitumor action; And existing Nano medication system does not have good endosome escape capability usually, this usually causes the medicine entering cell to be degraded in lysosome, can not give full play to its drug effect.
In order to more effectively play a role in medicament transport to Cytoplasm, research worker adopts the various ways such as virus, protein, polypeptide, micromolecular compound, photosensitizer and synthesis macromolecule to break endosome/lysosomal envelope barrier.Wherein, synthesize macromolecule due to its accurate designability, can scale preparation and good endosome escape capability be subject to extensive concern.In the recent period, Stayton etc. are by poly-for block copolymer (N, N-dimethylaminoethyl methacrylate)-b-(N, N-diethyl aminoethyl acrylate-co-n-BMA), namely PDMAEMA-b-P (DEA-co-BMA) is for gene delivery (Biomaterials, 2012,33,2301-2309).Experimental result shows, P (DEA-co-BMA) block shows strong endosome escape capability when BMA content is 30-40%.Possible reason is that P (DEA-co-BMA) block DEA in endosome/lysosomal sour environment (pH ~ 5) is changed into protonated by deprotonation, cause dissociating of the responsive micelle of this pH, and then impel the phosphide bilayer of the butyl of BMA primitive and film to interact to destroy the film of endosome.Nanoparticle is finally made to escape out from endosome/lysosome.Liu etc. and then synthesized the block copolymer with endosome escape function, poly-(N, N-DMAA)-b-(N, N-diethyl aminoethyl acrylate-co-n-BMA), i.e. PDMA-b-P (DEA-co-BMA), and on two block, distinguish pH sensitivity on labelling fluorescent dye and the insensitive interior mark molecule of pH.Gained novel polymer based pH fluorescent probe has good endosome escape function and can pH change procedure (Liuetal., Biomacromolecules, 2014,15 (11): 4293-301) in Real-Time Monitoring Cytoplasm delicately.
Valine-arginine-glycine-aspartic acid-glutamic acid cyclic peptide, is called for short cRGD, is a kind of effective targeting peptides, verified its of numerous experiment has good Targeting Effect (Jamesetal. to tumor vessel, AdvDrugDeliverRev, 2008,60:1615-1626).If cRGD can be combined with response medicine nanoparticle, build Nano medication tumor tissues to good specificity target function, inventor believes that it will have certain facilitation to improving curative effect of medication.
Summary of the invention
For all deficiencies existed in prior art, applicant aims to provide a kind of tumor-targeting drug with endosome escape function.
In the present invention, inventor obtains containing P (DEA-co-BMA) and poly-oligomeric ethylene glycol methacrylate (POEGMA) polymer chain, the scopiform copolymer with endosome escape function by controllable polymerization means, and adopt esterase response β-sulfo-ester bond to be covalently attached on this polymer by antitumor drug Toadpoison Medicine (BUF), adopt stable amido link to be connected on this polymer by cRGD tumor neogenetic blood vessels to selectively targeted function, be finally prepared into the cancer target prodrug and nanometer formulation thereof with endosome escape function.Wherein, the long-chain due to POEGMA can make nano-carrier effectively the engulfing of escape reticuloendothelial system, thus reaches macrocyclic object.Because β-sulfo-key can be hydrolyzed rapidly the former medicine of release BUF under esterase effect, it is made to play drug effect, the problem that the pharmaceutically active can effectively avoiding general chemistry key modification of pharmaceutical to cause significantly declines.On macromolecular chain, covalently bound targeting peptides cRGD promotes it in the enrichment of tumor tissues position to improve the bioavailability of medicine.Simultaneously, the introducing of P (DEA-co-BMA), can make to enter endosome in cell/lysosomal Nano medication therefrom to escape out in time and enter Cytoplasm and play drug effect, effectively can avoid the degraded of enzyme to drug molecule of strong acid and strong degradation capability in endosome/lysosome, improve utilization ratio of drug.
Therefore, first aspect, the invention provides a kind of cancer target prodrug with endosome escape function, and it is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).Wherein, POEGMA is the water soluble polymer with long circulating effect, BUF is the chemotherapeutics Toadpoison Medicine with anti-tumor activity, and cRGD is can the polypeptide of effective active targeting tumor tissues, and P (DEA-co-BMA) is for having the macromolecule of endosome escape function.
In order to prepare above-mentioned P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA), another technical problem to be solved by this invention is that P (DEA-co-BMA), the targeting peptides cRGD of how effective function of being escaped by endosome and antitumor drug BUF are incorporated on same polymer, make it to overcome BUF poorly water-soluble, the premature disconnection problem of method CPT in vivo in transportation that the low problem of bioavailability can effectively avoid conventional physical to embed again.Meanwhile, effectively can impel again entering intracellular Nano medication and escape out from endosome/lysosome and avoid being degraded, and really play a role, thus play curative effect of medication to greatest extent.
Second aspect, the invention provides a kind of above-mentioned preparation method with the cancer target prodrug of endosome escape function, comprises the following steps:
(1) intermediate product P (OEGMA-co-BSMA-co-BEMA) is prepared:
By a certain amount of RAFT initiator B PTPA, oligomeric ethylene glycol methacrylate OEGMA, containing the monomers B SMA of β-thiocarboxyl group, the monomers B EMA containing atom transferred free radical initiator, solvent and radical initiator add in glass tubing, tube sealing after vacuum freeze thawing three times; Afterwards, 0.5-40 hour is reacted under 20-80 DEG C of condition, obtain crude product P (OEGMA-co-BSMA-co-BEMA), finally this crude product P (OEGMA-co-BSMA-co-BEMA) purification process is obtained described P (OEGMA-co-BSMA-co-BEMA).
(2) intermediate product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA-co-BEMA), DEA, BMA, solvent and mantoquita part are added in glass tubing, after vacuum freeze thawing three times, adds mantoquita, then vacuum freeze thawing twice, then tube sealing; Afterwards, under 20-80 DEG C of condition, react 0.5-20 hour, obtain crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA); Finally this crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is crossed silicagel column removing mantoquita, concentrated, more purifiedly process to obtain described P (OEGMA-co-BSMA)-g-P (DEA-co-BMA).
(3) target product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA)-g-P (DEA-co-BMA), NHS-OH, BUF, condensing agent and catalyst are dissolved in stirring at room temperature 3-72 hour in organic solvent; Then, add a certain amount of cRGD and continue reaction 1-48 hour, obtain crude product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA); Finally this crude product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) purification process is obtained described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, and described purification process is: dialyse in water, then lyophilization.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, and the molecular weight of the described OEGMA in described step (1) is 100-50000.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described solvent in described step (1) be selected from DMF, DMSO, NMP, isopropyl alcohol, methanol, ethanol, dioxane and oxolane one or more.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described radical initiator in described step (1) be selected from cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl hydroperoxide, azodiisobutyronitrile, 2,2'-Azobis(2,4-dimethylvaleronitrile) one or more.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described initiator B PTPA:OEGMA:BSMA:BEMA in described step (1): the mol ratio of radical initiator is 1:10-200:0.5-200:0.5-200:0.01-1.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described solvent in described step (2) be selected from DMF, DMSO, NMP, isopropyl alcohol, methanol, ethanol and oxolane one or more.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, and the described mantoquita part in described step (2) is selected from bipyridyl, PMDETA and Me
6one or more in TREN.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described mantoquita in described step (2) be selected from cuprous bromide, Cu-lyt., copper bromide and copper chloride one or more.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the BEMA:DEA:BMA in the described P (OEGMA-co-BSMA-co-BEMA) in described step (2): mantoquita: the mol ratio of mantoquita part is 1:10-500:10-500:0.1-10:0.1-10.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described condensing agent in described step (3) be selected from DCC, EDC, DIC one or more.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described catalyst in described step (3) be selected from pyridine, dimethylamino naphthyridine, triethylamine and hydroxy benzo triazole one or more.
Preferably, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, and the mol ratio of in described P (the OEGMA-co-BSMA)-g-P (DEA-co-BMA) in described step (3) BSMA:NHS-OH:BUF: condensing agent: catalyst: cRGD is 1:0.01-0.1:0.1-0.99:1-10:0.01-0.5:0.01-0.1.
The third aspect, the invention provides a kind of above-mentioned nanometer formulation with the cancer target prodrug of endosome escape function, it is characterized in that, the particle diameter of nanoparticle is wherein 10 ~ 2000nm, and the described targeted prodrug comprised is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).Wherein, with P (OEGMA-co-RGD) for hydrophilic shell, with BUF and P (DEA-co-BMA) for hydrophobic core.
Nanometer formulation of the present invention can be obtained under mechanical agitation, ultrasonic, high pressure homogenizer effect, its particle diameter at 10 ~ 2000nm, smooth surface, good evenness, regular particles are good without adhesion, redispersibility, carrying drug ratio and envelop rate high; It can be used for the slow release nano-particle preparing vein or intramuscular injection or oral administration, as cancer target administration.The nanometer formulation of preparation can be dispersed in solid, semisolid or solution.Preferably make the pharmaceutical dosage forms of drug administration by injection, especially injection for intravenous is used.
Preferably, described nanometer formulation is nanoparticle solution, wherein, the concentration of described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is 0.001-30g/L, described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is after human body metabolism, and the molar concentration of the active medicine BUF of release is 0.001-10000 μm of ol/L.
Fourth aspect, the invention provides a kind of preparation method of above-mentioned nanoparticle solution, it is characterized in that, be selected from the one in following methods: multi-emulsion method, membrane emulsification method, emulsifying evaporation, interphase precipitate method, self-assembly method.Wherein, used organic solvent comprises the various organic solvents being suitable for preparing nanoparticle solution such as ethyl acetate, dichloromethane, chloroform, acetone, ethanol and dimethyl sulfoxine.
Preferably, described preparation method is multi-emulsion method, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in the mixed solvent of 200 μ L dichloromethane or dichloromethane and acetone, ultrasonic emulsification (10sx4), adding 2.2mL concentration is again in the pluronicF68 water dispersion medium of 1%, ultrasonic emulsification (10sx4) again.Then stirred at ambient temperature 0.5-5h removes organic facies, obtains nanoparticle solution.
Preferably, described preparation method is membrane emulsification method, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in 400 μ L acetone solvents, rotary evaporation film forming, add the aqueous solution of 4mL subsequently, stirred at ambient temperature 0.5-6h, obtains nanoparticle solution.
Preferably, described preparation method is emulsifying evaporation, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in the mixed solvent of 400 μ L acetone/dichloromethane, join 2.2mL concentration be 2% containing polyvinyl alcohol (PVA) water dispersion medium in, the newborn even emulsifying of ultrasonic or high pressure, emulsion at room temperature stirs 2-4h, waves most organic solvent, obtains nanoparticle solution.
Preferably, described preparation method is interphase precipitate method, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in 400 μ L acetone solvents, under continuous stirring condition, the concentration above-mentioned solution being injected 2.2mL is the PVA water dispersion medium of 2%, acetone is removed in pressurization volatilization, obtains nanoparticle solution.
Preferably, described preparation method is self-assembly method, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in 200 μ LDMSO, solution is instilled in the water that 2mL stirreds, afterwards solution is loaded in bag filter the 3-72 hour that dialyses, removing organic solvent, obtains nanoparticle solution.
Further preferably, the preparation method of described nanoparticle solution, it is characterized in that, described water dispersion medium be selected from dextrose former times 40-70, pluronicF68 or PVAC polyvinylalcohol one or more, and the quality concentration expressed in percentage by volume of described water dispersion medium is 0.01-10%.
Further preferably, the preparation method of described nanoparticle solution, is characterized in that, described ultrasonic intensity is 10-1000W.
Further preferably, the preparation method of described nanoparticle solution, is characterized in that, the scope of the molecular cut off of described bag filter is 1000-10000Da.
Preferably, described nanometer formulation is nanometer lyophilized preparation, wherein, lyophilizing caffolding agent is selected from trehalose, glucose, lactose, decoct in sugar, dextran, sorbitol, mannitol and Polyethylene Glycol one or more, and the mass percentage concentration of described lyophilizing caffolding agent is 0.01-20%.
Various preparation method of the present invention is easy, is suitable for large-scale production, is particularly useful for making and has long circulating, biodegradable, slow release, passive target, active targeting, transport active substance, anti-tumor drug, especially prepare the medicine of anti-intestinal cancer.The antineoplastic prodrug adopting method of the present invention to obtain and nanometer formulation thereof are suitable for the modes such as intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, oral or percutaneous dosing.
The cancer target prodrug nanometer formulation with endosome escape function of the present invention, under comparatively low dosage condition, effectively can kill and wound cancerous cell, it is obviously better than free Toadpoison Medicine medicine to the fragmentation effect of multiple cancerous cell.
Preparation method of the present invention is easy, is suitable for large-scale production, is adapted to preparation especially and has long circulating, biodegradable, slow release, passive target, active targeting, transport active substance, anti-tumor drug, especially prepare the medicine of anti-intestinal cancer.The anti-tumor drug adopting method of the present invention to obtain is suitable for the modes such as intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, oral or percutaneous dosing.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of a preferred embodiment of cancer target prodrug P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) of the present invention;
Fig. 2 is that P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) in a preferred embodiment of the present invention is at CDCl
3in
1hNMR collection of illustrative plates;
Fig. 3 is that P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) in a preferred embodiment of the present invention is at CDCl
3in
1hNMR collection of illustrative plates;
Fig. 4 is the grain size distribution of the nanoparticle of P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) in a preferred embodiment of the present invention;
Fig. 5 is that the nanoparticle of P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) in a preferred embodiment of the present invention is to the cell survival rate figure of LoVo cell strain effect after 48 hours.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further elaborated, but the present invention is not limited to following embodiment.
First aspect, the invention provides a kind of cancer target prodrug with endosome escape function, and it is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).Wherein, POEGMA is the water soluble polymer with long circulating effect, BUF is the chemotherapeutics Toadpoison Medicine with anti-tumor activity, and cRGD is can the polypeptide of effective active targeting tumor tissues, and P (DEA-co-BMA) is for having the macromolecule of endosome escape function.
Second aspect, the invention provides a kind of above-mentioned preparation method with the cancer target prodrug of endosome escape function, its synthetic route is shown in accompanying drawing 1, specifically comprises the following steps:
(1) intermediate product P (OEGMA-co-BSMA-co-BEMA) is prepared:
By a certain amount of RAFT initiator B PTPA, oligomeric ethylene glycol methacrylate OEGMA, containing the monomers B SMA of β-thiocarboxyl group, the monomers B EMA containing atom transferred free radical initiator, solvent and radical initiator add in glass tubing, tube sealing after vacuum freeze thawing three times; Afterwards, 0.5-40 hour is reacted under 20-80 DEG C of condition, obtain crude product P (OEGMA-co-BSMA-co-BEMA), finally this crude product P (OEGMA-co-BSMA-co-BEMA) purification process is obtained described P (OEGMA-co-BSMA-co-BEMA).
(2) intermediate product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA-co-BEMA), DEA, BMA, solvent and mantoquita part are added in glass tubing, after vacuum freeze thawing three times, adds mantoquita, then vacuum freeze thawing twice, then tube sealing; Afterwards, under 20-80 DEG C of condition, react 0.5-20 hour, obtain crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA); Finally this crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is crossed silicagel column removing mantoquita, concentrated, more purifiedly process to obtain described P (OEGMA-co-BSMA)-g-P (DEA-co-BMA).(3) target product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA)-g-P (DEA-co-BMA), NHS-OH, BUF, condensing agent and catalyst are dissolved in stirring at room temperature 3-72 hour in organic solvent; Then, add a certain amount of cRGD and continue reaction 1-48 hour, obtain crude product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA); Finally this crude product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) purification process is obtained described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, and described purification process is: dialyse in water, then lyophilization.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, and the molecular weight of the described OEGMA in described step (1) is 100-50000.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described solvent in described step (1) be selected from DMF, DMSO, NMP, isopropyl alcohol, methanol, ethanol, dioxane and oxolane one or more.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described radical initiator in described step (1) be selected from cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl hydroperoxide, azodiisobutyronitrile, 2,2'-Azobis(2,4-dimethylvaleronitrile) one or more.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described initiator B PTPA:OEGMA:BSMA:BEMA in described step (1): the mol ratio of radical initiator is 1:10-200:0.5-200:0.5-200:0.01-1.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described solvent in described step (2) be selected from DMF, DMSO, NMP, isopropyl alcohol, methanol, ethanol and oxolane one or more.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, and the described mantoquita part in described step (2) is selected from bipyridyl, PMDETA and Me
6one or more in TREN.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described mantoquita in described step (2) be selected from cuprous bromide, Cu-lyt., copper bromide and copper chloride one or more.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the BEMA:DEA:BMA in the described P (OEGMA-co-BSMA-co-BEMA) in described step (2): mantoquita: the mol ratio of mantoquita part is 1:10-500:10-500:0.1-10:0.1-10.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described condensing agent in described step (3) be selected from DCC, EDC, DIC one or more.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, the described catalyst in described step (3) be selected from pyridine, dimethylamino naphthyridine, triethylamine and hydroxy benzo triazole one or more.
In a preferred embodiment, above-mentioned have in the preparation method of the cancer target prodrug of endosome escape function, and the mol ratio of in described P (the OEGMA-co-BSMA)-g-P (DEA-co-BMA) in described step (3) BSMA:NHS-OH:BUF: condensing agent: catalyst: cRGD is 1:0.01-0.1:0.1-0.99:1-10:0.01-0.5:0.01-0.1.
The third aspect, the invention provides a kind of above-mentioned nanometer formulation with the cancer target prodrug of endosome escape function, it is characterized in that, the particle diameter of nanoparticle is wherein 10 ~ 2000nm, and the described targeted prodrug comprised is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).Wherein, with P (OEGMA-co-RGD) for hydrophilic shell, with BUF and P (DEA-co-BMA) for hydrophobic core.
In a preferred embodiment, described nanometer formulation is nanoparticle solution, wherein, the concentration of described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is 0.001-30g/L, described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is after human body metabolism, and the molar concentration of the active medicine BUF of release is 0.001-10000 μm of ol/L.
In a preferred embodiment, the invention provides a kind of preparation method of above-mentioned nanoparticle solution, it is characterized in that, be selected from the one in following methods: multi-emulsion method, membrane emulsification method, emulsifying evaporation, interphase precipitate method, self-assembly method.Wherein, used organic solvent comprises the various organic solvents being suitable for preparing nanoparticle solution such as ethyl acetate, dichloromethane, chloroform, acetone, ethanol and dimethyl sulfoxine.
In a preferred embodiment, described preparation method is multi-emulsion method, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in the mixed solvent of 200 μ L dichloromethane or dichloromethane and acetone, ultrasonic emulsification (10sx4), adding 2.2mL concentration is again in the pluronicF68 water dispersion medium of 1%, ultrasonic emulsification (10sx4) again.Then stirred at ambient temperature 0.5-5h removes organic facies, obtains nanoparticle solution.
In a preferred embodiment, described preparation method is membrane emulsification method, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in 400 μ L acetone solvents, rotary evaporation film forming, add the aqueous solution of 4mL subsequently, stirred at ambient temperature 0.5-6h, obtains nanoparticle solution.
In a preferred embodiment, described preparation method is emulsifying evaporation, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in the mixed solvent of 400 μ L acetone/dichloromethane, join 2.2mL concentration be 2% containing polyvinyl alcohol (PVA) water dispersion medium in, the newborn even emulsifying of ultrasonic or high pressure, emulsion at room temperature stirs 2-4h, waves most organic solvent, obtains nanoparticle solution.
In a preferred embodiment, described preparation method is interphase precipitate method, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in 400 μ L acetone solvents, under continuous stirring condition, the concentration above-mentioned solution being injected 2.2mL is the PVA water dispersion medium of 2%, acetone is removed in pressurization volatilization, obtains nanoparticle solution.
In a preferred embodiment, described preparation method is self-assembly method, comprise step: get 4mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) and be dissolved in 200 μ LDMSO, solution is instilled in the water that 2mL stirreds, afterwards solution is loaded in bag filter the 3-72 hour that dialyses, removing organic solvent, obtains nanoparticle solution.
In a further preferred embodiment, the preparation method of described nanoparticle solution, it is characterized in that, described water dispersion medium be selected from dextrose former times 40-70, pluronicF68 or polyvinyl alcohol (PVA) one or more, and the mass percent of described water dispersion medium is 0.01-10%.
In a further preferred embodiment, the preparation method of described nanoparticle solution, is characterized in that, described ultrasonic intensity is 10-1000W.
In a further preferred embodiment, the preparation method of described nanoparticle solution, is characterized in that, the scope of the molecular cut off of described bag filter is 1000-10000Da.
In a preferred embodiment, described nanometer formulation is nanometer lyophilized preparation, wherein, lyophilizing caffolding agent is selected from trehalose, glucose, lactose, decoct in sugar, dextran, sorbitol, mannitol and Polyethylene Glycol one or more, and the mass percentage concentration of described lyophilizing caffolding agent is 0.01-20%.
Embodiment 1
Poly-(the N of poly-(methacrylic acid oligomeric ethylene glycol ester-co-Toadpoison Medicine-co-RGD)-g-with endosome escape function of cRGD modification, N-diethyllaminoethyl methacrylate-co-n-BMA) cancer target prodrug, the i.e. preparation of P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA):
(1) preparation of P (OEGMA-co-BSMA-co-BEMA): by BPTPA (33mg0.1mmol), OEGMA (3.0g, 6mmol), BSMA (686mg, 2.5mmol), BEMA (140mg, 0.5mmol) add in glass tubing with AIBN (1.6mg), and add 10mL dioxane, tube sealing after vacuum freeze thawing three times.Afterwards, 70 DEG C are reacted 5 hours.Reaction gained crude product is dialysed and is removed impurity in 24 hours in water, after lyophilization, obtains described P (OEGMA-co-BSMA-co-BEMA).The molecular weight M of gained P (OEGMA-co-BSMA-co-BEMA) is measured through GPC
n=30,300, molecular weight distribution M
w/ M
n=1.07.
(2) preparation of P (OEGMA-co-BSMA)-g-P (DEA-co-BMA): by P (OEGMA-co-BSMA-co-BEMA) (606mg, 74 μm of olBr), DEA (822mg, 4.44mmol), BMA (420mg, 2.96mmol) with PMDETA (13mg, 74 μm of ol) add in glass tubing, and add 10mLDMF, CuBr (11mg is added after vacuum freeze thawing three times, 74 μm of ol), vacuum freeze thawing twice, then tube sealing again.Afterwards, 60 DEG C are reacted 3 hours.Reaction gained crude product crosses silicagel column removing mantoquita, concentrated, and 48 hours removing impurity of then dialysing in water, after lyophilization, obtains described P (OEGMA-co-BSMA)-g-P (DEA-co-BMA).The molecular weight M of gained P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is measured through GPC
n=70,900, molecular weight distribution M
w/ M
n=1.22, its nucleus magnetic hydrogen spectrum as shown in Figure 2.
(3) preparation of P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA):
By P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) (709mg, 259 μm of olCOOH), NHS-OH (1.7mg, 15 μm of ol), BUF (70mg, 181 μm of ol), DCC (53mg, 259 μm of ol) and DMAP (3mg) to be dissolved in dichloromethane stirring at room temperature 48 hours.Then add cRGD (3.7mg, 6 μm of ol) and continue reaction 24 hours.Reaction gained is crude product purified: 24 hours removing impurity of dialysing in water, after lyophilization, and obtained target product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).The molecular weight M of gained P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is measured through GPC
n=77,500, molecular weight distribution M
w/ M
n=1.21, its nucleus magnetic hydrogen spectrum as shown in Figure 3.
Embodiment 2
The preparation of P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) nanoparticle solution:
Getting 10mgP (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is dissolved in 1mLDMSO, solution is instilled in the water that 9mL stirreds, (molecular cut off is 7 afterwards solution to be loaded bag filter, dialysis 24 hours 000Da), removing organic solvent, obtains nanoparticle solution.Its particle diameter is about 148.4nm (± 0.65) (see Fig. 4), electromotive force-7.6mV (± 0.37).Cytotoxicity experiment shows, it is obviously better than free Toadpoison Medicine medicine to the fragmentation effect of multiple cancerous cell.As shown in Figure 5, targeted nano medicine is to the fragmentation effect of colorectal cancer cell lines LoVo, and its IC50 is far below the IC50 of free Toadpoison Medicine.
Be described in detail specific embodiments of the invention above, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, equalization conversion done without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.
Claims (26)
1. have a cancer target prodrug for endosome escape function, it is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).
2. a preparation method with the cancer target prodrug of endosome escape function according to claim 1, comprises the following steps:
(1) intermediate product P (OEGMA-co-BSMA-co-BEMA) is prepared:
By a certain amount of RAFT initiator B PTPA, oligomeric ethylene glycol methacrylate OEGMA, containing the monomers B SMA of β-thiocarboxyl group, the monomers B EMA containing atom transferred free radical initiator, solvent and radical initiator add in glass tubing, tube sealing after vacuum freeze thawing three times; Afterwards, 0.5-40 hour is reacted under 20-80 DEG C of condition, obtain crude product P (OEGMA-co-BSMA-co-BEMA), finally this crude product P (OEGMA-co-BSMA-co-BEMA) purification process is obtained described P (OEGMA-co-BSMA-co-BEMA);
(2) intermediate product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA-co-BEMA), DEA, BMA, solvent and mantoquita part are added in glass tubing, after vacuum freeze thawing three times, adds mantoquita, then vacuum freeze thawing twice, then tube sealing; Afterwards, under 20-80 DEG C of condition, react 0.5-20 hour, obtain crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA); Finally this crude product P (OEGMA-co-BSMA)-g-P (DEA-co-BMA) is crossed silicagel column removing mantoquita, concentrated, more purifiedly process to obtain described P (OEGMA-co-BSMA)-g-P (DEA-co-BMA);
(3) target product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is prepared:
A certain amount of P (OEGMA-co-BSMA)-g-P (DEA-co-BMA), NHS-OH, BUF, condensing agent and catalyst are dissolved in stirring at room temperature 3-72 hour in organic solvent; Then, add a certain amount of cRGD and continue reaction 1-48 hour, obtain crude product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA); Finally this crude product P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) purification process is obtained described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).
3. the preparation method with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, described purification process is: dialyse in water, then lyophilization.
4. the preparation method with the cancer target prodrug of endosome escape function according to claim 2, is characterized in that, the molecular weight of the described OEGMA in described step (1) is 100-50000.
5. the preparation method with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, the described solvent in described step (1) be selected from DMF, DMSO, NMP, isopropyl alcohol, methanol, ethanol, dioxane and oxolane one or more.
6. the preparation method with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, the described radical initiator in described step (1) be selected from cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl hydroperoxide, azodiisobutyronitrile, 2,2'-Azobis(2,4-dimethylvaleronitrile) one or more.
7. the preparation method with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, the described initiator B PTPA:OEGMA:BSMA:BEMA in described step (1): the mol ratio of radical initiator is 1:10-200:0.5-200:0.5-200:0.01-1.
8. the preparation method with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, the described solvent in described step (2) be selected from DMF, DMSO, NMP, isopropyl alcohol, methanol, ethanol and oxolane one or more.
9. the preparation method with the cancer target prodrug of endosome escape function according to claim 2, is characterized in that, the described mantoquita part in described step (2) is selected from bipyridyl, PMDETA and Me
6one or more in TREN.
10. the preparation method with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, the described mantoquita in described step (2) be selected from cuprous bromide, Cu-lyt., copper bromide and copper chloride one or more.
11. preparation methoies with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, the BEMA:DEA:BMA in the described P (OEGMA-co-BSMA-co-BEMA) in described step (2): mantoquita: the mol ratio of mantoquita part is 1:10-500:10-500:0.1-10:0.1-10.
12. preparation methoies with the cancer target prodrug of endosome escape function according to claim 2, is characterized in that, the described condensing agent in described step (3) be selected from DCC, EDC, DIC one or more.
13. preparation methoies with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, the described catalyst in described step (3) be selected from pyridine, dimethylamino naphthyridine, triethylamine and hydroxy benzo triazole one or more.
14. preparation methoies with the cancer target prodrug of endosome escape function according to claim 2, it is characterized in that, the mol ratio of in described P (the OEGMA-co-BSMA)-g-P (DEA-co-BMA) in described step (3) BSMA:NHS-OH:BUF: condensing agent: catalyst: cRGD is 1:0.01-0.1:0.1-0.99:1-10:0.01-0.5:0.01-0.1.
15. 1 kinds of nanometer formulations with the cancer target prodrug of endosome escape function according to claim 1, it is characterized in that, the particle diameter of nanoparticle is wherein 10 ~ 2000nm, and the described targeted prodrug comprised is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA).
16. nanometer formulations according to claim 15, it is characterized in that, described nanometer formulation is nanoparticle solution, wherein, the concentration of described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is 0.001-30g/L, described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA) is after human body metabolism, and the molar concentration of the active medicine BUF of release is 0.001-10000 μm of ol/L.
The preparation method of 17. 1 kinds of nanoparticle solution according to claim 16, is characterized in that, is selected from the one in following methods: multi-emulsion method, membrane emulsification method, emulsifying evaporation, interphase precipitate method, self-assembly method.
The preparation method of 18. nanoparticle solution according to claim 17, it is characterized in that, described preparation method is multi-emulsion method, comprise step: be dissolved in the mixed solvent of dichloromethane or dichloromethane and acetone by described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA), ultrasonic emulsification, then join in water dispersion medium, ultrasonic emulsification again, then stirred at ambient temperature 0.5-5 hour, removing organic facies, obtains nanoparticle solution.
The preparation method of 19. nanoparticle solution according to claim 17, it is characterized in that, described preparation method is membrane emulsification method, comprise step: be dissolved in acetone by described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA), rotary evaporation film forming, add aqueous solution subsequently, stirred at ambient temperature 0.5-6 hour, obtain nanoparticle solution.
The preparation method of 20. nanoparticle solution according to claim 17, it is characterized in that, described preparation method is emulsifying evaporation, comprise step: be dissolved in the mixed solvent of acetone/dichloromethane by described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA), join in water dispersion medium, carry out the ultrasonic or newborn even emulsifying of high pressure, gained emulsion at room temperature stirs 2-4 hour, wave most organic solvent, obtain nanoparticle solution.
The preparation method of 21. nanoparticle solution according to claim 17, it is characterized in that, described preparation method is interphase precipitate method, comprise step: be dissolved in acetone by described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA), under constant agitation, be injected in water dispersion medium by gained acetone soln, acetone is removed in pressurization volatilization, obtains nanoparticle solution.
The preparation method of 22. nanoparticle solution according to claim 17, it is characterized in that, described preparation method is self-assembly method, comprise step: be dissolved in DMSO by described P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA), by in a certain amount of water that stirred of gained solution instillation, afterwards solution is loaded in bag filter the 3-72 hour that dialyses, removing organic solvent, obtains nanoparticle solution.
The preparation method of 23. nanoparticle solution according to any one of claim 18,20,21, it is characterized in that, described water dispersion medium be selected from dextrose former times 40-70, pluronicF68 or polyvinyl alcohol (PVA) one or more, and the quality concentration expressed in percentage by volume of described water dispersion medium is 0.01-10%.
24. according to the preparation method of the nanoparticle solution described in claim 18 or 20, and it is characterized in that, described ultrasonic intensity is 10-1000W.
The preparation method of 25. nanoparticle solution according to claim 22, is characterized in that, the scope of the molecular cut off of described bag filter is 1000-10000Da.
26. nanometer formulations according to claim 15, it is characterized in that, described nanometer formulation is nanometer lyophilized preparation, wherein, lyophilizing caffolding agent is selected from trehalose, glucose, lactose, decoct in sugar, dextran, sorbitol, mannitol and Polyethylene Glycol one or more, and the mass percentage concentration of described lyophilizing caffolding agent is 0.01-20%.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2551979A (en) * | 2016-06-30 | 2018-01-10 | Rs Arastirma Egitim Danismanlik Llac Sanayi Ticaret Ltd | Cleavable polymer drug conjugates |
| CN107236100A (en) * | 2017-06-21 | 2017-10-10 | 西南大学 | A kind of linear diblock of pH stimulating responsives polymerize the preparation method of prodrug |
| CN107236100B (en) * | 2017-06-21 | 2019-03-29 | 西南大学 | A kind of preparation method of the linear diblock polymerization prodrug of pH stimulating responsive |
| CN111484840A (en) * | 2020-04-24 | 2020-08-04 | 四川大学 | Conjugated c (RGDFC) sulfur-nitrogen double-doped graphene quantum dot and preparation method and application thereof |
| CN111484840B (en) * | 2020-04-24 | 2022-04-19 | 四川大学 | Conjugated c (RGDFC) sulfur-nitrogen double-doped graphene quantum dot and preparation method and application thereof |
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