CN107596385A - A kind of tumor-targeting and environment pH stimuli responsive type medicine controlled releasing nano-carriers and preparation method thereof - Google Patents
A kind of tumor-targeting and environment pH stimuli responsive type medicine controlled releasing nano-carriers and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of tumor-targeting and environment pH stimuli responsive type medicine controlled releasing nano-carriers and preparation method thereof.Main body with dendritic macromole nano-macromolecule material daiamid PAMAM as structure, connect amphipathic nature block polymer methoxy poly (ethylene glycol)（PEG）Poly- aspartic acid（PLA）, adriamycin（DOX）Covalently it is conjugated to the hydrophobic patches of amphipathic nature block polymer arm（That is, PLA）, and connected by hydrazone key sensitive pH so that system has the characteristics of intelligent medicine releasing in vivo, and the release of medicine can be controlled by internal pH value.F3 polypeptide nucleolin targeting ligands are connected by hydrophilic PEG chain segment again, the tumor-targeting of system is realized in tumour-specific intake and nuclear location.The present invention has potential clinical value.And provide strong technical support for the treatment of other kinds of malignant cell.
Description
Technical field
The present invention relates to a kind of tumor-targeting and environmental PH stimuli responsive type medicine controlled releasing nano-carrier, preparation method,
Belong to bioabsorbable polymer material and field of nanometer technology.
Background technology
The treatment of cancer is always the problem that medical domain attempts to capture for a long time.The major defect of cancer treatment method
It is：Medicine or treatment means are not high to the targeting of cancer cell, it is impossible to distinguish cancer cell and normal cell, particularly chemotherapy and
Some pharmaceutical grade proteins have very high cytotoxicity, and very macrolesion is also caused to normal body while treatment.It is and new
Gene therapy easily digested in vivo or viral vector toxicity etc. due to nucleic acid, there is also problem in actual applications.Open
Send out more efficient and safe tumor therapeuticing method tool is of great significance.
In recent years, the development with nanometer technology and its continuous infiltration to medical domain, nanometer technology and tumor target
Combination to medicine-feeding technology is increasingly becoming a big focus of research.Improve treatment targeting with have and biomolecule match
The nano material of size combines, and can advantageously be transported in human body environment, is the detection of cancer and improves treatment of cancer effect
Provide effective way.Developed using nano material as the nanosecond medical science frontier of medicine or gene transmission vector also very fast
Speed.Therefore, targeting drug delivery system can significantly lower the wind that side effect occurs for patient while chemotherapeutical medicine curative effect is improved
Danger.Improve water-soluble medicine and stability, enhancing curative effect of medication in addition, administration nano-drug administration system also has, reduce drug toxicity, prolong
Sustained release is put, reduces internal release rate, changes the advantages that distribution of medicine in vivo, thus designs and build a kind of cancer target
The property and composite Nano medicine for being capable of control release is focus and difficult point in current medical technology research.
The content of the invention
In order to solve the problems, such as that prior art is present, it is an object of the invention to provide a kind of tumor-targeting and environmental PH to pierce
Swash response type medicine controlled releasing nano-carrier, the nano-carrier does not only have the excellent of Tumor Targeting Drug Delivery System noninvasive laser therapy tumour
Gesture, but also have water-soluble nanometer medicine-feeding technology improvement medicine and stability concurrently, delay to discharge, reduce internal release rate, change
The advantages that becoming the distribution of medicine in vivo.
It is a further object of the present invention to provide the preparation method of above-mentioned nano-carrier.
Described in technical scheme text specific as follows in terms of the two：
First aspect disclosed by the invention is to provide a kind of tumor-targeting and environment pH stimuli responsive type medicine controlled releasings nanometer carries
Body PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH3/ F3, by amphipathic nature block polymer PBLA-b-PEG-OCH3Connect polyamides
Amine-amine (PAMAM) dendritic macromole forms PAMAM-PBLA-b-PEG-OCH3, amphipathic nature block polymer has core-shell type
Structure, autonomous dress forms polymer micelle in aqueous for it, and hydrophilic block forms micella shell, and hydrophobic block is formed in micella
Core, polyamide-amide (PAMAM) dendritic macromole are stated from micelle inner core, and cancer is covalently attached by hydrazone key sensitive pH
Medicine DOX medicines are to polyamide-amide (PAMAM) dendritic macromole system the inside, the acceptor that tumor cell surface altimeter reaches
Dentate F3 polypeptides be incorporated in polyamide-amide (PAMAM) dendritic macromole surface；Its amphipathic nature block polymer by
Unimolecular micelle is self-assembly of in water.
Second aspect disclosed by the invention is to provide a kind of tumor-targeting and environment pH stimuli responsive type medicine controlled releasings are received
Meter Zai Ti PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH3/ F3 preparation method, comprises the following steps：
1）The preparation of dendroid nano-prodrug
A, amphipathic nature block polymer (PBLA-b-PEG-OCH3) synthesis:80mg -100mg BLA- NCA are taken to be dissolved in 6mL rooms
In anhydrous DMF solution under temperature, then by PEG-NHs of the 100mg-200mg containing methoxyl group2、MPEG-NH2、MAL-PEG-NH2In
Any one add in the solution, pour into 0OPrecipitation and separation in C ether；The sediment is collected by filtration, washing, most
It is dried under vacuum eventually；
B, the multifunctional tumor targeted nano based on dendritic macromole PAMAM passs release system：1mol PAMAM-COOH and 1mol
PBLA-B-PEG-Mal and 1mol PBLA-b-PEG-OCH3And input is anhydrous in 100mL with the DCC and NHS of COOH equivalent
Reacted in DMF, the reactant mixture is stirred at room temperature 12 hours；Product PAMAM-PBLA-b-PEG-OCH3/ MAL, use
Cellulose dialysis film dialyse DMF, 48 hours；Then, solution is added to cold diethyl ether, collects sediment as product, by its
Dried under vacuum；
C、PAMAM-P(LA-Hyd-DOX)-b-PEG-OCH3Prepare：1.77g, 0.02mol PAMAM-PBLA-b-PEG-
OCH3/ MAL adds the 200 anhydrous hydrazine reactions of μ L in dry DMF, hereafter, carries out dialysis 48 hours, is then freeze-dried；I.e.
Obtain PAMAM-P（LA-hydrazide）-b-PEG-OCH3/ MAL, then by product PAMAM-P obtained in the previous step（LA-
hydrazide）-b-PEG-OCH3It is dissolved in the dry DMF of fresh distillation, and adds excessive DOX；By mixture in room temperature
Lower stirring obtains PAMAM-P in 24 hours（LA-HYD-DOX）-b-PEG-OCH3/ MAL, by DI water dialysis purification 48 hours；
D、PAMAM-P(LA-Hyd-DOX)-b-PEG-OCH3/ F3 preparation：3mol F3 polypeptides are added to 10mL 1mol
PAMAM-P（LA-HYD-DOX）-b-PEG-CH3In/MAL the aqueous solution, stir the product that collection in 2 hours obtains and pass through DI water dialysis
Purifying 48 hours；
2）It is prepared by the preparation of hyperbranched nano-micelle：PAMAM-P（LA-HYD-DOX）-b-PEG-OCH3/ F3 copolymers are dissolved in
DI water, dialyse 96 hours, then freeze-drying, obtain PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH3/ F3 micellas.
The present invention can be by hydrophilic in adjustment and control system（Polyethylene glycol, PEG）And hydrophobic block（Poly-aspartate, PLA）
Ratio come flexibly control the size of nano-micelle and ensure its good stability；Further through dendritic structure by the system
Poly-aspartate block section contains multiple repeat units, so as to improve the drugloading rate of system.
The third aspect disclosed by the invention is to provide a kind of tumor-targeting and environment pH stimuli responsive type medicine controlled releasings are received
Meter Zai Ti PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH3Applications of/the F3 in the medicine for preparing treatment tumour.
The beneficial effects of the present invention are：
The effect of the present invention is that a kind of environment pH stimuli responsive types release the drug and the nano-medicament carrier with targeting drug delivery system,
The nano-carrier does not only have the advantage of Tumor Targeting Drug Delivery System noninvasive laser therapy tumour, but also has a nanometer medicine-feeding technology concurrently
Improve water-soluble medicine and stability, delay to discharge, reduce internal release rate, change the advantages that distribution of medicine in vivo.
Drug administration carrier is passed through blood barrier, be targeted to specific cells, and then be deeply targeted to organelle, improve chemotherapeutics and treat
Significantly lower the risk that side effect occurs for patient while effect, preferably complete the cancer target delivering of antineoplastic.Hair
The bright Nano medication purpose is the treatment for utilizing " targeting " to solve tumour, and realizes internal intelligence while tumor locus delivering
Can drug release.
（1）Improve biocompatibility.Biosafety issues are considered first from aspartic acid.The material is to organism
And its different aspects such as organ, tissue, cell, molecule, gene will not caused by corresponding toxicological effect and rejection, using poly-
Aspartic acid is the hydrophobic chain of block copolymer, is the good biological degradability for having structures shape because of poly-aspartate,
Poly-aspartate it is intermolecular by peptide key connection, similar with the connected mode of protein, this means that poly-aspartate meeting
There is the biological degradability similar to protein, can be by cancer therapy drug, adriamycin（DOX）Covalently it is conjugated to amphipathic nature block polymer
The hydrophobic patches of arm（That is, PLA）And the unstable hydrazones of pH passed through connect this and make it possible to control by internal pH value well
The release of medicine.And it is easily introduced the features such as side chain synthon can be copolymerized with other amino acid.
（2）PAMAM (polyamidoamine dendrimer) is used as preferable nanoscale structures unit.Its structural cavities,
It is nontoxic as having that stability is good when carrying medicine, the characteristics of delivering efficiency high, it is not easy before medicine enters tumor locus point
Solution, play preferably targeting transhipment effect.It can pass through fast fast-growing between nanometer range plus PAMAM dendritic macromoles size
The cell membrane of cancer cell long, hole is larger, but not by the cell membrane of normal cell, therefore immune response will not be caused,
It is easy to transport or heeling-in in human body.It is that nano-carrier synthesizes amphiphilic with PAMAM (polyamidoamine dendrimer)
The unimolecule nano-micelle system of property block copolymer.Can be by hydrophilic in adjustment and control system（Polyethylene glycol, PEG）With it is hydrophobic embedding
Section（Poly-aspartate, PLA）Ratio come flexibly control the size of nano-micelle and ensure its good stability；Further through tree
Poly-aspartate block section in the system is contained multiple repeat units by dendritic morphology, so as to improve the drugloading rate of system.
（3）F3 peptides target aptamers, contribute to the delay tumour and its surrounding ring of targeting positioning and multifunctional nanoparticle
Border.F3 peptides are bound to paranuclein cell surface and are transported in a manner of kernel dependence in nucleus.Kernel is a kind of height
Conservative nuclear protein is to participate in ribosomal ripe it also can be transported as shuttling proteins between cytoplasm and nucleus
Goods.In normal cell, kernel is resided in nucleus, however, in tumour cell between cell surface and nucleus
Shuttle.Due to its unique positioning on tumor cell membrane, the specific antagonists of cell surface paranuclein also turn into cancer target
Focus
（4）The covalent bond of adriamycin：The cancer therapy drug in medicament-carried nano system is more by way of physically encapsulation at present, this class
Topic passes through the sensitive hydrazone keys of pH to connect adriamycin from covalently bound method, can extend medicine circulation time in blood,
And using infiltration enhancement effect of the solid tumor to macromolecular, passive target is accumulated in tumor tissues；Targeting is introduced in system
Head base F3 peptides, can make nanometer system active targeting to tumor tissues.After tumor tissues are entered, due to the pH sensitiveness of hydrazone key,
The pH that i.e. hydrazone key can be broken under the slightly acidic environment of tumor tissues and will not be broken under the pH environment in normal structure is quick
Perception, the intelligent control release of medicine is realized, medicine is only just discharged in tumor tissues；And medicine is in normal structure and polymer
It is firmly combined together, is not easy to discharge.So while the bioavilability of medicine is improved and medicine can be substantially reduced
The toxic side effect of normal tissue.
Brief description of the drawings
Fig. 1 is the nuclear magnetic resonance of amphiphilic hyper-branched block copolymer（1HNMR）Collection of illustrative plates,
Fig. 2 is dynamic light scattering DLS granularmetric analysis figures；
Fig. 3 is the TEM dyed with 1% Salkowski's solution；
Fig. 4 is insoluble drug release tendency chart；
Fig. 5 is fluorescence picture of the cell under fluorescence microscope,
Left side figure is blank assay, and the right figure is PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH3/ F3 nano-micelles.
Embodiment
By combination accompanying drawing described further below it will be further appreciated that the features and advantages of the invention.The implementation provided
Example is only explanation to the inventive method, remaining content without limiting the invention in any way announcement.
Material and reagent
Aspartic acid-N- carbonyl cyclic lactams（BLA）（Pacify resistance to Jilin Chemical producer）Tetrahydrofuran, dicyclohexylcarbodiimide
(DCC), N- hydroxysuccinimides (NHS) are produced by traditional Chinese medicines, PEG (MW5000) lark prestige Science and Technology Ltd.,
PAMAM-COOH and F3 peptides are provided by SIGMAALDRICH companies（www.sigmaaldrich.com）
【Embodiment 1】The preparation of dendroid nano-prodrug
（1）Amphipathic nature block polymer (PBLA-b-PEG-OCH3) synthesis：Using NCA methods synthesized poly-aspartate benzyl ester with
PEG copolymer, utilize L-Aspartic acid benzyl ester（BLA）Reacted with Triphosgene and prepare N- carboxyl-L-Aspartic acid-benzyl esters-
Ring inner-acid anhydride（BLA-NCA）.With methoxy poly (ethylene glycol) amine（MPEG-NH2）For initiator, trigger NCA ring-opening polymerisations, synthesis
The PEG-PASP benzyl ester amphipathic nature block polymer of different molecular weight.
80 mg-100 mg BLA-NCA are taken to be dissolved in the anhydrous DMF solutions of 6mL at room temperature.Then, by 100mg-
The PEG-NH of 200mg methoxyl groups2（MPEG-NH2）（Or MAL-PEG-NH2）Add in the solution.Pour into 0ODivide in C ether
From precipitation.The sediment is collected by filtration, washing.Finally it is dried under vacuum.
(2) the multifunctional tumor targeted nano based on dendritic macromole PAMAM passs release system：With PAMAM- COOH with
The Amphipathilic block polymer that end group is-NH2 occurs acid amides and reacts to form amphiphilic hyper-branched block copolymer, (PAMAM-
PBLA-b-PEG-OCH3) preparation
1 mol PAMAM-COOH and 1 mol PBLA-B-PEG-Mal and 1molPBLA-b-PEG-O CH3And input
1molDCC and 1molNHS reacts in 100mL dry DMFs.The reactant mixture is stirred at room temperature 12 hours.The product
PAMAM-PBLA-b-PEG-OCH3/ MAL, use 48 hours in cellulose dialysis film dialysis DMF.Then, solution is added to cold
Ether collects sediment as product, is dried under vacuum.
(3)PAMAM-P(LA-Hyd-DOX)-b-PEG-OCH3Prepare
Anhydrous hydrazine introduces hydrazine group with upper step reaction product ester group by nucleophilic substitution, and last hydrazine group divides with DOX
Carboxyl reaction on son, form hydrazone key, PAMAM-PBLA-B-PEG-OCH 3/ MAL benzyl group is changed into hydrazides and passes through 1.77g
PAMAM-PBLA-b-PEG-OCH3/ MAL, the 200 anhydrous hydrazine reactions of μ L are added in dry DMF.Hereafter, it is small to carry out dialysis 48
When, then it is freeze-dried.PAMAM-P（LA-hydrazide）-b-PEG-OCH3/ MAL, it is then dissolved in fresh distillation drying
DMF, and add excessive DOX.Mixture is stirred at room temperature 24 hours and obtains PAMAM-P（LA-HYD-DOX）-b-
PEG-OCH 3/ MAL, it passes through DI water dialysis purification 48 hours.
（4）PAMAM-P(LA-Hyd-DOX)-b-PEG-OCH3/ F3 preparation
3molF3 polypeptides are added to 1molPAMAM-P（LA-HYD-DOX）-b-PEG-CH3In/MAL the aqueous solution.The reaction is stirred
Obtained product is collected after mixing 2 hours and passes through DI water dialysis purification 48 hours.
【Embodiment 2】The preparation of hyperbranched nano-micelle
The Macromolecule Prodrug that embodiment 1 obtains can be realized by being self-assembly of in aqueous medium with nuclear shell structured nano micella
Into after target target position tumor tissues, due to the pH sensitiveness of hydrazone key, i.e. hydrazone key can break under the slightly acidic environment of tumor tissues
Split, and will not be broken under the pH environment of normal structure, to realize that the intelligent control of medicine discharges.
PAMAM-P（LA-HYD-DOX）-b-PEG-OCH3/ F3 copolymers are dissolved in DI water.Dialysis 96 hours, then freezing
Dry, obtain PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH3/ F3 micellas.
【Embodiment 3】Carry preparation and the sign of DOX Macromolecule Prodrugs
Using PAMAM as macromolecular carrier, amphipathy macromolecule prodrug PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH is prepared3/
F3, and to reaction raw materials medicine and often walk reaction product and carry out nuclear magnetic resonance（1HNMR）Characterize；（Such as Fig. 1）,1H NMR (400
MHz, DMSO) δ 7.94 (s, 1H), 5.33 (s, 1H), belong to DOX hydrogen 3.44 (d,J = 59.2 Hz,
20H), belong to PEG peak 1.05 (d,J=151.7 Hz, 1H) hydrogen on .PAMAM.
【Embodiment 4】Carry the preparation of adriamycin DOX nanoparticles and performance study
0.05mol/l nanoparticle solution is prepared at the nano-granule freeze-dried powder end that embodiment 2 is obtained, and is determined using dynamic light scattering flat
Equal particle diameter, it is measured using Nano-ZS 90 (Malvern, UK) Malvern Particle Size Analyzer, temperature setting 25OC, survey
Amount pattern is arranged to automatic.The average grain diameter result measured is 91nm（Such as Fig. 2）.
Using transmission electron microscope（TEM）Observe the surface appearance feature of nanoparticle；The TEM dyed with 1% Salkowski's solution schemes
（Such as Fig. 3）It is 30nm in the average grain diameter of transmissioning electric mirror determining, spherical surface is smooth, and form is homogeneous.Pass through DLS and TEM knot
Fruit, which can see, prepares amphiphilic hyper-branched block copolymer size range in Nano grade.
【Embodiment 5】The measure of its drugloading rate of the nanometer transmission system of target administration of the present invention
By 1mg PAMAM-P（LA-hyd-DOX）-b-PEG-OCH3/ F3 nano-micelles are dissolved in 200 mL 0.1N HCl solutions
UV measure is carried out under 485nm wavelength by ultraviolet-uisible spectrophotometer UV-2600 after stirring 48 hours.
As a result show, the drugloading rate of its nano-micelle is 16.5%.The amphipathic nature polyalcohol carrier possesses very high medicine
Carrying capacity.
【Embodiment 6】Carry the research of adriamycin nano-particles release in vitro
PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH is determined using ultraviolet calibration curve method3/ F3 nano-micelles are in different pH
Release performance in dissolution medium.Selection pH 7.4, pH 6.6 simulate physiological condition, cell respectively with the dissolution mediums of pH 5.3
Epimatrix and intracellular environment, by determining the cumulative release amount of DOX in certain time, pH values are investigated to carrying DOX nanometers system
The influence of system.
DOX rate of release increases always with the reduction of pH value, under 7.4 pH value, DOX burst sizes after 45 hours
For 12.1%, however, be 5.3 and 6.6 in pH value, the DOX amounts of release be about 45h after respectively 90% and 83%, the result table
The unstable hydrazone keys of pH between bright DOX and nano-carrier can be quite stable in physiological conditions.Such as Fig. 4.Confirm this hair
Bright amphiphilic hyper-branched block copolymer has in cancer location（PH=5.5 or so）Intelligent medicine releasing the characteristics of.
【Embodiment 7】The experimental evaluation of cell in vitro
Cellular uptake behavior and intracellular distribution based on PAMAM unimolecular micelles are swept using laser co-focusing analysis laser simultaneously
Retouch microscope, selection be SKOV-3 cells and HOSPIC cells contrast, treat cell culture 24h, after being paved with bottom hole, training is abandoned in suction
Base is supported, is washed with PBS and removes free dead cell, 1mL sample solutions is added, continues culture 0,0.5,1,2,4h respectively, shifting is abandoned
Culture medium, after washing 3 times with PBS, after fixing cell 30min with 4% paraformaldehyde, PBS is washed 3 times again, adds 200 μ
LDAPI dyestuffs dye to nucleus, duration 10min, are washed 3 times with PBS, are placed under inverted fluorescence microscope and observe carefully
Born of the same parents absorb situation.
From fluoroscopic image（Fig. 5）In as can be seen that PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH3/ F3 nano-micelles exist
SKOV-3 is distributed into the cell, illustrates amphiphilic hyper-branched block copolymer PAMAM-P (LA-Hyd-DOX)-b- prepared by the present invention
PEG-OCH3/ F3 has targeting in cancer cell.
Claims (3)
1. a kind of tumor-targeting and environment pH stimuli responsive type medicine controlled releasing nano-carrier PAMAM-P (LA-Hyd-DOX)-b-
PEG-OCH3/ F3, it is characterised in that by amphipathic nature block polymer PBLA-b-PEG-OCH3Connect polyamide-amide (PAMAM) tree
Dendritic macromolecules form PAMAM-PBLA-b-PEG-OCH3, amphipathic nature block polymer has core-shell type structure, and it is water-soluble
Autonomous dress forms polymer micelle in liquid, and hydrophilic block forms micella shell, and hydrophobic block forms micelle inner core, polyamide-amide
(PAMAM) dendritic macromole is stated from micelle inner core, and being covalently attached cancer drug DOX medicines by hydrazone key sensitive pH arrives
Inside polyamide-amide (PAMAM) dendritic macromole system, the dentate F3 polypeptides for the acceptor that tumor cell surface altimeter reaches
It is incorporated in polyamide-amide (PAMAM) dendritic macromole surface；Its amphipathic nature block polymer in water by being self-assembly of
Unimolecular micelle.
2. tumor-targeting and environment pH stimuli responsive type medicine controlled releasing nano-carrier PAMAM-P (LA- described in claim 1
Hyd-DOX)-b-PEG-OCH3/ F3 preparation method, comprises the following steps：
1）The preparation of dendroid nano-prodrug
A, amphipathic nature block polymer (PBLA-b-PEG-OCH3) synthesis:80mg -100mg BLA- NCA are taken to be dissolved in 6mL room temperatures
Under anhydrous DMF solution in, then by PEG-NHs of the 100mg-200mg containing methoxyl group2、MPEG-NH2、MAL-PEG-NH2In
Any one is added in the solution, pours into 0OPrecipitation and separation in C ether；The sediment is collected by filtration, washing, finally
It is dried under vacuum；
B, the multifunctional tumor targeted nano based on dendritic macromole PAMAM passs release system：1mol PAMAM-COOH and 1mol
PBLA-B-PEG-Mal and 1mol PBLA-b-PEG-OCH3And input is anhydrous in 100mL with the DCC and NHS of COOH equivalent
Reacted in DMF, the reactant mixture is stirred at room temperature 12 hours；Product PAMAM-PBLA-b-PEG-OCH3/ MAL, use
Cellulose dialysis film dialyse DMF, 48 hours；Then, solution is added to cold diethyl ether, collects sediment as product, by its
Dried under vacuum；
C、PAMAM-P(LA-Hyd-DOX)-b-PEG-OCH3Prepare：1.77g, 0.02mol PAMAM- PBLA-b-PEG-
OCH3/ MAL adds the 200 anhydrous hydrazine reactions of μ L in dry DMF, hereafter, carries out dialysis 48 hours, is then freeze-dried；I.e.
Obtain PAMAM-P（LA-hydrazide）-b-PEG-OCH3/ MAL, the dry DMF of fresh distillation is then dissolved in, and added
Excessive DOX；Mixture is stirred at room temperature 24 hours and obtains PAMAM-P（LA-HYD-DOX）-b-PEG-OCH3/ MAL,
By DI water dialysis purification 48 hours；
D、PAMAM-P(LA-Hyd-DOX)-b-PEG-OCH3/ F3 preparation：3mol F3 polypeptides are added to 10mL 1mol
PAMAM-P（LA-HYD-DOX）-b-PEG-CH3In/MAL the aqueous solution, stir the product that collection in 2 hours obtains and oozed by DI water
Analysis purifying 48 hours；
2）It is prepared by the preparation of hyperbranched nano-micelle：PAMAM-P（LA-HYD-DOX）-b-PEG-OCH3/ F3 copolymers are dissolved in DI
Water, dialyse 96 hours, then freeze-drying, obtain PAMAM-P (LA-Hyd-DOX)-b-PEG-OCH3/ F3 micellas.
3. tumor-targeting and environment pH stimuli responsive type medicine controlled releasing nano-carrier PAMAM-P (LA- described in claim 1
Hyd-DOX)-b-PEG-OCH3Applications of/the F3 in the medicine for preparing treatment tumour.
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| CN110393700A (en) * | 2019-04-02 | 2019-11-01 | 武汉理工大学 | The PAMAM of F3 polypeptide guiding is the preparation and application of the tumour medicine nano-carrier of core |
| CN110859965A (en) * | 2019-12-17 | 2020-03-06 | 深圳大学 | Multifunctional nano particle with AIE characteristic and preparation method and application thereof |
| CN114672031A (en) * | 2022-04-15 | 2022-06-28 | 苏州市焕彤科技有限公司 | PH response polymer nano-drug and preparation method thereof |
| CN115487155A (en) * | 2021-06-18 | 2022-12-20 | 兰州大学 | PH/enzyme dual-response nucleus-targeted nano-carrier and preparation and application thereof |
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| CN115487155A (en) * | 2021-06-18 | 2022-12-20 | 兰州大学 | PH/enzyme dual-response nucleus-targeted nano-carrier and preparation and application thereof |
| CN114672031A (en) * | 2022-04-15 | 2022-06-28 | 苏州市焕彤科技有限公司 | PH response polymer nano-drug and preparation method thereof |
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