CN103976949A - Construction method of intelligent anticancer polymer drug system - Google Patents
Construction method of intelligent anticancer polymer drug system Download PDFInfo
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- CN103976949A CN103976949A CN201410181833.2A CN201410181833A CN103976949A CN 103976949 A CN103976949 A CN 103976949A CN 201410181833 A CN201410181833 A CN 201410181833A CN 103976949 A CN103976949 A CN 103976949A
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Abstract
The invention discloses an intelligent anticancer polymer drug system. Phosphatidylcholine is subjected to an atom transfer radical polymerization reaction to obtain poly-phosphatidylcholine. Lysine benzyl ester carboxylic acid anhydride is subjected to a ring-opening polymerization reaction to obtain poly lysine benzyl ester. The poly lysine benzyl ester is grafted to doxorubicin through a hydrazone bond. The poly-phosphatidylcholine is bonded to the poly lysine benzyl ester in a manner of click chemistry to obtain a block copolymer. The block copolymer is 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 drug carrier micelle. The drug carrier micelle has a core-shell double-layer structure with an external layer being hydrophilic poly-phosphatidylcholine and an internal layer being drug 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 amount and good in stability. 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 intelligent anticancer polymer drug system, particularly relate to a kind of preparation method of the block macromolecular material pharmaceutical carrier micelle with 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, but many cancer therapy drugs exist and are insoluble in the defect such as 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 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-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.Connect Dox with hydrazone key, and utilize Fol to modify PEG end group, prepare pH responsive type target drug-carrying micelle, cellular uptake amount and cytotoxicity are tested, prove that Dox discharges (Yang X, Grailer JJ, Pilla S fast due to the fracture of hydrazone key under acid condition, Steeber DA, Gong S.
bioconjugate Chem2010; 21 (3): 496-504.).
Although linear polymer micelle is as the carrier of poorly water soluble drugs, in medicine process, demonstrates huge advantage and potentiality passing, but still had 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, 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, 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 intelligent anticancer polymer drug system, this pharmaceutical carrier micelle 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; Can by amycin key connect with block polymer on; Macromolecular material has two hydrophilic segments, a hydrophobic segment: its hydrophilic section of macromolecular material, for poly-phosphatidylcholine, is modified by folic acid.Hydrophobic section is polylysine, by hydrazone keyed jointing branch amycin; High molecular micellar structure has nucleocapsid double-decker, and outer is the poly-phosphatidylcholine of hydrophilic, 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 micelle is as follows:
1) prepare nitrine micromolecule initiator
2) atom transfer radical polymerization and the modified with folic acid of poly-Phosphorylcholine
3) both arms alkynes end group polylysine benzyl ester is synthetic
?
4) Dox molecule is connected with the hydrazone key of polylysine benzyl ester
?
5) star block copolymer is synthetic
6) prepare nano-micelle
Prepare polymer nano micelle by dialysis.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) pH sensitive drug carrier micelle volume is little, has nanoscale structures, can pass through various barriers in human body;
2) pH sensitive drug carrier micelle critical micelle concentration is little, Stability Analysis of Structures;
3) pH sensitive drug carrier micelle load capacity is large, and good biocompatibility;
4) pH sensitive drug carrier micelle has targeting release pharmic function, can effectively reduce medicine normal tissue organ toxic and side effects.
Brief description of the drawings
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.
Detailed description of the invention
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 a kind of chemical constitution schematic diagram of intelligent anticancer polymer drug system.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 five-membered ring and the polylysine that 1,3-Dipolar Cycloaddition obtains 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 intelligent anticancer polymer drug system is by this AB
2assorted arm star block macromolecular assembling forms.Its structure is respectively by 1. folic acid micromolecule; 2. poly-phosphatidylcholine molecules; 3. polylysine; 4. the composition such as amycin molecule.Macromolecule by hydrophobic interaction, can self assembly be spherical micellar structure in aqueous solution, and high molecular micellar structure has nucleocapsid double-decker:
Outer gather phosphatidylcholine 2. for hydrophilic;
Internal layer be polylysine 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 globular micelle structure that self assembly forms in aqueous solution.Prove that macromolecule forms globular micelle structure homogeneous, good dispersion is not reunited in aqueous solution, is conducive to realize delivery and the release function to drug molecule.
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. standby 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.The mixed solution obtaining is the crude product of product, after mixed solution is concentrated, 90
oc distills and obtains pure substance.The 2-nitrine ethoxy ethanol obtaining
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 step 2-nitrine ethoxy ethanol 2g making, 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 that is precipitated out in course of reaction is filtered, and wash with dichloromethane.Extract with sodium bicarbonate solution (5%), be then dried with anhydrous magnesium sulfate.After reduced vacuum is dry, separate 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. atom transfer radical polymerization and the modified with folic acid of poly-Phosphorylcholine
By the 2-nitrine ethyoxyl bromo acid 12mg obtaining in step 2, be dissolved in 25mL DMSO the ratio in 2:1:1 simultaneously with 5.4g methacrylic acid hydroxyl Acetoxon acyl choline and add methanol, bipyridyl and cuprous bromide.By bleeding-ventilate for three times-thaw cycles carries out tube sealing to polymerization pipe.After polymerization 24 hours, polymer is precipitated out with methanol, filters, dry stand-by.Prepared 2g poly-phosphatidylcholine is dissolved in 20mL dichloromethane, adds 2.8mL ethylenediamine, the terminal groups of poly-phosphatidylcholine is modified, obtain the polymer of end group band primary amine.The poly-phosphatidylcholine 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 polylysine benzyl 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, at the mixed solution that utilizes benzene/methanol (9/1 v/v), mixed solution is carried out to recrystallization, 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 the product N-amine ethyl 3 obtaining in 0.39g step 2,5-diethyl alkynyloxy group aniline is as initiator, utilize ring-opening polymerisation mode polymer poly lysine benzyl ester carboxylic acid anhydrides 6.78g, 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 polylysine benzyl ester.
4. amycin molecule is connected with the hydrazone key of polylysine benzyl ester
The both arms alkynes end group polylysine benzyl ester obtaining in 7.84mL hydrazine and 4.78g 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 polylysine benzyl ester.This product 5g and 0.98g 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 polylysine benzyl ester of amycin molecule grafting.
5. AB
2synthesizing of assorted arm star block copolymer
The poly-phosphatidylcholine that 3.45g end group is modified and the polylysine benzyl ester of 8.34g amycin molecule grafting are dissolved in 20mL dry DMF, and add 9.56mgPMDETA.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.The mixed solution that reaction obtains is crossed silicagel column to remove unnecessary mantoquita and other impurity.After solution is concentrated, precipitate with absolute methanol, finally obtain AB
2assorted arm star block copolymer.
6. the preparation of polymer nano micelle
Prepare polymer nano micelle by dialysis.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.
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 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 claim scope of the present invention.
Claims (8)
1. an intelligent anticancer polymer drug system, its architectural feature is: described macromolecular material is the AB being formed by two hydrophilic poly-phosphatidylcholine segments and the coupling of a hydrophobic polylysine benzyl ester segment
2type copolymer.
2. a method of preparing a kind of intelligent anticancer polymer drug system claimed in claim 1 is carried out as follows:
1) for causing nitrine micromolecule initiator synthetic of phosphatidylcholine monomer;
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 Phosphorylcholine micromolecule and carry out atom transfer radical polymerization, obtain poly-phosphatidylcholine, utilize folic acid-NHS molecular modification to gather phosphatidylcholine simultaneously;
4) both arms alkynes end group polylysine benzyl ester is synthetic;
5) utilize amycin molecule to carry out grafting to polylysine benzyl ester, this reaction is to utilize hydrazone key to connect;
6) utilize the synthetic star block copolymer of click chemistry reaction;
7) prepare polymer nano micelle by dialysis.
3. the preparation method of a kind of intelligent anticancer polymer drug system according to claim 2, is characterized in that solvent that in said method, step 1) synthesized nitrine micromolecule initiator uses is any in acetone, butanone, dioxane, acetonitrile.
4. the preparation method of a kind of intelligent anticancer polymer drug system according to claim 2, is further characterized in that step 4 in said method) polymerization single polymerization monomer that uses is lysine benzyl ester carboxylic acid anhydrides.
5. the preparation method of a kind of intelligent anticancer polymer drug system 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. the preparation method of a kind of intelligent anticancer polymer drug system 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. the intelligent anticancer polymer drug of one according to claim 2 system, is characterized in that: this macromolecular material is the star block copolymer being formed by coupling by the poly-phosphatidylcholine segment of modified with folic acid and the polylysine of amycin grafting.
8. the intelligent anticancer polymer drug of one according to claim 2 system, is further characterized in that: described macromolecule micelle has nucleocapsid double-decker, and outer is the poly-phosphatidylcholine of hydrophilic, and internal layer is drug molecule integument.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108498483A (en) * | 2018-05-08 | 2018-09-07 | 江南大学 | A kind of preparation method of pH/ reduction response polyaminoacid amphoteric ion nano particle |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104337794A (en) * | 2013-08-06 | 2015-02-11 | 成都市绿科华通科技有限公司 | Intelligent amphiphilic targeting drug carrier system |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104337794A (en) * | 2013-08-06 | 2015-02-11 | 成都市绿科华通科技有限公司 | Intelligent amphiphilic targeting drug carrier system |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108498483A (en) * | 2018-05-08 | 2018-09-07 | 江南大学 | A kind of preparation method of pH/ reduction response polyaminoacid amphoteric ion nano particle |
| WO2019214219A1 (en) * | 2018-05-08 | 2019-11-14 | 江南大学 | Method for preparing ph/reduction responsive polyamino acid zwitterionic nanoparticles |
| CN108498483B (en) * | 2018-05-08 | 2020-10-09 | 江南大学 | Preparation method of pH/reduction responsive polyamino acid zwitterion nanoparticles |
| US10933028B2 (en) | 2018-05-08 | 2021-03-02 | Jiangnan University | Method of preparing pH/reduction responsive polyamino acid zwitterionic nanoparticles |
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Application publication date: 20140813 |