CN107349188A - The preparation method of the sensitive intelligent nano-medicament carriers of pH - Google Patents

The preparation method of the sensitive intelligent nano-medicament carriers of pH Download PDF

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Publication number
CN107349188A
CN107349188A CN201710558756.1A CN201710558756A CN107349188A CN 107349188 A CN107349188 A CN 107349188A CN 201710558756 A CN201710558756 A CN 201710558756A CN 107349188 A CN107349188 A CN 107349188A
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preparation
carrier
tpgs
nano
phis
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CN201710558756.1A
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潘杰
李具恒
李佩娇
雷帅权
张宝月
万冬
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Tianjin Polytechnic University
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Tianjin Polytechnic University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/40—Polyamides containing oxygen in the form of ether groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/42—Polyamides containing atoms other than carbon, hydrogen, oxygen, and nitrogen

Abstract

The invention mainly relates to tumor research and the polymeric material field for the treatment of, the specifically preparation method on a kind of sensitive intelligent nano-medicament carriers of triblock polymer pH based on polyhistidyl change of configuration.Prepare the intelligent pH sensitivities nano-carrier TPGS for carrying Docetaxel3350‑PHis‑Folate.Polyethylene glycol is introduced in carrier canopy, realizes macrocyclic function in blood in vivo；PH sensitive materials poly- (L histidines) are introduced into nano-carrier structure, carrier is realized intelligent change under different pH：I.e. under normal physiological pH, targeted molecular folic acid, in carrier polyethylene glycol canopy, closes carrier active targeting function by hidden；And protonated in weak acid tumor tissues, poly- (L histidines), its water solubility becomes strong, and the hidden targeted molecular folic acid under polyethylene glycol canopy upholds out, and is opened exposed to the outermost end of carrier, its active targeting function；Carrier easily enters cell with folacin receptor mediated endocytic pathway again；Under acid endosome/lysosome environment, poly- (L histidines) starts gradually dissociation, makes medicine in intracellular quick release.

Description

The preparation method of the sensitive intelligent nano-medicament carriers of pH
Technical field
The invention mainly relates to tumor research and the polymeric material field for the treatment of, specifically on one kind based on poly- group ammonia The preparation method of the sensitive intelligent nano-medicament carriers of the triblock polymer pH of sour change of configuration.
Background technology
Nanometer technology achieves huge progress in the application of field of cancer treatment in recent years, such as by that will embed, inhale It is attached, be encapsulated or the mode of covalent bonding is combined chemotherapeutics with nano-carrier, medicament-carried nano system is prepared, with raising Treat the water solubility of medicine, stability, medicine anticancer effect and reduce the toxic side effect of its normal tissue and organ.Simultaneously Realize long circulating in medicament-carried nano carrier active targeting selectivity, internal blood and easily enter tumour cell, and in the cell The quick release of medicine is difficult, and this also has become the hot fields of nanometer medical research.
Docetaxel is a kind of new type antineoplastic medicine, passes through interference cell mitosis and inerphosei cells function Necessary microtubular network and rise antitumor action.Due to docetaxel poorly water-soluble, presently commercially available injection docetaxel (40g·L-1) it is that solubilizer is made using Tween-80, while be furnished with and make dilution containing 13% ethanol, but Tween 80 has haemolysis Property and stickiness is big, can produce obvious allergic reaction after injection.Most antineoplastics are treated to polytype recurrent tumor Perform poor, obvious multi-drug resistance phenomenon is presented.The generation of tumor multi-medicine drug-resistant is mainly due to tumour cell abc transport egg The overexpression (especially P- glycoprotein) of white family so that antineoplastic is arranged outside cells of resistant tumors, reduces tumour Intracellular drug concentration, cause clinical therapeutic efficacy bad.
TPGS full name polyethylene glycol 1000 vitamin E succinic acid esters, its hydrophilic and oleophilic value is 13, has higher emulsification Effect, low toxicity and the advantages that be readily cleaned.Further, TPGS can also improve entrapment efficiency, suppress P- glycoprotein and be situated between The advantages that tumor multi-medicine drug-resistant led, TPGS3350It is the polymer that polyethylene glycol is 3350, the carrier after modification advantageously reduces By the non-specific uptake of cell, effectively extend carrier circulation time in blood in vivo.
Folic acid is a kind of B family vitamin necessary to human body.For example oophoroma, breast cancer etc. can to folic acid for many tumour cells To there is very strong absorbability, the cell membrane surface of these tumours has a kind of special protein overexpression, this albumen Matter can be identified specifically, with reference to folic acid, so being referred to as folacin receptor.Folacin receptor is a kind of glycoprotein receptor on cell membrane, An and useful antineoplastic transmission targeting.Folic acid has the compatibility of height to folacin receptor, so, this can be utilized Targeting ligand of one characteristic using folic acid as antineoplastic, using folacin receptor in the overexpression of some tumor locus and The characteristic of normal structure low expression level realizes the targeting conveying of folacin coupled medicine, and the macromolecular carrier being coupled is advantageous to prolong Long internal retention time, improves curative effect.
Polyhistidyl is a kind of cationic acid-sensitive polymer containing proton donor group.Can be by active medicine Thing is embedded therein, takes on load medicine body.Intracellular pH is 7.0~7.5, and the pH of endosome is generally 5.0~6.0, lysosome PH 4.0~5.0, these sour environments of intra-tumor can be used as targeting signal, and pH is higher than proton donor under normal physiological During the pKa value of group, proton donor-based regiment headquarters point is not charged, is advantageous to nano-carrier and is formed；It is and small in acid tumor organization pH When its pKa value, proton donor group starts to protonate, and its electric charge is changed into positive, is easy to medicament-carried nano carrier to enter cell.Can Contained antineoplastic is released in tumor tissues, reduces distribution of the antineoplastic in normal structure, increases medicine In the distribution of normal structure, toxic side effect, the purpose of raising activity are reduced so as to reach.
The sensitive intelligent nano-medicament carriers of pH of the present invention have active targeting, internal long circulating and easily enter tumour simultaneously Cell, and the function of Intracellular drug quick release, new thinking is provided for the treatment of cancer, this, which also has become, receives The hot fields of rice medical research.
The content of the invention
The present invention is a kind of while has active targeting, internal long circulating and easily enter tumour cell, and intracellular medicine The sensitive intelligent nano-medicament carriers of the pH of the function of thing quick release, facility is provided for oncotherapy.It is new by synthesizing Amphipathic pH sensitivities copolymer TPGS3350- PHis-Folate, in conjunction with PLA-mPEG2000Copolymer passes through solvent evaporation method system It is standby to go out to be loaded with the PLA-mPEG of anticarcinogen Docetaxel2000/TPGS3350- PHis-Folate intelligent pH sensitivities nanometer carries Body.Under normal physiological pH, PLA-mPEG2000/TPGS3350PEG forms the canopy of carrier in-PHis-Folate nano-carriers, Effectively extend carrier circulation time in blood, and now poly- (L-Histidine) (dissociation constant pKa 6.5) and PLA- in vivo mPEG2000/TPGS3350- PHis-Folate hydrophobic side composition nano-carrier hydrophobic inner core, by targeted molecular folic acid it is hidden PLA-mPEG2000Hold PEG2000Canopy, close nano-carrier active targeting function；In the weak acid of tumor tissues (pH is less than 7.0) Under the conditions of, poly- (L-Histidine) protonates, and is changed into positive charge, and now water-soluble also becomes strong, it is at this moment hidden PEG2000Targeted molecular folic acid under canopy is upheld out and beaten exposed to the outermost end of nano-carrier, carrier active targeting function Open；Carrier easily enters cell with folacin receptor mediated endocytic pathway again；In acid endosome/lysosome (pH ＜ 6.5) environment Under, poly- (L-Histidine) starts gradually dissociation, is advantageous to medicine in intracellular quick release.The nano-carrier will have active target To, internal long circulating and cell, and intracellular medicine quick release multi-functional are easily entered, significantly improves Taxotere alcoholization The anticancer effect for the treatment of, reduce its toxic side effect.
To solve above technical problem, the technical scheme that the present invention takes is as follows：Novel amphiphilic pH sensitivity copolymers TPGS3350- PHis-Folate preparation method, including synthetic reaction, crystallization, purification, drying；Carry DTX PLA-mPFG2000/ TPGS3350The preparation of-PHis-Folate intelligent pH sensitivities nano-carrier, including additional proportion, dissolution solvent, emulsifying agent, The volatilization of solvent, cleaning, the freeze-drying of medicine.
In the present invention, TPGS is characterized with HNMR, GPC, FTIR etc.3350- PHis-Folate the structure of matter and relative Molecular mass etc., it was demonstrated that material has synthesized.In the present invention, the surface for carrying drug carrier is characterized with thermal field surface sweeping Electronic Speculum FESEEM Pattern, it can be seen that carry the nano particle that drug carrier is approximate spheres.In the present invention, the load of carrier is surveyed with high performance liquid chromatography Dose.In the present invention, it is PLA-mPEG to make A by anticarcinogen DTX and carrier same ratio2000Nano-carrier；B is PLA- mPEG2000/TPGS3350- Folate nano-carriers；C is PLA-mPEG2000/TPGS3350The intelligent pH of-PHis-Folate are sensitive Nano-carrier.A is surveyed at pH 5.0,6.5,7.4, the insoluble drug release of tri- kinds of nano-carriers of B, C, shows PLA-mPEG2000/ TPGS3350The intelligent pH sensitive medicament-carried nanometers carrier quick releases under the conditions of sour environment of-PHis-Folate.In the present invention In, carry out qualitatively and quantitatively analysis of fluorescence mark with confocal laser scanning microscope, CLSM and ELIASA under condition of different pH Nano-carrier is to human breast cancer cell line Bcap-37 active targeting and into ability, and the cell toxicant with CCK-8 method Study of Support Property, indicate the premium properties of intelligent carrier.
Brief description of the drawings
Fig. 1 .TPGS3350- PHis-Folate reaction structure schematic diagrames；
Fig. 2 .TPGS3350- PHis-Folate nuclear-magnetism phenograms；
Fig. 3 .TPGS3350- PHis-Folate IR Characterization figures；
Fig. 4 .TPGS3350- PHis-Folate GPC gel permeation chromatography figures；
Fig. 5 carry the preparation of the intelligent nano-carrier of Docetaxel and its structure change schematic diagram under different pH；
Fig. 6 carry the intelligent nano carrier surface sweeping Electronic Speculum pattern schematic diagram of Docetaxel；
Insoluble drug release of the nano-carrier of tri- kinds of load Docetaxels of Fig. 7 under different pH；
The nano-carrier of Fig. 8 load Docetaxels cytotoxicity figure under different pH；
The nano-carrier of Fig. 9 load Docetaxels cell imaging figure (A PLA-mPEG under different pH2000Nanometer carries Body；B is PLA-mPEG2000/TPGS3350- Folate nano-carriers；C is PLA-mPEG2000/TPGS3350- PHis-Folate receives Meter Zai Ti)；
Embodiment
With reference to example, the invention will be further described：
Embodiment 1
Histidine acid anhydrides Nim- DNP-L-histidine (NCA) preparation：
1) N is weigheda-CBZ-Nim- DNP-L-histidine (1mmol) is dissolved in tetrahydrofuran (10ml), is placed in round bottom burning Bottle, dissolving；
2) measure thionyl chloride (3mmol) and pour into above-mentioned round-bottomed flask, 25 DEG C are passed through nitrogen reaction 1h, and reaction eventually becomes Settled solution；
3) settled solution for handling step 2) well is added in absolute ether (80ml), produces yellow mercury oxide；
4) solution for obtaining step 3) filters, and collects yellow mercury oxide；
5) again with absolute ether washing step 4) obtained yellow mercury oxide；
6) obtained precipitation is placed in vacuum drying box and dried, it is standby；
Embodiment 2
TPGS3350-NH2Preparation：
1) D- alpha-tocofecol succinic acids ester, double amino-polyethyleneglycols, n-hydroxysuccinimide and N, the N hexamethylene of '-two are weighed Base carbodiimide (mol ratio 1: 1.2: 2: 2) is dissolved in dichloromethane, is added triethylamine, is placed in three-necked flask, is passed through nitrogen Gas, react two days at room temperature；
2) the completely reacted solution of step 1 is filtered, removes byproduct of reaction, solution is added in absolute ether, obtained White precipitate；
3) product for obtaining step 2) centrifuges, and outwells liquid, collects white precipitate；
4) white precipitate for obtaining step 3) is transferred into bag filter, and dialysis removes unreacted material；
5) sample for handling step 4) well is freeze-dried, and obtains TPGS3350-NH2White powder；
Embodiment 3
Use TPGS3350-NH2Triggering its step of NCA ring-opening polymerisations is：
1) TPGS is weighed3350-NH2(0.2mmol) and NCA (4mmol) are dissolved in DMF (15ml), room Nitrogen is passed through under temperature to react 3 days, triggers NCA ring-opening polymerisations；
2) solution for handling step 1) well is added in absolute ether (100ml), obtains yellow mercury oxide；
3) product for obtaining step 2) centrifuges, and outwells liquid, collects yellow mercury oxide；
4) yellow mercury oxide for obtaining step 3) is dissolved in dimethyl sulfoxide (DMSO) 1ml, is added dropwise in deionized water (25ml)；
5) sample for handling step 4) well is transferred into bag filter, removes organic solvent and unreacted material；
6) sample for handling step 5) well is freeze-dried, and obtains TPGS3350-PHis；
Embodiment 4
Use TPGS3350- PHis and folic acid react, then are deprotected with mercaptoethanol to obtain final products TPGS3350-Phis- Folate,
1) weigh folic acid (0.2mmol), n-hydroxysuccinimide, N, N '-dicyclohexylcarbodiimide (mol ratio 1: 2: 1.2) be dissolved in dimethyl sulfoxide (DMSO) (10ml), be placed in round-bottomed flask, lucifuge reacts 6h at 50 DEG C；
2) solution for handling step 1) well filters, and removes byproduct of reaction, standby；
3) TPGS is weighed3350- Phis is added in the solution of step 2, at room temperature stirring reaction 24h；
4) sample obtained to step 3) reaction is transferred into bag filter, removes organic solvent and unreacted material；
5) sample for handling step 4) well is freeze-dried, and obtains yellow powder；
6) yellow powder (0.5g) obtained step 5) is dissolved in DMF (20ml), adds sulfydryl second Alcohol (6ml), reaction 24h deprotection；
7) the completely reacted solution of step 6) is added in absolute ether, separates out precipitation, washed again with ether after centrifugation Precipitation；
8) precipitation for handling step 7) well is transferred into bag filter, removes organic solvent and unreacted material；
9) sample for handling step 8) well is freeze-dried, and obtains TPGS3350-PHis-Folate；
Embodiment 5
1) 10mg DTX, 20mg TPGS are weighed3350- PHis-Folate, 80mg PLA-TPGS, dissolved with 10ml DCM；
2) weigh 300mg polyvinyl alcohol and add the PVA solution that 60ml distilled water stirring and dissolving forms 0.5%w/v；
3) the DCM solution in 1) is poured into PVA solution 2)；
4) the cell pulverization instrument ultrasonic emulsion breaking 120s for being 25W with power output；
5) Rotary Evaporators volatile organic solvent 1h is used；
6) resulting solution is centrifuged into 15min in 10000r/min centrifuge；Supernatant is outwelled, it is rear to add distillation moisture Under equal conditions centrifuge washing again after scattering, repeated washing 3 times；
7) sample finally obtained is freeze-dried, obtains medicament-carried nano carrier.

Claims (11)

1. one kind has active targeting, internal long circulating and easily enters cell, and intracellular medicine quick release multi-functional The sensitive intelligent nano-medicament carriers of pH preparation,
Comprise the following steps：Novel amphiphilic pH sensitivity copolymers TPGS3350- PHis-Folate preparation method, including synthesis Reaction, crystallization, purification, drying；Carry DTX PLA-mPEG2000/TPGS3350- PHis-Folate intelligent pH sensitivities nanometer carries The preparation of body, including additional proportion, dissolution solvent, emulsifying agent, the volatilization of solvent, cleaning, the freeze-drying of medicine.
2. preparation method according to claim 1, synthesis histidine acid anhydrides NCA is characterized in that：By 1mmol histidine lists Body DNP is dissolved in 10ml anhydrous tetrahydro furans, then adds excessive 3mmol thionyl chlorides, precipitate, filter through excess diethyl ether, It is recrystallized to give product.
3. preparation method according to claim 1, synthesize TPGS3350-NH2When be characterized in that：D- alpha-tocofecol succinic acids Ester, double amino-polyethyleneglycols, n-hydroxysuccinimide and N, N '-dicyclohexylcarbodiimide mol ratio be 1: 1.2: 2: 2.
4. preparation method according to claim 1, ring-opening polymerization is characterized in that：TPGS3350-NH2With rubbing for NCA You are than being 1: 20.
5. preparation method according to claim 1, it is characterized in that when introducing folic acid：After folic acid is activated at 50 DEG C Again with TPGS3350- PHis reacts.
6. preparation method according to claim 1, obtain final product TPGS3350- PHis-Folate is characterized in that： Material containing pH non-sensitive parts is finally deprotected with mercaptoethanol, adds crystallizing from ether, washing, dialysis.
7. preparation method according to claim 1, obtain the drug-carrying nanometer particle period of the day from 11 p.m. to 1 a.m and be characterized in that：Anticarcinogen DTX is added, TPGS3350- PHis-Folate and PLA-mPEG2000Ratio be 1: 2: 8.
8. preparation method according to claim 1, obtain the drug-carrying nanometer particle period of the day from 11 p.m. to 1 a.m and be characterized in that：Obtained with solvent evaporation method The nano particle diameter arrived is uniform, good dispersion.
9. preparation method according to claim 1, it is characterised in that：Organic solvent DCM is removed with rotary evaporation, during saving Between, volatilization is thorough.
10. preparation method according to claim 1, obtain the drug-carrying nanometer particle period of the day from 11 p.m. to 1 a.m and be characterized in that：Use redistilled water Cleaning three times, removes surfactant and free medicine, centrifugal rotational speed 10000r/min, each centrifugation time 15min.
11. preparation method according to claim 1, obtain the drug-carrying nanometer particle period of the day from 11 p.m. to 1 a.m and be characterized in that：With freeze-drying water Final nano-particle is obtained, solubility is good, without ethanol or Tween 80 solubilising.
CN201710558756.1A 2017-07-06 2017-07-06 The preparation method of the sensitive intelligent nano-medicament carriers of pH Pending CN107349188A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Application publication date: 20171117