CN104448331A - Anticancer macromolecule drug preparation method - Google Patents
Anticancer macromolecule drug preparation method Download PDFInfo
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- CN104448331A CN104448331A CN201310422035.XA CN201310422035A CN104448331A CN 104448331 A CN104448331 A CN 104448331A CN 201310422035 A CN201310422035 A CN 201310422035A CN 104448331 A CN104448331 A CN 104448331A
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Abstract
The present invention discloses an anticancer macromolecule drug preparation method, which comprises: adopting an atom transfer radical polymerization method to polymerize methacrylic acid to obtain polymethacrylic acid; modifying the polymethacrylic acid with folic acid molecules; adopting a ring-opening polymerization method to polymerize aspartic acid benzyl ester carboxylic anhydride to obtain poly aspartic acid benzyl ester; grafting adriamycin on the poly aspartic acid benzyl ester; bonding the polymethacrylic acid and the poly aspartic acid benzyl ester through a click chemistry method to obtain a block copolymer; respectively dissolving the block polymer in tetrahydrofuran, transferring into a dialysis bag, carrying out dialysis with purified water, and filtering the dialyzed solution with a filtration membrane; and carrying out freeze-drying on the filtered solution to obtain the drug-loaded micelles, wherein the drug carrier micelles have a core-shell double-layer structure, the outer layer is the hydrophilic polymethacrylic acid, and the inner layer is the drug molecule wrapping layer. According to the present invention, the material has the following advantages that: the material belongs to the nanoparticles; the targeted drug delivery on the cancer cells and the pH-sensitive drug release in the cancer cells can be achieved; the drug loading is high; the stability is good; and with the targeting function, the toxic-side effect of the drug on the normal tissues and organs can be effectively reduced.
Description
Technical field
The present invention relates to a kind of preparation method of anticancer polymer drug, particularly relate to a kind of preparation method with the block macromolecular material pharmaceutical carrier micella 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 of Therapeutic cancer is pharmacological agent, but many cancer therapy drugs also exist and are insoluble in the defect such as water, poor stability.As camptothecine, taxol, Zorubicin, 5 FU 5 fluorouracil etc. are all difficult to because of poor solubility be utilized well by organism, solve the crux that its water solubility problems is this kind of pharmaceutical preparation clinical application.In addition, oncotherapy and its effect of diagnostic medicine are nonselective mostly, and some healthy tissues organs often have more distribution, and under therapeutic dose, normal tissue organ toxic side effect is large.Therefore solve how solubilising insoluble cancer therapy drug and increase medicine stability, improve the selectivity of cancer cells extremely urgent.Therefore, finding a kind of reliable target medicine carrier is the key solving above two problems.
What macromolecule micelle pharmaceutical carrier generally adopted is all linear polymeric micella.The research work that Bae seminar carries out is the most noticeable, and it points out in delivered research paper, is linked on main polymer chain by Dox key with hydrazone key, and utilizes pH in cancer cells microenvironment to be that slightly acidic makes hydrazone bond rupture, achieves the target spot release of Dox.And, one section 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 aspartic acid) on, thus having targeted delivery and the target spot release multifunctionality of medicine concurrently, Flow cytometry experiments (FCM) shows that cell is not 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 polymaleic acid
caprolactone random copolymers is kernel, and PEG is shell, has prepared polymer nano micelle.Dox is connected with hydrazone key, and the PEG end group that utilized Fol to modify, prepare pH responsive type target drug-carrying micella, test cellular uptake amount and cytotoxicity, prove that Dox discharges (Yang X, Grailer JJ, Pilla S fast due to the fracture of hydrazone key in acid condition, Steeber DA, Gong S.
bioconjugate Chem2010; 21 (3): 496-504.).
Although linear polymer micella is as the carrier of poorly water soluble drugs, demonstrate huge advantage and potential passing in medicine process, but still there is micella poor stability, solubilizing effect is not obvious, drug release rate is low problem.The drug loading of current polymer micelle can only reach about 5% usually, obtain higher drug loading very difficult.Research finds, polymkeric substance connects medicine monomer by chemical bond, can reach higher drug loading.And linear block copolymers carrying 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.
Shanghai Communications University Yan De high mountain (Liu J, Pang Y, Huang W, Huang X, Meng L, Zhu X, Zhou Y, Yan D.
biomacromolecules2011; 12 (5): 1567-1577.) synthesize dendroid poly phosphate-polylactic-acid block copolymer and be applied to pharmaceutical carrier research, after parcel Dox, have obvious restraining effect to HeLa cell.Another representative research is that Chinese University of Science and Technology Liu generation is brave, utilizes functionalization
the polymaleic anhydride star-type polymer modified with Fol and Dox prepared by cyclodextrin, and key has connected the gadolinium element to magnetic resonance effect sensitivity simultaneously, finds in mouse experiment, polymer micelle has obvious reinforcement (Liu T, Li X, Qian Y in the gathering at liver, kidney position, Hu X, Liu S.
biomaterials2012; 33 (8): 2521-2531.).
But because polymer architecture in star-type polymer is comparatively complicated, poor biocompatibility appears in prepared pharmaceutical carrier, drug encapsulation ability declines, the problems such as dendrimer surface drug macromolecule water-solubility reduction.In addition, dendrimer complex structure, synthesis cost is higher.These problems all limit the application of star-type polymer nano medicament carrying system.Therefore, no matter be property polymkeric substance or common star-type polymer pharmaceutical carrier, can not possess: target-oriented drug simultaneously, high drug carrying capacity, micellar structure is stablized, the pH susceptibility of target spot release, biocompatibility height these several plays the performance of most important effect to the clinical application of polymer drug carrier system.
Summary of the invention
The object of the invention is the preparation method setting up a kind of anticancer polymer drug, this pharmaceutical carrier micella has the following advantages: belong to nanoparticle; Medicine can be realized to pH susceptibility release in cancer cells targeted delivery and cancer cells; Drug loading is large; Good stability; Its target function can effectively reduce medicine normal tissue organ toxic side effect.
This micella is a kind of star block copolymer with wetting ability and hydrophobic block; Can by Zorubicin key connect with block polymer on; Macromolecular material has two hydrophilic segments, a hydrophobic segment: its hydrophilic section of macromolecular material is polymethyl acrylic acid, is modified by folic acid.Hydrophobic section is poly aspartic acid, by hydrazone keyed jointing branch Zorubicin; High molecular micellar structure has nucleocapsid bilayer structure, and skin is wetting ability polymethyl acrylic acid, and internal layer is drug molecule integument.
Described block polymer is the polymkeric substance in following structural formula:
The technology of preparing scheme of block copolymer micelle is as follows:
1) nitrine small molecules initiator is prepared
2) synthesis of folic acid-NHS molecule
3) atom transfer radical polymerization of polymethyl acrylic acid and modified with folic acid
4) synthesis of both arms alkynes end group poly aspartic acid benzyl ester
5) Dox molecule is connected with the hydrazone key of poly aspartic acid benzyl ester
6) synthesis of star block copolymer
7) nano-micelle is prepared
Polymer nano micelle is prepared by dialysis method.Concrete grammar is: after one or both star polymers are dissolved in THF respectively, moves in dialysis tubing, with 1000 mL pure water dialysis, refreshes the water periodically.After dialyzate membrane filtration, lyophilize obtains copolymer carrier micelle.
By above technical scheme, tool of the present invention has the following advantages: 1) this anticancer polymer drug volume is little, has nanoscale structures, can pass through various barrier in human body;
2) this anticancer polymer drug micelle-forming concentration is little, Stability Analysis of Structures;
3) this anticancer polymer drug charge capacity is large, and good biocompatibility;
4) this anticancer polymer drug has Targeting delivery pharmic function, can effectively reduce medicine normal tissue organ toxic side effect.
Accompanying drawing explanation
Fig. 1 is this high molecular structural representation;
Fig. 2 is the schematic diagram of this macromolecule micelle;
Fig. 3 is the AFM scintigram of this macromolecule micelle.
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 structure schematic diagram of this anticancer polymer drug.This polymer is AB
22. type block macromolecular, have two hydrophilic section, and 3. a hydrophobic section formed.Key on each segment has connected different molecular structures:
Folic acid small molecules 1. key is connected in polymethyl acrylic acid molecule segment and 2. goes up, and is 2. prepared by Transfer Radical Polymerization;
3. the five-ring utilizing 1,3-Dipolar Cycloaddition to obtain and poly aspartic acid carry out coupling;
Utilize hydrazone key by segment 3. with Doxorubicin molecules 4. key link up.
As shown in Figure 2, this anticancer polymer drug is by this AB
2assorted arm star block macromolecular assembling is formed.Its structure is respectively by 1. folic acid small molecules; 2. polymethyl acid molecule; 3. poly aspartic acid; 4. the composition such as Doxorubicin molecules.Polymer is in aqueous by hydrophobic interaction, and can self-assembly be spherical micellar structure, high molecular micellar structure has nucleocapsid bilayer structure:
Skin be wetting ability polymethyl acrylic acid 2.;
Internal layer be poly aspartic acid 3., be drug molecule integument, internal layer can make drug molecule be wrapped in ball interior, thus realizes drug carrier function.
Figure 3 shows that AB
2assorted arm star segmented copolymer is the AFM scan image of globular micelle structure that formed of self-assembly in aqueous.Prove that polymer forms globular micelle structure homogeneous, good dispersity, does not reunite in aqueous, is conducive to realizing the delivery to drug molecule and release function.
Provide embodiment below to be specifically described the present invention; 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. nitrine small molecules initiator is prepared
Step one: 2-chloroethoxyethanol 5mL is dissolved in 25mL butanone, adds 4.5g NaN in solution
3, 2.5gBu
4nI, 10mg bicyclohexane also-hexaoxacyclooctadecane-6-6, mixture is heated to boiling, stir 24 hours.Filtered by mixture, precipitation acetone carries out cleaning down.The mixing solutions obtained is the crude product of product, after mixing solutions is concentrated, 90
oc carries out distillation and obtains pure substance.The 2-nitrine ethoxy ethanol obtained
1h NMR (CDCl
3):
3.70 (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 for step obtained 2-nitrine ethoxy ethanol 2g, alpha-chloro acyl chlorides 5.09g is dissolved in 30mL methylene dichloride, reaction system is transferred in ice territory, 6.8g dicyclohexylcarbodiimide is slowly added in reaction vessel, and stir.0.4g Dimethylamino pyridine is dissolved in methylene dichloride and instilled in reaction vessel in 10 minutes.Whole reaction system is 0
oreact 1 hour under C condition, then at room temperature react 24 hours.The cyclohexyl urea be precipitated out in reaction process is filtered, and washs with methylene dichloride.Extract with sodium hydrogen carbonate solution (5%), then carry out drying with anhydrous magnesium sulfate.After reduced vacuum drying, be separated with silica gel chromatographic column, finally obtain product 2-chloro nitrine Ethoxyethane.
1H NMR (CDCl
3):
4.30 (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. the synthesis of folic acid-NHS molecule
By 1.0g folic acid and 0. 495g N, N-dicyclohexylcarbodiimide (DCC) and 0. 463g N-hydroxysuccinimide (NHS) are dissolved in 20mL DMSO, at N
2the lower room temperature reaction 24h of protection, cross and filter byproduct of reaction N, N-dicyclohexyl urine (DCU), utilizes silica gel chromatographic column to be separated, can obtain folic acid-NHS molecule.
3. the atom transfer radical polymerization of polymethyl acrylic acid and modified with folic acid
By the 2-nitrine oxyethyl group bromo acid 12mg obtained in step 2, add methyl alcohol, dipyridyl and cuprous bromide with the 5.4g methacrylic acid ratio be dissolved in simultaneously in 2:1:1 in 25mL DMSO.By bleeding-ventilate for three times-thaw cycles carries out tube sealing to polymerizing pipe.Be polymerized after 24 hours, with methyl alcohol, polymkeric substance be precipitated out, filter, dry stand-by.Polymethyl acrylic acid obtained by 2g is dissolved in 20mL methylene dichloride, adds 2.8mL quadrol, the terminal group of polymethyl acrylic acid is modified, obtain the polymkeric substance of end group band primary amine.The polymethyl acrylic acid that 2g end group is modified is warming up to 50
oc reacts 6h.Reaction solution is loaded dialysis tubing (MWCO=3500) after having reacted, the 2 days free folic acid of removing afterwards of dialysing in deionized water, changes water every day 3 times.Dialyzate ether sedimentation, vacuum-drying obtains product.
4. the synthesis of both arms alkynes end group poly aspartic acid benzyl ester
Step one: 16.8g 3,5-methyl dihydroxy benzoate and 26.2g propargyl bromide are dissolved in 300mL acetone, add 15.1g sodium carbonate in the solution, 0.1g bicyclohexane also-hexaoxacyclooctadecane-6-6.Reaction soln is carried out be heated to backflow, react 24 hours.By sedimentation and filtration after reaction terminates, filtrate carries out concentrating under reduced pressure, in methyl alcohol, carry out recrystallization, obtains product 3,5-diacetylene aminobenzoic acid methyl esters.
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: 6.25g3,5-diacetylene aminobenzoic acid methyl esters is dissolved in 30mL methyl alcohol, 73.9g quadrol is dissolved in 120mL quadrol, and 0
oslowly be added dropwise in reaction vessel under C condition, the process that drips needs 1 hours, and reaction 96 hours under room temperature again after being added dropwise to complete.Be less than 40
orevolve in the water-bath of C to steam and remove unnecessary solvent, utilizing the mixing solutions of benzene/methyl alcohol (9/1 v/v) to carry out recrystallization to mixing solutions, in vacuum drying oven, drying 24 hours, obtains 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 the product N-amine ethyl 3 obtained in 0.16g step 2,5-diethyl alkynyloxy group aniline is as initiator, utilize ring-opening polymerization mode polymer poly aspartic acid benzyl ester carboxylic acid anhydride 5.19g, monomer and initiator are added in polymerizing pipe, and add dry DMF 15mL, react 24 hours under room temperature.Polymkeric substance anhydrous diethyl ether precipitates, dry 24 hours of vacuum drying oven.Obtain product both arms alkynes end group poly aspartic acid benzyl ester.
5. Doxorubicin molecules is connected with the hydrazone key of poly aspartic acid benzyl ester
The both arms alkynes end group poly aspartic acid benzyl ester obtained 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 anhydrous diethyl ether is precipitated, and by sedimentation and filtration, dry 24 hours of vacuum drying oven, obtains amido both arms alkynes end group poly aspartic acid benzyl ester.This product 5g and 0.34g Zorubicin monomer are dissolved in DMSO, reaction system is heated to 30
oc, react 48 hours, the reaction mixture anhydrous methanol obtained precipitates, and by sedimentation and filtration, dry 24 hours of vacuum drying oven.The poly aspartic acid benzyl ester of obtained Doxorubicin molecules grafting.
6. AB
2the synthesis of assorted arm star segmented copolymer
The polymethyl acrylic acid modify 3.8g end group and the poly aspartic acid benzyl ester of 7.8g Doxorubicin molecules grafting are dissolved in 20mL dry DMF, and add 6.93mg PMDETA.Reaction system is carried out-ventilation-thaw cycles of bleeding for three times, add rapidly cuprous bromide 5.47mg.Reaction is 35
oreact 24 hours under C condition.React the mixing solutions obtained and cross silicagel column to remove unnecessary mantoquita and other impurity.The concentrated later anhydrous methanol of solution precipitates, and finally obtains AB
2assorted arm star segmented copolymer.
7. the preparation of polymer nano micelle
Polymer nano micelle is prepared by dialysis method.Concrete grammar is: after one or both star polymers are dissolved in THF respectively, moves in dialysis tubing, with 1000 mL pure water dialysis, refreshes the water periodically.After dialyzate membrane filtration, lyophilize obtains copolymer carrier micelle.
Finally it should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art should understand, can a point 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 right of the present invention.
Claims (8)
1. an anticancer polymer drug, its constitutional features is: described macromolecular material is the AB by two hydrophilic polymethyl acrylic acid segments and the coupling of a hydrophobic poly aspartic acid benzyl ester segment
2type multipolymer.
2. the method preparing anticancer polymer drug according to claim 1 is carried out as follows:
1) for causing the synthesis of the nitrine small molecules initiator of methacrylic acid monomer;
2) utilize folic acid small molecules to carry out NHS activation, prepare folic acid-NHS molecule;
3) utilize the nitrine small molecules initiator prepared by step 1), cause methacrylic acid small molecules and carry out atom transfer radical polymerization, obtain polymethyl acrylic acid, utilize folic acid-NHS molecular modification polymethyl acrylic acid simultaneously;
4) synthesis of both arms alkynes end group poly aspartic acid benzyl ester;
5) utilize Doxorubicin molecules to carry out grafting to poly aspartic acid benzyl ester, this reaction utilizes hydrazone key to connect;
6) click chemistry Reactive Synthesis star block copolymer is utilized;
7) polymer nano micelle is prepared by dialysis method.
3. the preparation method of a kind of anticancer polymer drug according to claim 2, is characterized in that solvent that in aforesaid method, synthesized by step 1), nitrine small molecules initiator uses is any one in acetone, butanone, dioxane, acetonitrile.
4. the preparation method of a kind of anticancer polymer drug according to claim 2, is further characterized in that the polymerization single polymerization monomer that in aforesaid method, step 4) uses is aspartic acid benzyl ester carboxylic acid anhydride.
5. the preparation method of a kind of anticancer polymer drug according to claim 2, is further characterized in that the polymkeric substance coupled reaction that in aforesaid method, step 6) is carried out must adopt Huisgen 1,3-Dipolar Cycloaddition.
6. the preparation method of a kind of anticancer polymer drug according to claim 2, is further characterized in that in aforesaid method and needs to adopt following small molecules initiator:
1) 2-chloro nitrine Ethoxyethane
2) N-amine ethyl 3,5-diethyl alkynyloxy group aniline.
7. anticancer polymer drug according to claim 2, is further characterized in that: this macromolecular material is the star block copolymer formed by coupling by the polymethyl acrylic acid segment of modified with folic acid and the poly aspartic acid of Zorubicin grafting.
8. anticancer polymer drug according to claim 2, is further characterized in that: described macromolecule micelle has nucleocapsid bilayer structure, and skin is wetting ability polymethyl acrylic acid, and internal layer is drug molecule integument.
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|---|---|---|---|---|
| CN103059312A (en) * | 2012-12-12 | 2013-04-24 | 中科院广州化学有限公司 | Amphipathic ternary molecular brush polymer constructed multichannel nanocapsule |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059312A (en) * | 2012-12-12 | 2013-04-24 | 中科院广州化学有限公司 | Amphipathic ternary molecular brush polymer constructed multichannel nanocapsule |
Non-Patent Citations (2)
| Title |
|---|
| 冯秀娥等: "聚甲基丙烯酸-苯乙烯-甲基丙烯酸的合成", 《日用化学工业》 * |
| 汤继辉等: "聚氨基酸作为药物载体的研究进展", 《中国药科大学学报》 * |
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