CN103976948A - Polymer medicament containing polyacrylic acid - Google Patents
Polymer medicament containing polyacrylic acid Download PDFInfo
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- CN103976948A CN103976948A CN201410181756.0A CN201410181756A CN103976948A CN 103976948 A CN103976948 A CN 103976948A CN 201410181756 A CN201410181756 A CN 201410181756A CN 103976948 A CN103976948 A CN 103976948A
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Abstract
The invention discloses a polymer medicament containing polyacrylic acid. Acrylic acid is subjected to an atom transfer radical polymerization reaction to obtain polyacrylic acid. Glutamic acid octadecanyl glutamate carboxylic acid anhydride is subjected to a ring-opening polymerization reaction to obtain poly(octadecanyl glutamate). The poly(octadecanyl glutamate) is grafted to doxorubicin through a hydrazone bond. The polyacrylic acid is bonded to the poly(octadecanyl glutamate) in a manner of click chemistry to obtain a block copolymer. The block copolymer is respectively dissolved in tetrahydrofuran to obtain a solution. The solution is transferred to a dialysis bag for carrying out a dialysis process through pure water to obtain a dialysate which is filtered through a filter membrane. A freeze drying process is carried out to the filtered solution to obtain a medicament carrier micelle. The drug carrier micelle has a core-shell double-layer structure with an external layer being hydrophilic polyacrylic acid and an internal layer being medicament molecule wrapping layer. The drug carrier micelle has advantages of belonging to nano particles and enabling a targeting transmission of a drug to cancer cells and a pH-sensitive releasing process in the cancer cells to be achieved. The drug carrier micelle is large in drug carrying capacity and good in stability. A targeting function of the drug carrier micelle can effectively reduce toxic and side effects of drugs on normal tissues and organs.
Description
Affiliated technical field
The present invention relates to a kind of polyacrylic polymeric medicine that contains, particularly relate to a kind of preparation method with the block macromolecular material pharmaceutical carrier microcapsule of cancer cell targeting.Belong to polymer chemistry and technical field of polymer.
Background technology
Cancer has become the main disease of harm humans health, and one of important means for the treatment of cancer is Drug therapy, yet many cancer therapy drugs exist defects such as being insoluble in water, poor stability.If camptothecine, paclitaxel, amycin, 5-fluorouracil etc. are all because poor solubility is difficult to be utilized well by organism, solve the crux that its water solublity problem is this class pharmaceutical preparation clinical practice.In addition, its effect of oncotherapy and diagnostic medicine is nonselective mostly, and some normal structure organs often have more distribution, and under therapeutic dose, normal tissue organ toxic and side effects is large.Therefore how to solve solubilising slightly solubility cancer therapy drug and increase medicine stability, improve extremely urgent to the selectivity of cancerous cell.Therefore, finding a kind of reliable target medicine carrier is the key that solves above two problems.
What macromolecule micelle pharmaceutical carrier generally adopted is all linear polymeric micelle.The research work that Bae seminar carries out is the most noticeable, and it points out in delivered research paper, with hydrazone key, Dox key is linked on main polymer chain, and is utilized in cancerous cell microenvironment pH to be faintly acid to make hydrazone bond fission, and the target spot of having realized Dox discharges.And, one piece of paper (Bae Y, Jang W-D, Nishiyama N, Fukushima S, Kataoka K. that Bae delivered on Molecular BioSystems magazine in 2005
mol BioSyst2005; 1 (3): 242-250.), first simultaneously by Fol and Dox respectively key link PEG and PASP(poly-aspartate) on, thereby the targeted delivery and the target spot that have medicine concurrently discharge multifunctionality, and fluidic cell experiment (FCM) shows that cell is not more significantly increased containing the polymer micelle of Fol the intake of polymer micelle.Gong Shaoqin seminar has also been engaged in similar research.It is with poly
caprolactone random copolymer is kernel, and PEG is shell, has prepared polymer nano micelle.With hydrazone key, connect Dox, and utilize Fol to modify PEG end group, prepared pH responsive type target drug-carrying micelle, cellular uptake amount and cytotoxicity have been tested, proof Dox under acid condition discharges (Yang X, Grailer JJ, Pilla S fast due to the fracture of hydrazone key, Steeber DA, Gong S.
bioconjugate Chem2010; 21 (3): 496-504.).
Although linear polymer micelle, as the carrier of poorly water soluble drugs, has demonstrated huge advantage and potentiality in passing medicine process, but still there is micelle poor stability, solubilizing effect is not obvious, drug release rate is low problem.The drug loading of polymer micelle can only reach 5% left and right conventionally at present, obtain higher drug loading very difficult.Research discovery, polymer connects medicine monomer by chemical bond, can reach higher drug loading.And linear block copolymers load capacity is often on the low side, if but cross multikey to connect its micellar structure of drug molecule unstable again.And star-type polymer can overcome this deficiency.
The Yan De of Shanghai Communications University high mountain (Liu J, Pang Y, Huang W, Huang X, Meng L, Zhu X, Zhou Y, Yan D.
biomacromolecules2011; 12 (5): 1567-1577.) synthesized dendroid poly phosphate-polylactic-acid block copolymer and be applied to pharmaceutical carrier research, after parcel Dox, HeLa cell has been had to obvious inhibitory action.Another representative research is that Chinese University of Science and Technology's Liu's generation is brave, utilizes functionalization
cyclodextrin has been prepared the polymaleic anhydride star-type polymer of modifying with Fol and Dox, and key has connected the gadolinium element to magnetic resonance effect sensitivity simultaneously, in mouse experiment, finds, the gathering of polymer micelle at liver, kidney position has obvious reinforcement (Liu T, Li X, Qian Y, Hu X, Liu S.
biomaterials2012; 33 (8): 2521-2531.).
But because polymer architecture in star-type polymer is comparatively complicated, prepared pharmaceutical carrier occurs that biocompatibility is poor, drug encapsulation ability declines, the problems such as dendrimer surface drug macromolecule water-solubility reduction.In addition, dendrimer complex structure, synthetic cost is higher.These problems have all limited the application of star-type polymer nano medicament carrying system.Therefore, no matter be property polymer or common star-type polymer pharmaceutical carrier, can not possess: target-oriented drug simultaneously, high drug loading ability, micellar structure is stable, the pH sensitivity that target spot discharges, high these several the clinical practices to polymer drug carrier system of biocompatibility play the performance of most important effect.
Summary of the invention
The object of the invention is to set up a kind of polyacrylic polymeric medicine that contains, this pharmaceutical carrier microcapsule has the following advantages: belong to nanoparticle; Can realize medicine discharges pH sensitivity in cancerous cell targeted delivery and cancerous cell; Drug loading is large; Good stability; Its target function can effectively reduce medicine normal tissue organ toxic and side effects.
This micelle is a kind of star block copolymer with hydrophilic and hydrophobicity block; Amycin key can be connected with block polymer on; Macromolecular material has two hydrophilic segments, a hydrophobic segment: its hydrophilic section of macromolecular material is polyacrylic acid, by folic acid, modifies.Hydrophobic section is polyglutamic acid, by hydrazone keyed jointing branch amycin; High molecular micellar structure has nucleocapsid double-decker, and skin is hydrophilic polyacrylic, and internal layer is drug molecule integument.
Described block polymer is the polymer in following structural formula:
The technology of preparing scheme of block copolymer microcapsule is as follows:
1) prepare nitrine micromolecule initiator
2) polyacrylic atom transfer radical polymerization
3) both arms alkynes end group polyglutamic acid octadecane ester is synthetic
?
4) Dox molecule is connected with the hydrazone key of polyglutamic acid octadecane ester
?
5) star block copolymer is synthetic
6) prepare capsule of nano
By dialysis, prepare polymer nanocomposite microcapsule.Concrete grammar is: one or both star polymers are dissolved in respectively after THF, move in bag filter, with 1000 mL pure water dialysis, refresh the water periodically.Dialysis solution is with after membrane filtration, and lyophilization obtains copolymer carrier micelle.
By above technical scheme, tool of the present invention has the following advantages: 1) little containing polyacrylic polymeric medicine volume, there is nanoscale structures, and can pass through various barriers in human body;
2) little containing polyacrylic polymeric medicine critical micelle concentration, Stability Analysis of Structures;
3) large containing polyacrylic polymeric medicine drug loading amount, and good biocompatibility;
4) containing polyacrylic polymeric medicine, there is targeting and discharge pharmic function, can effectively reduce medicine normal tissue organ toxic and side effects.
Accompanying drawing explanation
Fig. 1 is this high molecular structural representation;
Fig. 2 is the schematic diagram of this high molecule microcapsule;
Fig. 3 is the AFM scintigram of this high molecule microcapsule.
The specific embodiment
For making enforcement object of the present invention, technical scheme and advantage more clear, below in conjunction with the drawings and specific embodiments of the present invention, the present invention is described in detail:
As shown in Figure 1, be the chemical constitution schematic diagram containing polyacrylic polymeric medicine.This macromolecule is AB
22. type block macromolecular, have two hydrophilic section, and 3. a hydrophobic section forms.Key on each segment has connected different molecular structures:
2. be to prepare by Transfer Radical Polymerization;
Utilize the resulting five-membered ring of 1,3-Dipolar Cycloaddition and polyglutamic acid 3. to carry out coupling;
Utilize hydrazone key by segment 3. with amycin molecule 4. key link up.
As shown in Figure 2, a kind of containing polyacrylic polymeric medicine by this AB
2assorted arm star block macromolecular assembling forms.Its structure is respectively by 1. active end group; 2. polyacrylic acid molecule; 3. polyglutamic acid; 4. the composition such as amycin molecule.Macromolecule by hydrophobic interaction, can self assembly be spherical micellar structure in aqueous solution, and high molecular microcapsule structure has nucleocapsid double-decker:
Skin be hydrophilic polyacrylic 2.;
Internal layer be polyglutamic acid 3., be drug molecule integument, internal layer can make drug molecule be wrapped in spheroid inside, thereby realizes medicine delivery function.
Figure 3 shows that AB
2the AFM scanogram of the assorted arm star block copolymer spherical microcapsule structure that self assembly forms in aqueous solution.Proof macromolecule forms globular micelle structure homogeneous, and good dispersion is not reunited in aqueous solution, is conducive to realize the delivery of drug molecule and release function.
Provide embodiment below so that the present invention is specifically described; but it is worthy of note that following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that the person skilled in the art in this field makes the present invention according to the invention described above content and adjustment still belong to protection scope of the present invention.
Embodiment 1:
1. for nitrine micromolecule initiator
Step 1: 2-chloroethoxy ethanol 5mL is dissolved in 25mL butanone, adds 4.5g NaN in solution
3, 2.5gBu
4nI, 10mg bicyclohexane also-hexaoxacyclooctadecane-6-6, by mixture be heated to boiling, stir 24 hours.Mixture is filtered, and precipitation is carried out cleaning down with acetone.Resulting mixed solution is the crude product of product, after mixed solution is concentrated, 90
oc distills and obtains pure substance.Resulting 2-nitrine ethoxy ethanol
1h NMR (CDCl
3):
δ3.70 (t, 2 H, C
h 2oH), 3.65 (t,
2h, HOCH
2c
h 2o), 3.56 (t, 2H, N
3cH
2c
h 2o), 3.37 (t, 2H, C
h 2n
3), and 2.56 (s, 1H, OH).
Step 2: by a kind of 2-nitrine ethoxy ethanol 2g making of step, alpha-chloro acyl chlorides 5.09g is dissolved in 30mL dichloromethane, and reaction system is transferred in ice territory, slowly adds 6.8g dicyclohexylcarbodiimide in reaction vessel, and stirs.0.4g dimethylamino naphthyridine is dissolved in dichloromethane and was splashed in reaction vessel in 10 minutes.Whole reaction system is 0
ounder C condition, react 1 hour, then at room temperature react 24 hours.The cyclohexyl urea being precipitated out in course of reaction is filtered, and wash with dichloromethane.With sodium bicarbonate solution (5%), extract, then with anhydrous magnesium sulfate, be dried.After reduced vacuum is dry, with silica gel chromatographic column, carry out separation, finally obtain product 2-chloro nitrine Ethoxyethane.
1H?NMR?(CDCl
3):
δ4.30?(t,?2H,?CH
2OCO),?3.73?(t,?2H,?COOCH
2C
H 2O),?3.67?(t,?2H,?N
3CH
2C
H 2O),?3.35?(t,?2H,?C
H 2N
3),?and?1.92?(s,?6H,?(CH
3)
2C)。
2. polyacrylic atom transfer radical polymerization
2-nitrine ethyoxyl bromo acid 12mg by obtaining in step 2, is dissolved in 25mL DMSO and in the ratio of 2:1:1, adds methanol, bipyridyl and cuprous bromide simultaneously with 5.4g acrylic acid.By bleeding-ventilate for three times-thaw cycles carries out tube sealing to polymerization pipe.After polymerization 24 hours, with methanol, polymer is precipitated out, filters, dry stand-by.The prepared polyacrylic acid of 2g is dissolved in 20mL dichloromethane, adds 2.8mL ethylenediamine, polyacrylic terminal groups is modified, obtain the polymer of end group band primary amine.The polyacrylic acid that 2g end group is modified is warming up to 50
oc reacts 6h.After having reacted, reactant liquor is packed into bag filter (MWCO=3500), after dialysing 2 days, remove free folic acid in deionized water, change water every day 3 times.Dialysis solution ether sedimentation, vacuum drying obtains product.
3. both arms alkynes end group polyglutamic acid octadecane ester is synthetic
Step 1: by 16.8g 3,5-methyl dihydroxy benzoate and 26.2g propargyl bromide are dissolved in 300mL acetone, add 15.1g sodium carbonate in solution, 0.1g bicyclohexane also-hexaoxacyclooctadecane-6-6.Reaction solution is heated to reflux, reacts 24 hours.After reaction finishes, by sedimentation and filtration, filtrate is carried out concentrating under reduced pressure, carries out recrystallization in methanol, obtains product 3,5-diacetylene p-methoxybenzoic acid methyl ester.
1H?NMR?in?CDCl
3,?
δ(ppm):?2.55?(2H,?
CCH),?3.91(3H,?
CH 3 O),?4.73?(4H,?
CH 2 CCH),?6.82?(1H,?aromatic),?7.29?(2H,?aromatic)。
Step 2: by 6.25g3,5-diacetylene p-methoxybenzoic acid methyl ester is dissolved in 30mL methanol, is dissolved in 73.9g ethylenediamine in 120mL ethylenediamine, and 0
ounder C condition, be slowly added dropwise in reaction vessel, dropping process needs about 1 hour, and under room temperature, reacts 96 hours after being added dropwise to complete again.Be less than 40
oin the water-bath of C, revolve to steam and remove unnecessary solvent, utilizing the mixed solution of benzene/methanol (9/1 v/v) to carry out recrystallization to mixed solution, in vacuum drying oven, be dried 24 hours, obtain product N-amine ethyl 3,5-diethyl alkynyloxy group aniline.
1H?NMR?in?CDCl
3,?
δ(ppm):?1.61?(2H,
CH
2 NH 2),?2.55?(2H,?
CCH),?2.95?(2H,?
CH 2NH
2),?3.49?(2H,?CONH
CH 2),?4.73?(4H,?
CH 2CCH),?6.68?(1H,?CO
NH),?6.76?(1H,?aromatic),?7.05?(2H,?aromatic)。
Step 3: by resulting product N-amine ethyl 3 in 0.16g step 2,5-diethyl alkynyloxy group aniline is as initiator, utilize ring-opening polymerisation mode polymer poly glutamic acid octadecane ester carboxylic acid anhydrides 5.19g, monomer and initiator are added in polymerization pipe, and add dry DMF 15mL, under room temperature, react 24 hours.Polymer precipitates with absolute ether, dry 24 hours of vacuum drying oven.Obtain product both arms alkynes end group polyglutamic acid octadecane ester.
4. amycin molecule is connected with the hydrazone key of polyglutamic acid octadecane ester
The both arms alkynes end group polyglutamic acid octadecane ester obtaining in 5.8mL hydrazine and 2.43g above-mentioned steps is dissolved in the dry DMF of 25mL, reaction system is heated to 40
oc, reacts 1 hour.Thick product is precipitated with absolute ether, and by sedimentation and filtration, dry 24 hours of vacuum drying oven, obtains amido both arms alkynes end group polyglutamic acid octadecane ester.This product 5g and 0.34g amycin monomer are dissolved in DMSO, reaction system is heated to 30
oc, reacts 48 hours, and the reaction mixture obtaining precipitates with absolute methanol, and by sedimentation and filtration, dry 24 hours of vacuum drying oven.Make the polyglutamic acid octadecane ester of amycin molecule grafting.
5. AB
2synthesizing of assorted arm star block copolymer
The polyacrylic acid that 3.8g end group is modified and the polyglutamic acid octadecane ester of 7.8g amycin molecule grafting are dissolved in 20mL dry DMF, and add 6.93mg PMDETA.Reaction system is carried out to bleed-ventilation-thaw cycles three times, add rapidly cuprous bromide 5.47mg.Reaction is 35
ounder C condition, react 24 hours.React resulting mixed solution and cross silicagel column to remove unnecessary mantoquita and other impurity.After solution is concentrated, with absolute methanol, precipitate, finally obtain AB
2assorted arm star block copolymer.
6. the preparation of polymer nanocomposite microcapsule
By dialysis, prepare polymer nanocomposite microcapsule.Concrete grammar is: one or both star polymers are dissolved in respectively after THF, move in bag filter, with 1000 mL pure water dialysis, refresh the water periodically.Dialysis solution is with after membrane filtration, and lyophilization obtains copolymer drug-loading microcapsule.
Finally it should be noted that, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art should understand, can a minute technical scheme for invention be modified or be replaced on an equal basis, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of claim scope of the present invention.
Claims (8)
1. containing a polyacrylic polymeric medicine, its architectural feature is: described macromolecular material is the AB being formed by two hydrophilic polyacrylic acid segments and the coupling of a hydrophobic polyglutamic acid octadecane ester segment
2type copolymer.
2. prepare the method containing polyacrylic polymeric medicine claimed in claim 1 and carry out as follows for one kind:
1) for causing nitrine micromolecule initiator synthetic of acrylic monomers;
2) utilize folic acid micromolecule to carry out NHS activation, prepare folic acid-NHS molecule;
3) utilize the prepared nitrine micromolecule initiator of step 1), cause acrylic acid micromolecule and carry out atom transfer radical polymerization, obtain polyacrylic acid; Utilize folic acid-NHS molecular modification polyacrylic acid simultaneously;
4) both arms alkynes end group polyglutamic acid octadecane ester is synthetic;
5) utilize amycin molecule to carry out grafting to polyglutamic acid octadecane ester, this reaction is to utilize hydrazone key to connect;
6) utilize the synthetic star block copolymer of click chemistry reaction;
7) by dialysis, prepare polymer nano micelle.
3. a kind of preparation method containing polyacrylic polymeric medicine according to claim 2, is characterized in that solvent that in said method, step 1) synthesized nitrine micromolecule initiator is used is any in acetone, butanone, dioxane, acetonitrile.
4. a kind of preparation method containing polyacrylic polymeric medicine according to claim 2, is further characterized in that the polymerization single polymerization monomer that in said method, step 4) is used is glutamic acid octadecane ester carboxylic acid anhydrides.
5. a kind of preparation method containing polyacrylic polymeric medicine according to claim 2, is further characterized in that the polymer coupling reaction that in said method, step 6) is carried out must adopt Huisgen 1,3-Dipolar Cycloaddition.
6. a kind of preparation method containing polyacrylic polymeric medicine according to claim 2, is further characterized in that and in said method, needs to adopt following micromolecule initiator:
1) 2-chloro nitrine Ethoxyethane
2) N-amine ethyl 3,5-diethyl alkynyloxy group aniline.
7. according to claim 2 a kind of containing polyacrylic polymeric medicine, be further characterized in that: this macromolecular material is by the formed star block copolymer of coupling by the polyacrylic acid segment of modified with folic acid and the polyglutamic acid of amycin grafting.
8. a kind of polyacrylic polymeric medicine that contains according to claim 2, is further characterized in that: described macromolecule micelle has nucleocapsid double-decker, and skin is hydrophilic polyacrylic, and internal layer is drug molecule integument.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105169406A (en) * | 2015-09-10 | 2015-12-23 | 成都市龙华新科技有限公司 | Macromolecular drug microcapsule containing polyacrylamide |
| CN111875721A (en) * | 2020-07-24 | 2020-11-03 | 广西民族大学 | Modified polyacrylic acid copolymer and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104415344A (en) * | 2013-08-30 | 2015-03-18 | 成都市绿科华通科技有限公司 | Polymer drug microcapsule containing polyacrylic acid |
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2014
- 2014-04-30 CN CN201410181756.0A patent/CN103976948A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104415344A (en) * | 2013-08-30 | 2015-03-18 | 成都市绿科华通科技有限公司 | Polymer drug microcapsule containing polyacrylic acid |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105169406A (en) * | 2015-09-10 | 2015-12-23 | 成都市龙华新科技有限公司 | Macromolecular drug microcapsule containing polyacrylamide |
| CN111875721A (en) * | 2020-07-24 | 2020-11-03 | 广西民族大学 | Modified polyacrylic acid copolymer and preparation method and application thereof |
| CN111875721B (en) * | 2020-07-24 | 2023-04-07 | 广西民族大学 | Modified polyacrylic acid copolymer and preparation method and application thereof |
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Application publication date: 20140813 |