CN104415007A - Preparation method of tumor cell micro-environmentally responsive nano-micelle - Google Patents

Preparation method of tumor cell micro-environmentally responsive nano-micelle Download PDF

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CN104415007A
CN104415007A CN201310381711.3A CN201310381711A CN104415007A CN 104415007 A CN104415007 A CN 104415007A CN 201310381711 A CN201310381711 A CN 201310381711A CN 104415007 A CN104415007 A CN 104415007A
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threonine
tumor cell
tert
drug
micelle
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不公告发明人
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Chengdu Green Kht Science And Technology Ltd
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Chengdu Green Kht Science And Technology Ltd
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Abstract

The invention discloses a preparation method of a tumor cell micro-environmentally responsive nano-micelle. The preparation method comprises the following steps: polymerizing pyrrolidone by utilizing an atom transfer radical polymerization method, thus obtaining polypyrrolidone; modifying polypyrrolidone by utilizing folic acid molecules; polymerizing O-tert-butyl-L-threonine carboxylic acid anhydride by utilizing a ring opening polymerization method, thus obtaining poly(O-tert-butyl-L-threonine); grafting adriamycin onto poly(O-tert-butyl-L-threonine) via hydrazone bonds; connecting polypyrrolidone with poly(O-tert-butyl-L-threonine) with bonds through click chemistry, thus obtaining block copolymers; after dissolving the block copolymers in tetrahydrofuran respectively, transferring the solutions into a dialysis bag, dialyzing the solutions with pure water, and filtering the dialysate with a filter membrane; freeze-drying the solutions after filtration, thus obtaining a drug loading micelle. The drug carrier micelle has a core/shell double-layer structure, wherein the outer layer is formed by hydrophilic polypyrrolidone, and the inner layer is a drug molecule coated layer. The material has the advantages that the material belongs to nanoparticles; the drug can achieve targeting delivery of cancer cells and pH-sensitive release in the cancer cells; the material has high drug loading capacity and good stability; the toxic and side effects of the drug on normal tissues and organs can be effectively reduced via the targeting function of the drug.

Description

A kind of preparation method of tumor cell microenvironment responsive nano micelle
Technical field
The present invention relates to a kind of preparation method of tumor cell microenvironment responsive nano micelle, particularly relate to a kind of preparation method with the block macromolecular material pharmaceutical carrier micelle 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 Drug therapy, but many cancer therapy drugs also exist and are insoluble in the defect such as water, poor stability.As camptothecine, paclitaxel, amycin, 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 practice.In addition, oncotherapy and its effect of diagnostic medicine are 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 solve how solubilising slightly solubility cancer therapy drug and increase medicine stability, improve the selectivity of cancerous cell 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 micelle.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 cancerous cell microenvironment to be that faintly acid makes hydrazone bond fission, 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-aspartate) 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 poly caprolactone random copolymer 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 micelle, 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 micelle is as the carrier of poorly water soluble drugs, demonstrate huge advantage and potential passing in medicine process, but still there is micelle 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, 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.
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 inhibitory action 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 polymer or common star-type polymer pharmaceutical carrier, can not possess: target-oriented drug simultaneously, high drug carrying capacity, micellar structure is stablized, the pH sensitivity of target spot release, biocompatibility height these several plays the performance of most important effect to the clinical practice of polymer drug carrier system.
Summary of the invention
The object of the invention is the preparation method setting up a kind of tumor cell microenvironment responsive nano micelle, this pharmaceutical carrier micelle has the following advantages: belong to nanoparticle; Medicine can be realized to pH sensitivity release 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 hydrophobic 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 is polypyrrole alkane ketone, is modified by folic acid.Hydrophobic section is poly-threonine, by hydrazone keyed jointing branch amycin; High molecular micellar structure has nucleocapsid double-decker, and skin is hydrophilic polypyrrole alkane ketone, and internal layer is drug molecule integument.
Described block polymer is the polymer in following structural formula:
The technology of preparing scheme of pharmaceutical carrier micelle is as follows:
1) nitrine micromolecule initiator is prepared
2) synthesis of folic acid-NHS molecule
3) atom transfer radical polymerization of polypyrrole alkane ketone and modified with folic acid
4) both arms alkynes end group gathers the synthesis of the O-tert-butyl group-L-threonine
5) Dox molecule is connected with the hydrazone key of the poly-O-tert-butyl group-L-threonine
6) synthesis of star block copolymer
7) nano-micelle is prepared
Polymer nano micelle is prepared by dialysis.Concrete grammar is: after the star-type polymer of synthesis is dissolved in THF respectively, moves in bag filter, with 1000 mL pure water dialysis, refreshes the water periodically.After dialysis solution membrane filtration, lyophilization obtains copolymer carrier micelle.
By above technical scheme, tool of the present invention has the following advantages: 1) this tumor cell microenvironment responsive nano micelle volume is little, has nanoscale structures, can pass through various barrier in human body;
2) this tumor cell microenvironment responsive nano micelle critical micelle concentration is little, Stability Analysis of Structures;
3) this tumor cell microenvironment responsive nano Micellar drug load capacity is large, and good biocompatibility;
4) this tumor cell microenvironment responsive nano micelle has Targeting delivery 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 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 the chemical constitution schematic diagram of this tumor cell microenvironment responsive nano micelle.This macromolecule 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 micromolecule 1. key is connected in polypyrrole alkane ketone molecule segment and 2. goes up, and is 2. prepared by Transfer Radical Polymerization;
3. the five-membered ring utilizing 1,3-Dipolar Cycloaddition to obtain and poly-threonine carry out coupling;
Utilize hydrazone key by segment 3. with Doxorubicin molecules 4. key link up.
As shown in Figure 2, this tumor cell microenvironment responsive nano micelle a kind of is by this AB 2assorted arm star block macromolecular assembling is formed.Its structure is respectively by 1. folic acid micromolecule; 2. polypyrrole alkane ketone molecule; 3. poly-threonine; 4. the composition such as Doxorubicin molecules.Macromolecule is in aqueous by hydrophobic interaction, and can self assembly be spherical micellar structure, high molecular micellar structure has nucleocapsid double-decker:
Skin be hydrophilic polypyrrole alkane ketone 2.;
3. internal layer for gathering threonine, and 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 block copolymer is the AFM scanogram of globular micelle structure that formed of self assembly in aqueous.Prove that macromolecule forms globular micelle structure homogeneous, good dispersion, 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 micromolecule 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 mixed solution obtained is the crude product of product, after mixed solution 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 dichloromethane, reaction system is transferred in ice territory, is slowly added in reaction vessel by 6.8g dicyclohexylcarbodiimide, and stir.0.4g dimethylamino naphthyridine is dissolved in dichloromethane 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 course of reaction is filtered, and washs with dichloromethane.Extract with sodium bicarbonate 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 polypyrrole alkane ketone and modified with folic acid
By the 2-nitrine ethyoxyl bromo acid 12mg obtained in step 2, add methanol, bipyridyl and cuprous bromide with the 5.4g vinyl pyrrolidone 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 polymerization pipe.Be polymerized after 24 hours, with methanol, polymer be precipitated out, filter, dry stand-by.Polypyrrole alkane ketone obtained by 2g is dissolved in 20mL dichloromethane, adds 2.8mL ethylenediamine, the terminal groups of polypyrrole alkane ketone is modified, obtains the polymer of end group band primary amine.The polypyrrole alkane ketone that 2g end group is modified is warming up to 50 oc reacts 6h.Reactant liquor is loaded bag filter (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.Dialysis solution ether sedimentation, vacuum drying obtains product.
4. both arms alkynes end group gathers the synthesis of the O-tert-butyl group-L-threonine
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 solution 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 methanol, carry out recrystallization, 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: 6.25g3,5-diacetylene p-methoxybenzoic acid methyl ester is dissolved in 30mL methanol, 73.9g ethylenediamine is dissolved in 120mL ethylenediamine, 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 mixed solution of benzene/methanol (9/1 v/v) to carry out recrystallization to mixed solution, 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 the ring-opening polymerisation mode polymer poly O-tert-butyl group-L-threonine carboxylic acid anhydrides 5.19g, monomer and initiator are added in polymerization pipe, and add dry DMF 15mL, react 24 hours under room temperature.Polymer absolute ether precipitates, dry 24 hours of vacuum drying oven.Obtain product both arms alkynes end group and gather the O-tert-butyl group-L-threonine.
5. Doxorubicin molecules is connected with the hydrazone key of the poly-O-tert-butyl group-L-threonine
The both arms alkynes end group obtained in 5.8mL hydrazine and 2.43g above-mentioned steps is gathered the O-tert-butyl group-L-threonine to be dissolved in the dry DMF of 25mL, reaction system is heated to 40 oc, reacts 1 hour.Thick product absolute ether is precipitated, and by sedimentation and filtration, dry 24 hours of vacuum drying oven, obtains amido both arms alkynes end group and gathers the O-tert-butyl group-L-threonine.This product 5g and 0.34g amycin monomer are dissolved in DMSO, reaction system is heated to 30 oc, react 48 hours, the reaction mixture absolute methanol obtained precipitates, and by sedimentation and filtration, dry 24 hours of vacuum drying oven.The poly-O-tert-butyl group-L-threonine of obtained Doxorubicin molecules grafting.
6. AB 2the synthesis of assorted arm star block copolymer
The polypyrrole alkane ketone modify 3.8g end group and the poly-O-tert-butyl group-L-threonine 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 mixed solution obtained and cross silicagel column to remove unnecessary mantoquita and other impurity.The concentrated later absolute methanol of solution precipitates, and finally obtains AB 2assorted arm star block copolymer.
7. the preparation of polymer nano micelle
Polymer nano micelle is prepared by dialysis.Concrete grammar is: after one or both star polymers are dissolved in THF respectively, moves in bag filter, with 1000 mL pure water dialysis, refreshes the water periodically.After dialysis solution membrane filtration, lyophilization 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. a tumor cell microenvironment responsive nano micelle, its architectural feature is: described macromolecular material is the AB by two hydrophilic polypyrrole alkane ketone segments and a hydrophobic poly-O-tert-butyl group-L-threonine segment coupling 2type copolymer.
2. the method preparing tumor cell microenvironment responsive nano micelle according to claim 1 is carried out as follows:
1) for causing the synthesis of the nitrine micromolecule initiator of pyrrolidone monomeric;
2) utilize folic acid micromolecule to carry out NHS activation, prepare folic acid-NHS molecule;
3) utilize the nitrine micromolecule initiator prepared by step 1), cause ketopyrrolidine micromolecule and carry out atom transfer radical polymerization, obtain polypyrrole alkane ketone, utilize folic acid-NHS molecular modification polypyrrole alkane ketone simultaneously;
4) both arms alkynes end group gathers the synthesis of the O-tert-butyl group-L-threonine;
5) utilize Doxorubicin molecules to carry out grafting to the poly-O-tert-butyl group-L-threonine, 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.
3. the preparation method of a kind of tumor cell microenvironment responsive nano micelle according to claim 2, is characterized in that solvent that in said method, synthesized by step 1), nitrine micromolecule initiator uses is any one in acetone, butanone, dioxane, acetonitrile.
4. the preparation method of a kind of tumor cell microenvironment responsive nano micelle according to claim 2, is further characterized in that the polymerization single polymerization monomer that in said method, step 4) uses is the O-tert-butyl group-L-threonine carboxylic acid anhydrides.
5. the preparation method of a kind of tumor cell microenvironment responsive nano micelle 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 tumor cell microenvironment responsive nano micelle according to claim 2, is further characterized in that in said method and needs to adopt following micromolecule initiator:
1) 2-chloro nitrine Ethoxyethane
2) N-amine ethyl 3,5-diethyl alkynyloxy group aniline.
7. a kind of tumor cell microenvironment responsive nano micelle according to claim 2, is further characterized in that: this macromolecular material is the star block copolymer formed by coupling by the polypyrrole alkane ketone segment of modified with folic acid and the poly-threonine of amycin grafting.
8. a kind of tumor cell microenvironment responsive nano micelle according to claim 2, be further characterized in that: described macromolecule micelle has nucleocapsid double-decker, skin is hydrophilic polypyrrole alkane ketone, and internal layer is drug molecule integument.
CN201310381711.3A 2013-08-28 2013-08-28 Preparation method of tumor cell micro-environmentally responsive nano-micelle Pending CN104415007A (en)

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Cited By (1)

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CN103976980A (en) * 2014-04-30 2014-08-13 成都市绿科华通科技有限公司 Preparation method of tumor cell microenvironment responsive nanometer microcapsule

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Application publication date: 20150318