CN102464874A - Star-shaped multi-arm PLGA/PEG amphiphilic segmented copolymer and application thereof - Google Patents
Star-shaped multi-arm PLGA/PEG amphiphilic segmented copolymer and application thereof Download PDFInfo
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Abstract
The invention provides a novel COPD drug carrier material, particularly a series of novel star-shaped multi-arm PLGA/PEG amphiphilic segmented copolymers having excellent biocompatibility and amphipathicity, characterized in that: PEG is used as a hydrophilic chain segment and PLGA is used as a hydrophobic chain segment, and polymer chemical compositions are not changed; a plurality of targeted molecules are carried through abundant modifiable terminal groups, and the targeted molecules can be flexibly oriented in internal complex environment, so that the capacity of bonding the internal environment with the targeted molecules can be greatly increased; and the amphiphilic structure can be assembled to form a nuclear shell micelle, the star-shaped multi-arm molecular configuration makes a PEG hydrophilic layer on the micelle shell stable, so that the carrier can be effectively prevented from being removed by a human reticuloendothelial system to realize the internal long cycling. The copolymer can be used for preparing a plurality of dosage forms of lung targeted drugs to achieve the purpose of treating COPD. The copolymer also can increase the directivity and retention of drugs to the targeted issues, reduce the toxicity of the drugs to normal cells, reduce dosage, and increase the bioavailability of the medicinal preparations.
Description
Technical field:
(be not called for short chronic obstructive pulmonary disease to still there being effective treatment means delaying chronic obstructive lung disease at present; COPD) the course of disease or suppress the inflammation of little air flue and pulmonary parenchyma; A kind of novel C OPD drug carrier material is provided; Utilize the lung targeted drug of the multiple formulation that this material can prepare,, reach the purpose of treatment COPD through intravenous injection and inhalation; It can increase directive property and the anelasticity of medicine to target tissue, reduces medicine to Normocellular toxicity, reduces dosage, improves the bioavailability of pharmaceutical prepn.
Background technology:
Chronic bronchitis, chronic obstructive emphysema, chronic pulmonary heart disease even heart failure, respiratory insufficiency etc. medically are commonly referred to as chronic obstructive pulmonary disease; Add up according to the World Health Organization; Chronic obstructive pulmonary disease such as chronic bronchitis, pulmonary heart disease has been the 4th cause of death in the world; And in rising trend, China is more severe.
The increase day by day of COPD importance and sickness rate has worldwide caused widely to be paid close attention to, yet the pharmacological agent of COPD rarely has progress, have to inflammatory process, or to the structure cell.Some special treat-ment is to stop inflammatory cell entering air flue and pulmonary parenchyma in the COPD incidence and development, comprises the medicine that adopts antagonism adhesion molecule and chemokines, and antagonism TNF-α and the treat-ment that increases IL-10.Suppressing Fibrotic therapy at present mainly is the research to transforming growth factor-beta 1 and proteinase activated receptors-2.To the suppressor factor of Tryase and MMP, stop destruction to lung, block emophysematous development.In the early stage clinical study of new therapy treatment COPD, the problem that need are considered emphatically is how medicine to be transported to lung diseased region on every side effectively, and seek effective biochemical marker and guidance technology, and does not influence normal tissue and organ.Design and make up can specificity guiding diseased organ, tissue or cell target property transfer system, can medicine or photographic developer be enriched in diseased region, and in normal site distribution seldom, can reduce the toxic side effect of medicine greatly.The administration of target property also has very important significance to the pathogeny of study of disease, the sensitivity that improves clinical diagnostic imaging, realization personalized treatment, is the active demand of present clinical treatment COPD.
Discover that both at home and abroad the drug molecule of particle diameter in 5～30um scope concentrates in lung through passive target, too small easy arrival liver excessively is prone to embolism when quiet notes.Metal oxide-type, polypeptide and protein (enzyme), ucleotides, carbohydrate and other biological activity small molecules etc. have initiatively targeting.MOX or metallo-chelate as Physical Target to material; Guide effect through temperature field, magnetic field; The nanoparticle of bag medicine carrying thing is concentrated or is fixed in biological intravital some privileged sites or zone; And make medicine be able to slow release through diffusion and osmosis, and normal surrounding tissue is not produced toxic side effect.As in nuclear magnetic resonance image (MRI), for obtaining the clear image at a certain position, prevent that other organs from disturbing, through the magnetic targeting, near this organ, medicine forms area with high mercury with the magnetic contrast agent enrichment, slowly discharges.
Polypeptide and protein targeted molecular comprise acceptor of monoclonal antibody or antibody fragment, RGD small peptide class, ESC etc.Monoclonal antibody or antibody fragment are the most general targeted moleculars; Antibody commonly used has: antiplatelet endothelial cell adhesion molecule (PECAM)-1 antibody, antitumor related antigen (TAA) antibody, anti-tissue factor (TF) monoclonal antibody-factor VII (factor; F VII), anti-vascular endothelial growth factor (VEGF) monoclonal antibody etc., be targeting antibodies molecule commonly used in inflammation, the cardiovascular and tumor disease targeted therapy.The RGD small peptide is meant the small peptide molecule that contains essence-Gan-asparagus fern sequence fragment, and target can be regulated and control the adhesion of endotheliocyte and Fibrinogen, ln in the plain type adhesion receptor of the integration of endothelial cell surface, is the main target of pharmacological intervention.
The carbohydrate targeted molecular comprises that lactose, semi-lactosi for terminal gp, heparin etc., act on the asialoglycoprotein protein receptor on the hepatic parenchymal cells (PC), and the endocytosis of this receptor mediation makes the directed transhipment of its medicine that carries.The oligose of natural or synthetic and sLeX similar; Like licorice polysaccharide, lewis oligosaccharide and verivate thereof etc., can and combine with the plain specific recognition of selection, thereby be targeted to the blood vessel endothelium surface that is in state of activation; Plain physiology effectiveness is selected in blocking-up, reaches antiphlogistic purpose.
In theory; If we can design the carrier of simultaneously efficient medicine carrying and targeted molecular; Through the active targeting of targeted molecular,, promptly realize directly the illness cell being discharged medicine with the drug targeting diseased region; Can reduce the whole body toxic side effect of medicine greatly, with fundamentally changing present COPD treatment present situation.Therefore the multifunctional targeted property of research and development drug delivery system has very important significance, and is the active demand of current medical circle.
Based on the design of the active targeted drug of above demand and synthetic, become the core challenge of biomedicine field research.Require the pharmaceutical carrier molecule before and after carrying a target molecule, medicine carrying, not only to have security in stability, the body, also require to have a plurality of reactive groups to connect targeted molecular, not influence the activity of targeted molecular after connecting; Have adjustable wetting ability and hydrophobic chain segment flexibly, can carry diagnosis photographic developer, medicine, realize high medicine carrying capacity through chemistry or physical bond bag; Have simple relatively preparation technology, can be made into the needs that different dosage form adapts to different targeting moieties, different way of administration.
Current targeted drug be because the inaccuracy that exists target spot to select can cause immunogenicity, and single targeted integration is not strong, can cause the quick scavenging(action) of liver or liver or heart are caused damage, and cause the target efficient of drug delivery system very low.For example, the severe complication that the Herceptin that is used for breast cancer treatment has recently caused heart failure and heart function occur and descends, and the angiogenesis inhibitor target therapeutic agent usually cause spinoff such as hypertension.Design has the carrier molecule of a plurality of avtive spots, can combine a plurality of targeted moleculars and multiple medicine simultaneously, realizes the synergy of target polyvalency and medicine, can more accurately locate the distribution of medicine at lesions position, promotes illness to disappear quickly.
Candidate's carrier with these characteristics has polylactic acid PLA; Sodium bromoacetate homopolymer, SRU (PGA) and multipolymer (PLGA), gather the third two support amine (PPI) and peptide class dendritic macromole (containing the peptide bond structure) etc. at PLGA/ polyoxyethylene glycol (PEG) based block copolymer, PEG and polymethylmethacrylate (PMMA), paracyanogen base Bing Xisuandingzhi, the grafting that gathers 3-hydroxy butyrate, chitosan and polycaprolactone (PCL) or blended product, polymine (PEI), polyamide-amide type (PAMAM) dendritic macromole (dendrimer).
But existing PLGA/PEG segmented copolymer is mainly linear copolymers, but lacks decorating site in the molecular structure, can't connect the targeted molecular of effective dose, can not satisfy the requirement of targeting vector in the body.The investigator who has is at PLGA microsphere surface modified polysaccharide base polymer, like chitosan etc., increases the modifiability functional group on surface, though this method can solve the modification problem of targeted molecular, but lost the PLGA/PEG micellar and grown circulation function.
Solid support material with internal guide and target function still is in the preliminary research stage, lacks systematicness and regular, still has no a kind of success active targeted drug to transmit carrier so far and is used for clinical COPD treatment.
Summary of the invention:
The present invention adopts has good biocompatibility and amphipathic serial novel star-type multi-arm PLGA/PEG amphipathic nature block polymer; It is hydrophilic segment with PEG; PLGA is a hydrophobic segment; Do not change the polymer chemistry composition, but regulate and control its performance, kept original biological safety of single polymers and performance controllability through the change of molecular configuration; And, carry multiple targeted molecular through its abundant end group modified, and and the target molecule that can lead in the complex environment in vivo flexiblely, thus can greatly improve in the body and target molecule bonded ability; Its amphipathic structure can be assembled and formed the nucleocapsid micella, and the molecular configuration of star-type multi-arm can make the PEG hydrophilic layer of micella shell have more stability, thereby can more effectively protect carrier not removed by the human body reticuloendothelial system, realizes long circulation in the body.Have report to show that six arm polymkeric substance of same molecular amount will be higher than linear copolymers for the encapsulation rate of medicine, star-type multi-arm PLGA/PEG amphiphilic block will have unique advantages as target medicine carrier in the body.
The PLGA/PEG Amphiphilic Block Copolymer Micelles is characterized in that this segmented copolymer has the star-type multi-arm structure; It is hydrophilic segment with PEG, and PLGA is a hydrophobic segment; The end group of this multipolymer carries targeted molecular, and the target molecule that can lead in the complex environment in vivo; Its amphipathic structure can be assembled and formed the nucleocapsid micella, and the molecular configuration of star-type multi-arm can make the PEG hydrophilic layer of micella shell stable.This copolymer micelle and targeted molecular carry out covalently bound, and targeted molecular is one or more in glycan molecule, polypeptide or protein molecular, the nucleic acid molecule.Wherein glycan molecule is selected from one or more in lactose, semi-lactosi, seminose, licorice polysaccharide, the sialylated or fucosylated N-acetyllactosamine; Polypeptide or protein molecular are selected from one or more in the acceptor of monoclonal antibody or antibody fragment, RGD peptide, ESC; Being connected of polypeptide or protein molecular and end amido PLGA/PEG segmented copolymer carrier wherein, adopt that the amido idol connects that method connects with end carboxyl carrier idol, the carboxyl idol connects that method connects with the amino carrier idol of end or the sulfydryl idol connects method and connects with the amino carrier idol of end.
The composite drug-loaded micella of target that aforesaid PLGA/PEG amphipathic nature block polymer and drug molecule are processed; It is characterized in that; This micella is assembled two or more targeted moleculars and drug molecule system; Connect earlier targeted molecular and drug molecule respectively, then two individual system are mixed, obtain composite micelle; Or after carrier self-assembly medicine carrying, the substep idol connects every kind of targeted molecular, obtains composite micelle.
Above-mentioned copolymer micelle can wrap and carry the nanometer super-paramagnetic ferriferrous oxide; This micella bag carries the preparation method of the segmented copolymer of nanometer super-paramagnetic ferriferrous oxide; Its step is following: star-like PLGA/PEG multipolymer is dissolved in the hydrophobic organic solvent; With the nano ferriferrous oxide ultra-sonic dispersion in organic phase; Under high-speed stirring, organic phase is added drop-wise in the zero(ppm) water, can obtains being surrounded by the nano-micelle of ferrofluid after lasting stirring is volatilized organic solvent.
Aforesaid amphipathic nature block polymer is used for preparing the application of lung organ's target medicine carrier in the body; Aforesaid amphipathic nature block polymer is used for preparing the application of the pharmaceutical carrier of targeted therapy chronic obstructive pulmonary disease in the body; Aforesaid amphipathic nature block polymer, the medicine that it is characterized in that treating chronic obstructive pulmonary disease is reflunomide or bronchiectasis.
Detailed Description Of The Invention is following:
(1) serial multi-arm star-shaped PLGA/PEG block copolymer micelle bag carries the nanometer super-paramagnetic ferriferrous oxide
Nanometer super-paramagnetic ferriferrous oxide (SPIO) can be used for magnetic target location, MRI develops.The preparation method is dissolved in star-like PLGA/PEG multipolymer in the hydrophobic organic solvent; With the nano ferriferrous oxide ultra-sonic dispersion in organic phase; Under high-speed stirring, organic phase is added drop-wise in the zero(ppm) water; After volatilizing organic solvent, lasting stirring can obtain being surrounded by the nano-micelle of ferrofluid, shown in accompanying drawing 1.
(2) star-like PLGA/PEG segmented copolymer and targeted molecular is covalently bound
Be connected with carrier molecule with sugar, peptide or albumen, nucleic acid targeted molecular respectively.
(i) carbohydrate molecule is like lactose, semi-lactosi, seminose, licorice polysaccharide, sialylated and fucosylated N-acetyllactosamine (sLeX and sLeA) etc.For the carbohydrate of amino-contained not, its hydroxyl carried out carboxylation after, carry out idol through carboxyl with the star-like PLGA/PEG segmented copolymer of end amido and connect, for the carbohydrate that contains amido, directly connect by chance with its amino.As shown in Figure 3.
(ii) polypeptide or protein molecule are like acceptor of monoclonal antibody or antibody fragment, RGD peptide, ESC etc.Targeted molecular or polypeptide and protein medicaments molecule are connected with end amido star-like PLGA/PEG segmented copolymer carrier, adopt the amido idol to connect method and end carboxyl carrier idol and connect, adopt the carboxyl idol to connect method and the amino carrier idol of end to connect, adopts the sulfydryl idol to connect method and hold that amino carrier is even to be connected.Idol for protein and peptide class macromole and carrier molecule connects, and considers that idol connects the proteinic inactivation problem in back, therefore will select the particular proteins coupling agent, like sulfo-SMCC, under the condition of gentleness, carries out idol and connects, and avoids proteic inactivation as far as possible.Simultaneously, in proteinic coupling reaction,, need to consider that the targeted molecular idol connects the influence of back to copolymer structure and self-assembly form because proteic molecular weight is bigger.Therefore, adopt two kinds of idols to connect-assembling mode: idol connects the back assembling earlier; Or assembling back idol connects earlier.
(iii) nucleic acid ligands (aptamer) molecule.Connect behind the gene vector systems such as anti-nucleic acid antibody, affinity element-vitamin H, slow virus, adenovirus bind nucleic acid molecule again through end amido star-like PLGA/PEG segmented copolymer; Also can be through the direct bind nucleic acid molecule of positive charge effect of the amino star-like PLGA/PEG copolymerization carrier of end; Form polymer carrier-nucleic acid compound polyelectrolyte through the coulombic interaction self-assembly, the target property inactivation that causes but needs are considered the variation of nucleic acid ligands space structure.
(3) medicine carrying that has the star-like PLGA/PEG block copolymer micelle of targeted molecular is tested
(i) connection of antibody, nucleic acid ligands, prodrug (prodrug) type medicine, the same joint.
(ii) other micella self-assembling method hydrophilic, hydrophobic drug, hydrophobicity (is example with the reflunomide), wetting ability (is example with the ipratropium bromide).For hydrophobic drug; Be dissolved in star-like PLGA/PEG segmented copolymer, hydrophobic drug in the hydrophobic organic solvent jointly; This organic phase slowly is added drop-wise in a large amount of zero(ppm) water, continues to stir, make organic solvent evaporation; After solidifying, organic phase can obtain containing the nano-micelle of hydrophobic drug, shown in accompanying drawing 2.For hydrophilic medicament; Adopt the compound emulsion method embedding,, make its self-assembly formation nano-microcapsule structure in the aqueous solution through the hydrophilic segment and the ratio of hydrophobic segment of regulating amphipathic star-like PLGA/PEG segmented copolymer; Carry hydrophilic medicament through water bag in it, shown in accompanying drawing 3.
Short for the transformation period that overcomes current C OPD medicine, be subject to enzymolysis and be difficult to, in conjunction with the effective COPD medicine of various clinical such as reflunomide and bronchodilator, to reach better clinical therapeutic efficacy through shortcomings such as PCs.
(4) assembling of multifunctional targeted composite drug-loaded micellar system and sign
For the assembling of two or more targeted moleculars and drug molecule system, can adopt above method to connect targeted molecular and drug molecule respectively, then two individual system are mixed, obtain composite micelle; Also can be after carrier self-assembly medicine carrying, the substep idol connects every kind of targeted molecular, and the composite micelle that finally obtains is as shown in Figure 4.
Measure preparation back micellar drug loading, encapsulation rate and release in vitro according to the method for Chinese Pharmacopoeia 2005 editions.
Adopt the surface plasma resonance detection technique; On detection chip, solidify corresponding target molecules; Under simulation blood flow condition, measure binding constant and the binding capacity of modifying between back nano-micelle and the target molecules; Estimate dynamically, quantitatively carrier targeted molecular and target molecules combine active, binding capacity and combination stability.
The micelle-forming concentration of target drug-carrying mixture is intended and adopted pyrene is probe, measures with fluorescent method.
Micellar form, size, electrical; Dispersity, average aggregation number and inner core density, aggregate stability are intended through low temperature scanning Electronic Speculum (SEM), and methods such as transmission electron microscope (TEM), AFM (AFM), dynamic light scattering (DLS), static light scattering (SLS), zeta potentiometer characterize.Adopt surface infrared spectrum, x-ray photoelectron spectroscopy (XPS), fluorescence and the binding capacity of chemiluminescence determination targeted molecular in nano-micelle.
(5) the outer target positioning performance research of organism
(i) cell targeted, the controlled drug release of the multifunctional targeted medicament-carried nano micelle of cell in vitro culture studies and bioavailability.Adopt the targeted molecular of two interior medicines of fluorescent probes difference mark micellas and micelle surface, dynamic observe the state of nano-micelle in cell adhesion and cell absorption process, observation of cell process, mensuration cell intake through laser confocal microscope; Through affinity tag and lysosome detection reagent etc., the research cell is taken in approach and mechanism, estimates the external biological availability of medicine.
(ii) under the outside magnetic field effect, study of the influence of various rheology factors to the magnetic Nano micellar positioning performance in the test macro.
(iii) adopting the lung perfusion system that exsomatizes to study various rheology factors influences the reactive polymer adherent.During mensuration,, adopt the method for morphology or radionuclide, observe the stick situation of thrombocyte in subendothelial tissue by behind the certain flow rate blood perfusion.Adopt the lung perfusion system that exsomatizes to study various rheology factors targeted nano medicine-carrying micellar blood vessel is sticked influence.Observe nano-micelle through external fluorescent marker method the vascular injury site specificity is combined situation, and observe the situation of nano-micelle in the body target vascular therapy damage location and adhesion.
(6) biological safety evaluation
According to biomaterial country judgement criteria, the biological safety of target medicine carrier nano-micelle is comprised that cytotoxicity (as through tetrazolium bromide colourimetry, i.e. mtt assay) etc. carries out safety evaluation; Observe the influence of degraded product, comprise pH value, ionic concn etc. local physiological environment; Study degradation process and the distribution in vivo of various medicine-carried nano particles; Purge mechanism in research carrier molecule degraded back covalency or the huge legendary turtle targeting diagnosis that closes and cytotoxicity, immunotoxicity and the body of treating molecule; Adopt acute toxicity test in mice, sensitization test that new polymers is carried out preliminary biological safety evaluation.
The healing potion that the present invention selects for use all is that approval is gone on the market or got into the medicine of clinical experiment, like reflunomide and ipratropium bromide.
In sum, the content of application of the present invention is not seen reported in literature, has novelty/creativeness and practical feasibility.
Description of drawings:
1, accompanying drawing 1 is a magnetic Nano micella synoptic diagram.
2, accompanying drawing 2 carries the hydrophobic drug synoptic diagram for the carrier bag that is connected with targeted molecular.
3, accompanying drawing 3 carries the formed microcapsule structure synoptic diagram of hydrophilic medicament (like ipratropium bromide) for the carrier bag that is connected with targeted molecular.
4, the mixing synoptic diagram of 4 two or more years target molecules of accompanying drawing and target medicine molecular system
Claims (10)
1. a PLGA/PEG Amphiphilic Block Copolymer Micelles is characterized in that this segmented copolymer has the star-type multi-arm structure; It is hydrophilic segment with PEG, and PLGA is a hydrophobic segment; The end group of this multipolymer carries targeted molecular, and the target molecule that can lead in the complex environment in vivo; Its amphipathic structure can be assembled and formed the nucleocapsid micella, and the molecular configuration of star-type multi-arm can make the PEG hydrophilic layer of micella shell stable.
2. PLGA/PEG Amphiphilic Block Copolymer Micelles as claimed in claim 1 is characterized in that the micella bag carries the nanometer super-paramagnetic ferriferrous oxide.
3. PLGA/PEG Amphiphilic Block Copolymer Micelles as claimed in claim 1, it is covalently bound to it is characterized in that said copolymer micelle and targeted molecular carry out, and targeted molecular is one or more in glycan molecule, polypeptide or protein molecular, the nucleic acid molecule.
4. PLGA/PEG Amphiphilic Block Copolymer Micelles as claimed in claim 3 is characterized in that glycan molecule is selected from one or more in lactose, semi-lactosi, seminose, licorice polysaccharide, the sialylated or fucosylated N-acetyllactosamine.
5. PLGA/PEG Amphiphilic Block Copolymer Micelles as claimed in claim 3; It is characterized in that polypeptide or protein molecular are selected from one or more in the acceptor of monoclonal antibody or antibody fragment, RGD peptide, ESC; Being connected of polypeptide or protein molecular and end amido PLGA/PEG segmented copolymer carrier wherein, adopt that the amido idol connects that method connects with end carboxyl carrier idol, the carboxyl idol connects that method connects with the amino carrier idol of end or the sulfydryl idol connects method and connects with the amino carrier idol of end.
6. composite drug-loaded micella of processing like the described PLGA/PEG amphipathic nature block polymer of one of claim 1-5 and drug molecule of target; It is characterized in that; This micella is assembled two or more targeted moleculars and drug molecule system; Connect earlier targeted molecular and drug molecule respectively, then two individual system are mixed, obtain composite micelle; Or after carrier self-assembly medicine carrying, the substep idol connects every kind of targeted molecular, obtains composite micelle.
7. bag as claimed in claim 2 carries the preparation method of the segmented copolymer of nanometer super-paramagnetic ferriferrous oxide; Its step is following: star-like PLGA/PEG multipolymer is dissolved in the hydrophobic organic solvent; With the nano ferriferrous oxide ultra-sonic dispersion in organic phase; Under high-speed stirring, organic phase is added drop-wise in the zero(ppm) water, can obtains being surrounded by the nano-micelle of ferrofluid after lasting stirring is volatilized organic solvent.
8. be used for preparing the application of lung organ's target medicine carrier in the body like the described amphipathic nature block polymer of one of claim 1-6.
9. be used for preparing the application of the pharmaceutical carrier of targeted therapy chronic obstructive pulmonary disease in the body like the described amphipathic nature block polymer of one of claim 1-6.
10. like the described amphipathic nature block polymer of one of claim 1-6, the medicine that it is characterized in that treating chronic obstructive pulmonary disease is reflunomide or bronchodilator.
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| CN104815341A (en) * | 2015-03-27 | 2015-08-05 | 浙江大学 | Targeted polymer micelle magnetic nanoparticle, and preparation method and application thereof |
| WO2015127900A1 (en) * | 2014-02-27 | 2015-09-03 | 国玺干细胞应用技术股份有限公司 | Hollow microparticle |
| CN105820332A (en) * | 2015-01-09 | 2016-08-03 | 北京化工大学 | Star polyaminoacid and star polyaminoacid drug-loaded nano micelle and preparation method thereof |
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| CN109503848A (en) * | 2018-11-02 | 2019-03-22 | 宜春学院 | A kind of nanoscale medicine delivery system of hepatoma-targeting and its preparation method and application |
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| WO2015127900A1 (en) * | 2014-02-27 | 2015-09-03 | 国玺干细胞应用技术股份有限公司 | Hollow microparticle |
| CN105820332A (en) * | 2015-01-09 | 2016-08-03 | 北京化工大学 | Star polyaminoacid and star polyaminoacid drug-loaded nano micelle and preparation method thereof |
| CN105820332B (en) * | 2015-01-09 | 2018-06-29 | 北京化工大学 | A kind of star polyaminoacid and star polyaminoacid medicament-carried nano micelle and preparation method |
| CN104815341A (en) * | 2015-03-27 | 2015-08-05 | 浙江大学 | Targeted polymer micelle magnetic nanoparticle, and preparation method and application thereof |
| CN106137962A (en) * | 2016-07-27 | 2016-11-23 | 毕云科 | A kind of glioma target polymer micelle loading carmustine and preparation method thereof |
| CN106137962B (en) * | 2016-07-27 | 2019-10-01 | 毕云科 | A kind of glioma target polymer micella and preparation method thereof loading Carmustine |
| CN114681683A (en) * | 2016-09-30 | 2022-07-01 | 东丽株式会社 | Adhesion-preventing material |
| CN109503848A (en) * | 2018-11-02 | 2019-03-22 | 宜春学院 | A kind of nanoscale medicine delivery system of hepatoma-targeting and its preparation method and application |
| CN113717381A (en) * | 2021-10-11 | 2021-11-30 | 中国海洋大学 | Rhamnosyl linear and dendritic-star polymer, preparation method and application |
| CN114159393A (en) * | 2021-12-10 | 2022-03-11 | 上海中医药大学 | Tetrandrine-loaded hybrid nanoparticles, tetrandrine-loaded soluble microneedle drug delivery system and preparation method thereof |
| CN114159393B (en) * | 2021-12-10 | 2023-03-10 | 上海中医药大学 | Tetrandrine-loaded hybrid nanoparticles, tetrandrine-loaded soluble microneedle drug delivery system and preparation method thereof |
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Application publication date: 20120523 |