CN101632834A - Magnetic nano-carrier with targeted hydrophobic drug delivery to tumor and preparation method thereof - Google Patents

Magnetic nano-carrier with targeted hydrophobic drug delivery to tumor and preparation method thereof Download PDF

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CN101632834A
CN101632834A CN200910067365A CN200910067365A CN101632834A CN 101632834 A CN101632834 A CN 101632834A CN 200910067365 A CN200910067365 A CN 200910067365A CN 200910067365 A CN200910067365 A CN 200910067365A CN 101632834 A CN101632834 A CN 101632834A
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carrier
lactide
bimol
hydroxy
acetic acid
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徐力
郭轶
丁国斌
吕言云
张学忠
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Jilin University
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Jilin University
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Abstract

The invention belongs to the technical field of biomedical polymer material and nanobiomaterial, particularly relates to a magnetic nano-carrier with targeted hydrophobic drug delivery to tumor and a preparation method thereof. The magnetic nano-carrier is formed by encapsulating superparamagnetic nano-particles with amphiphilic segmented copolymer methoxy polye thylene glycol-poly(lactide- glycolide) (MePEG-PLGA) micelles. First, a large amount of MePEG-PLGA with good dispersion is synthesized by the improved solution polymerization process, and then the MePEG-PLGA is used as raw materials to encapsulate Fe3O4 nano-particles by the solvent evaporation process to obtain a magnetic nano drug carrier. The carrier is expected to solve the solubility problem of insoluble drugs, achieves slow release of drugs, and achieves the passive-targeting of the drugs by the EPR effect of tumor; Fe3O4 nano-particles are used in the active-targeting of the drugs to reduce the dosage and the side effect and improve the treatment efficiency; besides, the carrier can be used in the magnetic resonance imaging (MRI) of tumor.

Description

Magnetic nano-carrier that the dewatering medicament cancer target transmits and preparation method thereof
Technical field
The invention belongs to biological medical polymer material and nanometer biotechnology field, be specifically related to magnetic nano-carrier of a kind of hydrophobic drug cancer target transmission and preparation method thereof.
Background technology
Cancer remains one of the most terrified disease, is human life's main threat.American cancer be 85 years old with following people's main causes of death, surpassing heart disease first becomes No.1 killer.This alarming statistical data is not because the incidence rate of cancer has improved, but because the death that heart disease causes descended near half and the dead quantity relevant with cancer almost remains unchanged.The traditional standard therapy of most of cancers---chemotherapy in addition behind 50 years of researches still always the success, selectively do not transmit the toxicity cancer therapy drug to tumor and normal organ and tissue because traditional chemotherapy has, therefore can produce serious toxic and side effects normal organ and tissue.
Low aqueous solubility is the inwardness of many medicines and anticarcinogen, especially because manyly in them belong to big polycyclic compound.The clinical treatment of the medicine of hydrophobicity, poorly water-soluble is used and is had many serious problems, and absorption difference during as oral administration, bioavailability is low, blood halflife is short; During intravenously administrable not the aggregation that forms of soluble drug can cause blood vessel embolism, cause the serious side effects of respiratory system; The formation of drug aggregates can also cause the local drug concentration in drug deposition site too high, causes local toxicity and low systemic bioavailability.The medicine of poorly water-soluble has so serious problem, causes some main pharmaceutical factories to get rid of the chemical compound of poorly water-soluble very early in the drug screening process.According to estimates, 40% the drug candidate of identifying by high flux screening fails to enter the formulation development stage because water solublity of their differences is dropped.
Amphiphatic block copolymer can be self-assembled into the polymer micelle of core-shell type structure in aqueous solution, hydrophilic block forms shell, and hydrophobic block forms kernel.In recent years, polymer micelle has caused extensive concern as a kind of novel medicament nano-carrier, because it can improve the pharmacokinetics of medicine greatly, improves therapeutic efficiency.The core-shell type structure of polymer micelle has significant advantage for drug delivery applications: the first, and hydrophobic drug is wrapped in the micelle nuclear, has realized the solubilization of water-insoluble drug; The second, the blood halflife that polymer micelle can prolong drug because PEG has prevented opsonic action, has reduced micelle effectively by the absorption of reticuloendothelial system (RES); The 3rd, (10～100nm) make them be suitable for enhancing permeability and reservation (enhancedpermeability and retention, EPR) effect of injecting and being caused by tumor tissues vascular system seepage to their little sizes.Most of tumors have the pathophysiology feature of normal structure or the unexistent uniqueness of organ, cause high vascular system, defective vascular structure, impaired lymph discharge/recovery system and a large amount of generations of many vascular permeability factors as a large amount of blood vessels.This phenomenon is called lipid and macromolecular enhancing permeability and reservation (enhanced permeability and retention, EPR) effect, ubiquity in solid tumor.The EPR effect of solid tumor is one of distinctive a few feature of tumor, is just becoming the goldstandard (gold standard) that antitumor drug transmits.
Magnetic ferric oxide nano particles (γ-Fe 2O 3, Fe 3O 4) all have a wide range of applications at magnetic separation, VHD magnetic recording media, catalysis and biomedical sector.Especially at biomedical sector, magnetic ferric oxide nano particles all is widely used with external in vivo, and the interior application of body mainly concentrates on the magnetic fluid of drug targeting transmission, cell marking, spike and imaging (MRI) detection, tumor and crosses thermal therapeutical; And external application mainly concentrates on virus, oligonucleotide, DNA and proteinic super sensitivity detection and separates.
The relevant report of at present existing number of polymers micelle packaging medicine, but utilize polymer micelle simultaneously coated magnetic ferric oxide nano particles and medicine report seldom, yet there are no the relevant report of utilizing block copolymer MePEG-PLGA formed polymer micelle coated magnetic ferric oxide nano particles and medicine.
Summary of the invention
The objective of the invention is to make up a kind of magnetic nano-carrier of hydrophobic drug cancer target transmission and preparation method of this carrier of being used for.
Of the present invention is a kind of magnetic nano-carrier that the dewatering medicament cancer target transmits that is used for, by amphiphilic block copolymer micelle parcel superparamagnetism Fe 3O 4Nanoparticle is formed, and amphiphilic block copolymer has the core-shell type structure, and it is spontaneous formation polymer micelle in aqueous solution, and hydrophilic block forms the micelle shell, and hydrophobic block forms micelle kernel, Fe 3O 4Nanoparticle is loaded in the micelle kernel, is used for the magnetic targeted delivery of medicine, is used for nuclear magnetic resonance (MRI) in the body simultaneously, Fe in the gained magnetic nano-carrier 3O 4The mass content of nanoparticle is 5～20%.
Foregoing amphiphilic block copolymer be methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) (MePEG-PLGA), number-average molecular weight is 8～30kD, wherein hydrophilic block is methoxy poly (ethylene glycol) (MePEG), has biocompatibility, and number-average molecular weight is 2～5kD; Hydrophobic block is for gathering (lactide-Acetic acid, hydroxy-, bimol. cyclic ester) (PLGA), and biodegradable, number-average molecular weight is 3～28kD, DL lactide (D, L-Lactide is abbreviated as LA) with Acetic acid, hydroxy-, bimol. cyclic ester (Glycolide is abbreviated as GA) mol ratio be 1～4: 1 (LA: GA=1～4: 1).The usage ratio of methoxy poly (ethylene glycol) and lactide, Acetic acid, hydroxy-, bimol. cyclic ester is: methoxy poly (ethylene glycol): lactide: Acetic acid, hydroxy-, bimol. cyclic ester=1～2: 1～4: 1.
The magnetic nano drug that is used for the transmission of hydrophobic drug cancer target that the present invention is constructed mainly contains following advantage:
(1) amphiphilic block copolymer methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) mainly is synthetic by mass polymerization at present (MePEG-PLGA), the reaction temperature height, and the heat radiation difficulty, the gained polymer molecular weight distributes wide; We adopt improved solution polymerization process to synthesize this copolymer, low and the easy control of reaction temperature, initiator and monomer are uniformly dispersed, gained polymer molecular weight narrowly distributing, utilized four kinds of different organic solvent deposit agent---methanol, normal hexane, normal hexane/absolute ether (V/V=4: 1) or absolute ether come the precipitation polymerization product, product polydispersity (PDI) is all below 1.4;
(2) magnetic nano-carrier of the present invention's preparation is mainly used in the transmission of hydrophobic drug, hydrophobic drug can be wrapped in the hydrophobic inner core of polymer micelle, be expected to solve the solubility problem of hydrophobic drug, and because the hydrophobic inner core of pharmaceutical carrier is biodegradable, can realize the slow release of medicine, reduce the drug use amount thereby reduce administration number of times;
(3) magnetic nano-carrier provided by the present invention is of a size of 20～100nm, can make medicine tumor tissues enrichment and long-time the stop by the EPR effect of tumor tissues, realize the passive target transmission of medicine, improve bioavailability of medicament, reduce the injury of medicine normal structure;
(4) loaded the superparamagnetism Fe of cluster in the magnetic nano-carrier provided by the invention 3O 4Therefore nanoparticle can be realized the magnetic targeted delivery of medicine reducing the toxic and side effects of medicine to normal structure, simultaneously because superparamagnetism Fe 3O 4Nanoparticle is the negativity contrast agent of nuclear magnetic resonance, can be used for the nuclear magnetic resonance (MRI) of in-vivo tumour tissue.
The construction method that is used for the magnetic nano drug of hydrophobic drug cancer target transmission set forth in the present invention may further comprise the steps:
1. hydrophobicity superparamagnetism Fe 3O 4Synthesizing of nanoparticle, reference literature J.Am.Chem.Soc.2004,126, the described high-temperature decomposition of 273-279 synthesizes the Fe of 5～18nm, highly single dispersion, uniform particle diameter 3O 4Nanoparticle, its pattern such as accompanying drawing 1;
2. amphiphilic block copolymer methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) (MePEG-PLGA) (Mn=8～30kD, the mol ratio of LA and GA is 1～4: 1) synthesizing of micelle pharmaceutical carrier:
Synthesize this block copolymer by improved solution polymerization process, specifically describe and be: at N 2Under the protection, with stannous octoate [Sn (Oct) 2] as catalyst (0.05～0.205mL), methoxy poly (ethylene glycol) (MePEG) is as macromole evocating agent (2～10g), by the DL lactide (D, L-Lactide) (1.25～10g), Acetic acid, hydroxy-, bimol. cyclic ester (Glycolide) (1～2g) at toluene (ring-opening polymerization in 40～60mL) prepares the good MePEG-PLGA block copolymer of polydispersity.Again by four kinds of different organic solvent deposit agent---methanol, normal hexane, normal hexane/absolute ether (V/V=4: 1) or absolute ether precipitate block copolymer, the gained precipitation is dissolved with dichloromethane, sucking filtration, then filtrate is added in 60～80 ℃ of hot water and remove dichloromethane, last vacuum drying, promptly obtain the having Narrow Molecular Weight Distribution MePEG-PLGA block copolymer powder of (PDI is below 1.4);
3. realize that by solvent evaporated method amphiphilic block copolymer MePEG-PLGA micelle is to Fe 3O 4The loading of magnetic nano-particle: with 10～20mg MePEG-PLGA block copolymer and 1.3～2.7mg superparamagnetism Fe 3O 4Nanoparticle is dissolved in 1～2mL oxolane (THF) jointly, gained solution slowly joins in 10～20mL high purity water, ultrasonic, the decompression rotary evaporation is removed residual oxolane, simultaneously with solution concentration to 4～10mL, cross 0.45 μ m, 0.22 μ m filter membrane successively,, can obtain being used for the magnetic nano-carrier that the dewatering medicament cancer target transmits again by lyophilization.
Description of drawings
Fig. 1: by the Fe that the synthetic height list of high-temperature decomposition disperses, uniform particle diameter is about 8nm 3O 4The TEM figure of nanoparticle;
Fig. 2: block copolymer methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) (MePEG-PLGA) nuclear magnetic resonance, NMR of nano-carrier ( 1H NMR) collection of illustrative plates has provided the ownership of each hydrogen atom in the collection of illustrative plates;
Fig. 3: be used for the TEM figure of the magnetic nano-carrier of hydrophobic drug cancer target transmission, embedding figure is with single micellar TEM figure after the 2% Salkowski's solution negative staining.
The specific embodiment
Provide particle diameter below and be about 8nm superparamagnetism Fe 3O 4Nanometer particle process method, amphiphilic block copolymer methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) are (MePEG-PLGA) by the synthetic method of improved solution polymerization process and the specific embodiment that is used for the magnetic nano-carrier construction method of hydrophobic drug cancer target transmission; so that those skilled in the art is understood the present invention better, so nonessential improvement and adjustment that this technical professional is made according to the foregoing invention content also should belong to protection domain of the present invention.
1. particle diameter is about the superparamagnetism Fe of 8nm 3O 4Nanometer particle process method
Embodiment 1:
To high-purity N 2Add ferric acetyl acetonade [Fe (acac) in the there-necked flask of (purity 〉=99.999%, the huge foreign flavour body in Changchun Co., Ltd) protection 3] (1 * 10 -3Mol＜amount of substance 〉, purity 〉=97%, Sigma aldrich company), 1,2-12 dihydroxylic alcohols (5 * 10 -3Mol, purity 〉=90%, Sigma aldrich company), oleic acid (3 * 10 -3Mol, analytical pure, Tianjin recovery fine chemistry industry institute), oleyl amine (3 * 10 -3Mol, purity 〉=70%, Sigma aldrich company) mix benzyl oxide (10mL, purity 99%, Sigma aldrich company), magnetic agitation.Heat 2h under 200 ℃ of conditions of mixture; Stop logical N then 2, under about 300 ℃ of conditions, be heated to 1h again, stop heating, be cooled to room temperature.
Add the 20mL dehydrated alcohol in there-necked flask, the centrifugal 20min of 14000rpm abandons supernatant; In black precipitate, add 25 μ L oleic acid, 25 μ L oleyl amines, the 5mL normal hexane dissolves black precipitate again, and the centrifugal 10min of 6000rpm abandons precipitation; Upwards reset and add the ethanol into 10mL, the centrifugal 20min of 10000rpm abandons supernatant, and black precipitate disperses again with the 3.5mL normal hexane, changes sealing in the sample bottle over to, and 4 ℃ of cryopreservation wherein contain superparamagnetism Fe 3O 4Nanoparticle 80～100mg.
Characterize synthetic superparamagnetism Fe by transmission electron microscope 3O 4Nanoparticle is highly single dispersion, uniform particle diameter (about 8nm) (accompanying drawing 1).
2. by improved solvent evaporated method synthetic segmented copolymer methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) (MePEG-PLGA)
Embodiment 2:
In the there-necked flask that is connected to condensing tube, feed high-purity N in advance 2(purity 〉=99.999%, the huge foreign flavour body in Changchun Co., Ltd) makes to be full of N in the there-necked flask 2
Take by weighing MePEG (Mn=2000g/mol, Sigma aldrich company) 2.0g, DL lactide (D, L-Lactide, 〉=99.5mol%, Beijing unit gives birth to and melts Science and Technology Ltd.) 5.0g, Acetic acid, hydroxy-, bimol. cyclic ester (Beijing unit gives birth to and melts Science and Technology Ltd. for Glycolide, 〉=99.5mol%) 1.0g, the DL lactide is 4: 1 with the amount of substance ratio of Acetic acid, hydroxy-, bimol. cyclic ester, adds N 2In the there-necked flask of protection, add 50mL toluene, 0.205mL stannous octoate [Sn (Oct) 2,～95%, Sigma aldrich company], mixture N 2Be heated to refluxing toluene (about 111 ℃) under the protection, 10h is carried out in reaction.Stop heating, cessation reaction.In there-necked flask, add 100mL methanol extraction product, add the 60mL dichloromethane to precipitation, make its dissolving, gained solution sucking filtration adds the filtrate that obtains in 60～80 ℃ of hot water, removes dichloromethane, after vacuum drying obtains block copolymer MePEG-PLGA powder, product is analyzed through gel permeation chromatography (GPC), and number-average molecular weight is 13217Da, and polydispersity is 1.361.
Embodiment 3:
In the there-necked flask that is connected to condensing tube, feed high-purity N in advance 2(purity 〉=99.999%, the huge foreign flavour body in Changchun Co., Ltd) makes to be full of N in the there-necked flask 2Take by weighing MePEG (Mn=2000g/mol, Sigma aldrich company) 2.0g, DL lactide (D, L-Lactide, 〉=99.5mol%, Beijing unit gives birth to and melts Science and Technology Ltd.) 5.0g, Acetic acid, hydroxy-, bimol. cyclic ester (Beijing unit gives birth to and melts Science and Technology Ltd. for Glycolide, 〉=99.5mol%) 1.0g, the DL lactide is 4: 1 with the amount of substance ratio of Acetic acid, hydroxy-, bimol. cyclic ester, adds N 2In the there-necked flask of protection, add 50mL toluene, 0.05mL stannous octoate [Sn (Oct) 2,～95%, Sigma aldrich company], mixture N 2Be heated to refluxing toluene (about 111 ℃) under the protection, 9h is carried out in reaction.Stop heating, cessation reaction.In there-necked flask, add 100mL normal hexane precipitated product, add the 60mL dichloromethane to precipitation, make its dissolving, gained solution sucking filtration adds the filtrate that obtains in 60～80 ℃ of hot water, removes dichloromethane, after vacuum drying obtains block copolymer MePEG-PLGA powder, product is analyzed through gel permeation chromatography (GPC), and number-average molecular weight is 9925Da, and polydispersity is 1.329.
Embodiment 4:
In the there-necked flask that is connected to condensing tube, feed high-purity N in advance 2(purity 〉=99.999%, the huge foreign flavour body in Changchun Co., Ltd) makes to be full of N in the there-necked flask 2Take by weighing MePEG (Mn=2000g/mol, Sigma aldrich company) 2.0g, DL lactide (D, L-Lactide, 〉=99.5mol%, Beijing unit gives birth to and melts Science and Technology Ltd.) 5.0g, Acetic acid, hydroxy-, bimol. cyclic ester (Beijing unit gives birth to and melts Science and Technology Ltd. for Glycolide, 〉=99.5mol%) 1.0g, the DL lactide is 4: 1 with the amount of substance ratio of Acetic acid, hydroxy-, bimol. cyclic ester, adds N 2In the there-necked flask of protection, add 50mL toluene, 0.05mL stannous octoate [Sn (Oct) 2,～95%, Sigma aldrich company], mixture N 2Be heated to refluxing toluene (about 111 ℃) under the protection, 9h is carried out in reaction.Stop heating, cessation reaction.In there-necked flask, add 100mL normal hexane and absolute ether (v/v=4: 1) mixture precipitation product, add the 60mL dichloromethane to precipitation, make its dissolving, gained solution sucking filtration adds the filtrate that obtains in 60～80 ℃ of hot water, removes dichloromethane, after vacuum drying obtains block copolymer MePEG-PLGA powder, product is analyzed through gel permeation chromatography (GPC), and number-average molecular weight is 9728Da, and polydispersity is 1.291.
Through nuclear magnetic resonance, NMR ( 1H NMR) characterize, product has the structure (accompanying drawing 2) of block copolymer MePEG-PLGA.
Wherein: a.3.39ppm: corresponding to end-OCH of MePEG 3
B.3.65ppm about: corresponding to MePEG-CH 2-;
C.5.2ppm about: multiplet, corresponding to D, the L-lactide-CH-;
D.1.55ppm about: doublet, corresponding to D, L-lactide repetitive-CH 3
E.4.8ppm about: multiplet, corresponding to Acetic acid, hydroxy-, bimol. cyclic ester-CH 2-.
Embodiment 5:
In the there-necked flask that is connected to condensing tube, feed high-purity N in advance 2(purity 〉=99.999%, the huge foreign flavour body in Changchun Co., Ltd) makes to be full of N in the there-necked flask 2Take by weighing MePEG (Mn=2000g/mol, Sigma aldrich company) 2.0g, DL lactide (D, L-Lactide, 〉=99.5mol%, Beijing unit gives birth to and melts Science and Technology Ltd.) 5.0g, Acetic acid, hydroxy-, bimol. cyclic ester (Beijing unit gives birth to and melts Science and Technology Ltd. for Glycolide, 〉=99.5mol%) 1.0g, the DL lactide is 4: 1 with the amount of substance ratio of Acetic acid, hydroxy-, bimol. cyclic ester, adds N 2In the there-necked flask of protection, add 50mL toluene, 0.05mL stannous octoate [Sn (Oct) 2,～95%, Sigma aldrich company], mixture N 2Be heated to refluxing toluene (about 111 ℃) under the protection, 9h is carried out in reaction.Stop heating, cessation reaction.In there-necked flask, add 100mL absolute ether precipitated product, add the 60mL dichloromethane to precipitation, make its dissolving, gained solution sucking filtration adds the filtrate that obtains in 60～80 ℃ of hot water, removes dichloromethane, after vacuum drying obtains block copolymer MePEG-PLGA powder, product is analyzed through gel permeation chromatography (GPC), and number-average molecular weight is 10244Da, and polydispersity is 1.307.
3. the specific embodiment that is used for the magnetic nano-carrier construction method of hydrophobic drug cancer target transmission
Embodiment 6:
Block copolymer MePEG-PLGA 10mg, Fe 3O 4Magnetic nano-particle 1.3mg is dissolved in the 1mL oxolane (THF) jointly, and gained solution slowly adds high purity water ( V THF : V H 2 O = 1 : 10 ) In, ultrasonic, the decompression rotary evaporation is removed organic solvent, simultaneously with solution concentration, crosses 0.45 μ m, 0.22 μ m filter membrane successively, gets final product to such an extent that be used for the magnetic nano drug solution that the dewatering medicament cancer target transmits.
Magnetic nano drug is observed through transmission electron microscope (TEM), can see the Fe of cluster 3O 4Magnetic nano-particle is loaded in the micelle kernel that block copolymer forms, and the nano-carrier dimensional homogeneity is better, and size is 20～100nm, and wherein particle diameter is that the nano-carrier of 40～60nm accounts for 70～80%; Among the embedding figure negative staining experiment confirm magnetic nano drug have the core-shell type structure, the Fe of cluster 3O 4White rings circle around the magnetic nano-particle is MePEG-PLGA block copolymer (accompanying drawing 3).

Claims (3)

1, the magnetic nano-carrier of dewatering medicament cancer target transmission is characterized in that: be by amphiphilic block copolymer micelle parcel superparamagnetism Fe 3O 4Nanoparticle is formed, and amphiphilic block copolymer has the core-shell type structure, and it is spontaneous formation polymer micelle in aqueous solution, and hydrophilic block forms the micelle shell, and hydrophobic block forms micelle kernel, Fe 3O 4Nanoparticle is loaded in the micelle kernel, is used for the magnetic targeted delivery of medicine, is used for nuclear magnetic resonance in the body simultaneously, Fe in the magnetic nano-carrier 3O 4The mass content of nanoparticle is 5～20%.
2, the magnetic nano-carrier of dewatering medicament cancer target transmission as claimed in claim 1 is characterized in that: amphiphilic block copolymer is methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), and number-average molecular weight is 8～30kD; Wherein hydrophilic block is a methoxy poly (ethylene glycol), and number-average molecular weight is 2～5kD; Hydrophobic block is poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), and number-average molecular weight is 3～28kD; The usage ratio of methoxy poly (ethylene glycol) and lactide, Acetic acid, hydroxy-, bimol. cyclic ester is: methoxy poly (ethylene glycol): lactide: Acetic acid, hydroxy-, bimol. cyclic ester=1～2: 1～4: 1.
3, the preparation method of the magnetic nano-carrier of claim 1 or 2 described dewatering medicament cancer targets transmission, its step is as follows:
1) the superparamagnetism Fe of the synthetic 5～18nm of high-temperature decomposition, highly single dispersion, uniform particle diameter 3O 4Nanoparticle;
2) at N 2Under the protection, with 0.05～0.205mL stannous octoate Sn (Oct) 2As catalyst, 2～10g methoxy poly (ethylene glycol) is as macromole evocating agent, by 1.25～10g DL lactide, the ring-opening polymerization of 1～2g Acetic acid, hydroxy-, bimol. cyclic ester in 40～60mL toluene prepares the good methoxy poly (ethylene glycol) of polydispersity-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) block copolymer, precipitate block copolymer by organic solvent again, the gained precipitation is dissolved with dichloromethane, sucking filtration, then filtrate is added in 60～80 ℃ of hot water and remove dichloromethane, last vacuum drying, promptly obtain having methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) block copolymer powder of Narrow Molecular Weight Distribution, its PDI is below 1.4;
3) with 10～20mg methoxy poly (ethylene glycol)-poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) block copolymer and 1.3～2.7mg superparamagnetism Fe 3O 4Nanoparticle is dissolved in 1～2mL oxolane jointly, gained solution slowly joins in 10～20mL high purity water, ultrasonic, the decompression rotary evaporation is removed residual oxolane, simultaneously with solution concentration to 4～10mL, cross 0.45 μ m, 0.22 μ m filter membrane successively,, can obtain being used for the magnetic nano-carrier that the dewatering medicament cancer target transmits again by lyophilization.
CN200910067365A 2009-07-29 2009-07-29 Magnetic nano-carrier with targeted hydrophobic drug delivery to tumor and preparation method thereof Pending CN101632834A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103709715A (en) * 2013-12-26 2014-04-09 厦门大学 Superparamagnetic nano micelle containing POSS (polyhedral oligomeric silsesquioxane) and preparation method thereof
CN105916961A (en) * 2014-01-06 2016-08-31 纳米技术有限公司 Surface-modified nanoparticles
WO2018127270A1 (en) * 2017-01-04 2018-07-12 Pharmathen S.A. Process for preparing biodegradable polymers of high molecular weight
CN108333198A (en) * 2018-03-15 2018-07-27 长春黄金研究院有限公司 A kind of method for observing block copolymer micelle pattern under high temperature of efficiently and accurately
RU2773724C2 (en) * 2017-01-04 2022-06-08 Фарматен С.А. Method for producing biodegradable polymers with high molecular weight

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103709715A (en) * 2013-12-26 2014-04-09 厦门大学 Superparamagnetic nano micelle containing POSS (polyhedral oligomeric silsesquioxane) and preparation method thereof
CN105916961A (en) * 2014-01-06 2016-08-31 纳米技术有限公司 Surface-modified nanoparticles
CN105916961B (en) * 2014-01-06 2018-06-12 纳米技术有限公司 The nano-particle that surface is modified
WO2018127270A1 (en) * 2017-01-04 2018-07-12 Pharmathen S.A. Process for preparing biodegradable polymers of high molecular weight
CN110167990A (en) * 2017-01-04 2019-08-23 法尔玛赞公司 The method for being used to prepare high molecular weight biodegradable polymer
US11046810B2 (en) 2017-01-04 2021-06-29 Pharmathen S.A. Process for preparing biodegradable polymers of high molecular weight
RU2773724C2 (en) * 2017-01-04 2022-06-08 Фарматен С.А. Method for producing biodegradable polymers with high molecular weight
CN108333198A (en) * 2018-03-15 2018-07-27 长春黄金研究院有限公司 A kind of method for observing block copolymer micelle pattern under high temperature of efficiently and accurately

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