CN103800915B - Associating carrier micelle of a kind of targeted integration element receptor and preparation method thereof - Google Patents
Associating carrier micelle of a kind of targeted integration element receptor and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to biomedicine technical field, relate to administering drug combinations micelle of a kind of targeted integration element receptor and preparation method thereof.The present invention has synthesized the pluronic (Pluronic-COOH) that terminal carboxyl group is modified, and is connected by amido link with carboxyl with rgd peptide, obtains the pluronic copolymer (RGD-Pluronic) that RGD peptide is modified; After drug adriamycin (DOX) and pluronic (Pluronic) copolymerization, adopt thin film aquation method bag to carry another drug taxol (PTX) and prepares mixed micelle (RGD-FP-DP).The present invention can improve the drug loading of micelle, can increase antitumor drug at the drug level of target site and can reduce its accumulation at non-target site, effectively can improve the therapeutic index of medicine.
Description
Technical field
The invention belongs to biomedicine technical field, be specifically related to associating carrier micelle of a kind of targeted integration element receptor and preparation method thereof.
Background technology
Prior art discloses tumor tissues and be different from normal structure, its rich blood vessel, blood vessel wall gap are wider, poor structural integrity, lymphatic return lacks, and therefore the nanoparticle of bag medicine carrying thing can by EPR effect in tumor tissues enrichment.But research finds, after nanoparticle enters blood circulation, owing to mainly being absorbed by mononuclear phagocyte system (MPS), medicine is assembled in liver, spleen and lung, and this not only reduces the therapeutic index of medicine, causes very large toxic and side effects to these organs simultaneously.Build cancer target delivery system, reduce antitumor drug to the infringement of normal organ, the targeting realizing medicine passes releases the concern more and more causing researcher.
One of important member that integrin (Integrin) is cell adhesion molecule family is the major receptors family of extracellular matrix (ECM).There is research display, integin αV β in the endotheliocyte after malignant tumor and the angiogenic growth factor being subject to tumor cell secretion stimulate activation
3expression significance raise, and in the vascular endothelial cell and most normal structure organ of normal person's cylinder mature integin αV β
3in low expression level.Research also shows, integin αV β
3specific recognition and in conjunction with the RGD(arginine-glycine-aspartic acid in extracellular matrix ligands molecule) occurred conformation changes and activates, mediate downstream signal transduction after sequence, plays important regulating and controlling effect.Because all solid tumors or tumor cell become tumor process inevitable along with tumor angiogenesis, integin αV β
3as the total material in tumorigenesis process, there is certain specificity, therefore integin αV β
3it is the potential molecular target of oncotherapy.
Containing the polypeptide of RGD sequence, as the polymer of linear RGD peptide, ring-type RGD peptide and RGD peptide, have relative molecular mass little, stablize, be easy to preparation, and advantages such as non-immunogenicity.At present, the cyclic peptide of more existing RGD-containg peptide sequences enters clinical trial.
Clinical cancer therapy practice display, two or more administered in combination can reduce total dosage, produce complementary effect and multiple-effect, promote drug effect, reduce one of available strategy of drug toxicity, bag carries the different drug system of two kinds of physicochemical properties simultaneously, in oncotherapy, can reach desirable synergy with minimum dose.Polymeric materials prepare micellar carrier for antitumor drug send be in recent years delivery system research focus, but still the defect that the drug loading that there is micelle volume is low, associating medicine carrying then can make up the low defect of micelle medicine carrying amount, plays each self-applying of medicine and synergism simultaneously.Therefore the associating carrier micelle carrier of active targeting has potential advantage in structure cancer target delivery system.
Summary of the invention
The object of the invention is the defect for overcoming prior art, associating carrier micelle of a kind of targeted integration element receptor and preparation method thereof is provided.
The present invention has synthesized the pluronic (Pluronic-COOH) that terminal carboxyl group is modified, and is connected by amido link with carboxyl with rgd peptide, obtains the pluronic copolymer (RGD-Pluronic) that RGD peptide is modified; After drug adriamycin (DOX) and pluronic (Pluronic) copolymerization, adopt thin film aquation method bag to carry another drug taxol (PTX) and prepares mixed micelle (RGD-FP-DP).
More specifically,
In the present invention, provide the amphipathic copolymer and preparation method thereof with active group carboxyl.
In the present invention, provide amphipathic copolymer of the RGD peptide modification with integrin receptor target and preparation method thereof.
In the present invention, provide amphipathic copolymer with medicine copolymerization and preparation method thereof.
In the present invention, provide micelle of targeted integration element receptor and its preparation method and application.
In the present invention, the micellar carrier of above-mentioned targeted integration element receptor is applied to and carries two or more hydrophilic and hydrophobic anticancer drug simultaneously, obtain the micelle of the associating medicine carrying with active targeting.
Object of the present invention is achieved through the following technical solutions:
With the amphipathic copolymer (Pluronic-COOH) of active group carboxyl, amphipathic copolymer p luronic-DOX of polymeric drug doxorubicin hydrochloride and preparation method thereof, its synthetic method is as follows:
Wherein, the model that Pluronic selects usually is PluronicL35, L43, L44, L61, L62, L64, F68, L81, P84, P85, F87, F88, L92, F98, L101, P103, P104, P105, F108, L121, P123 and F127; Medicine selects water-soluble anti-tumor medicine usually.
In the present invention, the amphipathic copolymer that the RGD peptide with integrin receptor target is modified, its molecular formula general formula is: RGD-X-Pluronic, wherein, RGD-X is the polymer of linear RGD peptide, ring-type RGD peptide and RGD peptide containing Arg-Gly-Asp sequence, is prepared by following method:
Copolymer RGD-X-Pluronic, common amphipathic carrier Pluronic and Pluronic-DOX that the above-mentioned RGD peptide with amphipathic integrin receptor target is modified are mixed according to a certain percentage, be dissolved in altogether in organic solvent, adopt thin film-aquation legal system for targeting micelle.In embodiments of the invention, in this targeting micelle, the ratio of preferred three kinds of components be 1%-20%, Pluronic is 89%-20%, Pluronic-DOX by following mass percent: RGD-X-Pluronic is 10%-60%.
Hydrophobic antitumor drug (such as: paclitaxel (PTX)) is dissolved in organic solvent altogether with RGD-X-Pluronic, Pluronic, Pluronic-DOX, be prepared by thin film aquation method, the targeting micelle (such as PTX, DOX administering drug combinations targeting micelle) carrying two kinds of antitumor drug must be wrapped; Selected hydrophobic antitumor drug drug loading is 0.1%-20%.
In embodiments of the invention, the preferably micelle preparation method of the targeted integration element receptor of associating medicine carrying, it comprises step:
(1) each component is got by following mass percent: hydrophobic antitumor drug 0.1%-20%; RGD-X-Pluronic, Pluronic and Pluronic-DOX mixture 80-99.9%, in this mixture, RGD-X-Pluronic is 1%-20%, Pluronic be 89%-20%, Pluronic-DOX is 10%-60%;
(2) by above-mentioned each component organic solvent, be preferably dichloromethane or chloroform dissolving, ultrasonic carrier material and the medicine of making fully dissolves, rotary evaporation removing organic solvent, preferable temperature is 37 ° of C, ambient temperature in vacuum dried overnight, add deionized water, aquation, be preferably constant speed 700rpm, 37 ° of C water-baths, stir 30min, be cooled to room temperature, with 0.22 μm of acetyl cellulose membrane filtration, the targeting micellar solution of medicine carrying must be combined, preserve after lyophilizing.Particle size determination show, prepared micelle particle diameter at 10-400nm, as shown in Figure 3.
In the present invention, for antitumor drug paclitaxel (PTX)) there is excellent antitumor curative effect, but its dissolubility is less than 1 μ gml
-1, oral administration biaavailability is poor, and, existing paclitaxel injection taxol
with PTX albumin conjugates
all there is different side effect; With for DOX be a kind of cycle non-specific anticancer chemotherapeutic agent, be mainly used in treatment acute lymphoblastic leukemia, acute myeloblastic leukemia, breast carcinoma, pulmonary carcinoma, soft tissue sarcoma, hepatocarcinoma etc. clinically, but the untoward reaction that normal generation is serious in the process of chemotherapy; And DOX molecular weight is low, easily spreads in vivo, cause relatively average tissue distribution, normal tissue produces toxic and side effects, affects antitumor action simultaneously; Show according to clinical research, DOX and PTX administering drug combinations is better than individually dosed antitumous effect simultaneously, especially as the first-line treatment medicine being used for breast carcinoma; The copolymer RGD-X-Pluronic modified in conjunction with amphipathic RGD peptide has hydrophobic chain, self assembly can form the nano-complex of core-shell type, hydrophobicly endorses to store storehouse as the miniature of fat-soluble medicine; Pluronic two terminal hydroxy group can be oxidized into carboxyl and modify the hydrophilic medicament etc. with amino, and the administering drug combinations transmission system that the block copolymer RGD-X-Pluronic that RGD peptide is modified is incorporated into containing PTX and DOX is prepared targeting micelle by the present invention.Confirm through test, this administering drug combinations micellar system effectively can increase medicine in the concentration of target site and reduce its toxic and side effects at non-target sites such as liver spleens, can significantly improve the therapeutic index of medicine.
In the present invention, with the KBv cell of drug resistance for model, adopt mtt assay to investigate RGD-FP-DP, common micelle and free drug to the growth inhibited situation of cells of resistant tumors, result shows: RGD-FP-DP is significantly better than common micelle and free drug (as shown in Figure 4) to the suppression ratio of cells of resistant tumors.
In the present invention, with the red fluorescence of DOX for probe, investigate the picked-up situation of the KBv cell in drug resistance of targeting micelle and common micelle, result shows, and the fluorescence intensity of targeting micelle group mdr cell is significantly higher than common micelle group (as shown in Figure 5).
In the present invention, RGD-FP-DP is detected with AnnexinV-APC/7-AAD cell apoptosis detection kit, the apoptosis situation that the hybrid medicine (Taxol+DOX) of common micelle and Taxol and DOX causes, result shows, and the KBv early apoptosis of cells that RGD-FP-DP group causes and late apoptic are significantly better than common micelle and Taxol+DOX group (as shown in Figure 6).
In the present invention, the nude mice of KBv subcutaneous tumors is had for animal model with lotus, the targeting micelle of fluorescent probe DiR labelling and common micelle is given by vein, with CRi living imaging instrument, observe nano-complex distribution situation in vivo and the active targeting characteristic of tumor locus, result shows, and targeting micelle is in the accumulation of tumor locus apparently higher than common micelle, and display target obviously reduces (as shown in Figure 7) to the picked-up of micelle in position, liver spleen simultaneously.
In the present invention, there is the nude mice of KBv subcutaneous tumors for animal model with lotus, give RGD-FP-DP, common micelle and free drug by vein, carry out pharmacodynamic evaluation in body.Result shows, RGD-FP-DP is obviously better than all the other each group (as shown in Figure 8) the drug effect of KBv drug-resistant tumor, the dosage of amycin group wherein close to the maximum safe concentration of amycin, although tumor is minimum, but Mouse Weight reduces very many, shows that its toxicity is large.
The advantage of associating carrier micelle of the present invention has: the drug loading that can improve micelle, increases antitumor drug at the drug level of target site and reduces its accumulation at non-target site, effectively can improve the therapeutic index of medicine.
Accompanying drawing explanation
Fig. 1 is Pluronic, Pluronic-NHS and Pluronic-DOX
1h-NMR collection of illustrative plates.
Fig. 2 is the ultraviolet full wavelength scanner collection of illustrative plates of DOX, PluronicP105-COOH and PluronicP105-DOX.
Fig. 3 is the grain size distribution (A) of RGD-FP-DP; Transmission electron microscope (B) and atomic force microscopy (C).
Fig. 4 is that RGD-FP-DP and common micelle suppress curve to KBv growth of tumour cell.
Fig. 5 is that RGD-FP-DP and common micelle compare in the picked-up of KBv cell.
Fig. 6 is that AnnexinV-APC/7-AAD cell apoptosis detection kit detects matched group, the hybrid medicine of Taxol and DOX, the apoptosis situation that common micelle and RGD-FP-DP cause.
Fig. 7 is that fluorescent probe DiR labels targets has the nude mice distribution in vivo of KBv Subcutaneous tumor to micelle and common micelle lotus.
Fig. 8 is the tumor photo separated after each administration group KBv mice with tumor is put to death: normal saline (A), DOX (B), Taxol (C), Taxol+DOX (D), PF-DP (E) and RGD-FP-DP (F).
Detailed description of the invention
Elaborate to the present invention below in conjunction with embodiment, these embodiments are illustrative completely, and they are only used to be specifically described the present invention, and protection scope of the present invention is not limited to following embodiment.
Embodiment 1 prepares the amphipathic nature block polymer Pluronic-COOH with active group carboxyl
0.01MPluronic and 400ml acetone is placed in round-bottomed flask, is slowly warming up to solution clarification, lets cool to room temperature, add 17ml Jones reagent, in room temperature magnetic stirrer over night, add 5mL isopropyl alcohol cancellation reaction.Add 12.6g active carbon to continue to stir 2h, be heated to 40 ° of C, sucking filtration obtains settled solution while hot, reduction vaporization obtains thick white thing, add the normal hexane of pre-cooling, solid is separated out, vacuum drying obtains carboxylated Pluronic (Pluronic-COOH).With the purity of gel permeation chromatography (GPC) assay products, with
1in H-NMR collection of illustrative plates methylene, the peak area ratio of proton calculates the molecular weight of product.
Embodiment 2 prepares Pluronic-DOX
Take the Pluronic-COOH7.4mM in above-described embodiment 1, be at room temperature dissolved in 20mlN, dinethylformamide.1gEDC and 2gNHS is added in the solution of Pluronic-COOH.After reaction 15min, add 2.8ml2-mercaptoethanol, 3.48gDOX and 10mg triethylamine, continue to stir 12h, nitrogen protection in room temperature.After reacted, dialyse 2 days (MWCO3500) by deionized water lucifuge, namely concentrated solution lyophilization obtains Pluronic-DOX.Pass through
1h-NMR collection of illustrative plates is verified product; UV-VIS spectrophotometry measures absorbance, calculates mole bonding ratio of DOX.
Embodiment 3 prepares the amphipathic copolymer modified with RGD peptide
(1) Pluronic-NHS is prepared with NHS activated carboxyl:
Take the Pluronic-COOH0.053mM in above-described embodiment 1, DCC22mg and NHS12.2mg is dissolved in the chloroform of 5ml altogether, room temperature reaction 24h under nitrogen protection.Question response terminates, removal of solvent under reduced pressure, and with cold ether sedimentation.Vacuum drying will be precipitated to constant weight, obtain Pluronic-NHS.By 1H-NMR collection of illustrative plates, product is verified;
(2) the amphipathic copolymer that annular RGD peptide (c (RGDyK)) is modified prepares c (RGDyK)-Pluronic;
The Pluronic-COOH0.0053mM got in above-mentioned (1) is dissolved in the DMF of 1ml, obtains solution A; C (RGDyK) peptide getting 6.3mg (0.01mM) is dissolved in 0.1MHEPES, obtains solution B.Solution B is added drop-wise in solution A, and with N-Methyl-morpholine adjust ph 8.4.React 24h under room temperature, question response terminates, and dialyse product in normal saline 48h (MWCO3500), removes excessive free c (RGDyK) peptide.Treat that dialysis terminates, by product c (RGDyK)-Pluronic lyophilization; The amphipathic copolymer that c (RGDyK) peptide of synthesis is modified is passed through
1h-NMR collection of illustrative plates is verified product.
Embodiment 4
By 3mgPTX, 100mgPluronic-DOX, 167mgPluronic and 30mgc (RGDyK)-Pluronic, be placed in 50ml round-bottomed flask, adding 5ml dichloromethane makes carrier material and medicine fully dissolve, under 37 ° of C, rotary evaporation 40min is by solvent evaporate to dryness, ambient temperature in vacuum dried overnight; Add 5ml deionized water, in the 37 ° of C water-baths of 700rpm rotating speed, constant speed stirs 30min, is cooled to room temperature, with 0.22 μm of acetyl cellulose membrane filtration, removes the medicine of unentrapped, obtains RGD-FP-DP micelle, preserve after lyophilizing; The mean diameter of RGD-FP-DP micelle is 28.33 ± 3.61nm.
The micelle cellular uptake experiment of embodiment 5 targeted integration element receptor
By cultivate KBv cell with 0.25% trypsinization, every hole 5 × 105 cell is inoculated in 24 well culture plates.Under 37 ° of C, under 5%CO2 condition, cultivate 24h; Then discard culture fluid, RGD-FP-DP and common micelle, continue to hatch 1h.End to be hatched, washs three times with the PBS of pre-cooling, the situation of observation of cell picked-up micelle under fluorescence microscope; Result shows, and the KBv cell fluorescence intensity of picked-up RGD-FP-DP is significantly higher than common micelle group.
Embodiment 6RGD-FP-DP and common micelle are to KBv growth of tumour cell Inhibition test
By KBv cell with 0.25% trypsinization, every hole 5 × 10
5cell is inoculated in 96 well culture plates, under 37 ° of C, and 5%CO
224h is cultivated under condition; Then discard culture fluid, add the common micelle (FP-DP) of certain density paclitaxel solution (Taxol solution), DOX solution, Taxol+DOX, RGD-FP-DP and associating medicine carrying, continue to hatch 72h, cultivate after terminating, every hole adds 5mgml
-1mTT liquid 20 μ l, after 37 ° of C continue to cultivate 4h, stop cultivating, supernatant is abandoned in suction, every hole adds 200 μ lDMSO, and lucifuge vibration 10min makes crystal fully dissolve, and detects 570nm place measure OD value with microplate reader, calculate cell inhibitory rate, result shows: RGD-FP-DP is significantly better than common micelle to the suppression ratio of KBv tumor cell.
The cell apoptosis assay that embodiment 7 causes with the detection of AnnexinV-APC/7-AAD cell apoptosis detection kit RGD-FP-DP, FP-DP, Taxol, DOX and Taxol+DOX
By KBv cell with 0.25% trypsinization, every hole 5 × 10
5cell is inoculated in 6 well culture plates, under 37 ° of C, and 5%CO
224h is cultivated under condition, then culture fluid is discarded, add certain density each group of medicine, simultaneously to add the KBv cell of blank 1640 training liquid as negative control group, continue to hatch 24h, after hatching end, collect training liquid, the PBS centrifuge washing cell of employing pre-cooling 1 time, add appropriate 0.25% trypsin digestion cell, the training liquid merging above-mentioned collection and the cell suspension digested, centrifugal collecting cell, also count with PBS re-suspended cell for 3 times with the PBS washed cell of pre-cooling, with reference to the method process of AnnexinV-APC/7-AAD cell apoptosis detection kit, carry out flow cytomery, result shows, the KBv early apoptosis of cells that RGD-FP-DP group causes and late apoptic are significantly better than common micelle and each free drug group.
Embodiment 8
Get containing 5 × 10
6the right hind that the suspension of individual KBv cell is expelled to male balb/c nude mice is subcutaneous, until tumor grow to diameter be about 7mm time, fluorescent probe DiR labels targets is given to micelle and common micelle by tail vein, CRI living imaging instrument is observed the distribution of nano-complex, to investigate the active targeting of targeting micelle at tumor locus, result shows, and targeting micelle is in the accumulation of tumor locus apparently higher than common micelle, and display target obviously reduces to the picked-up of micelle in position, liver spleen simultaneously.
Embodiment 9
Get containing 5 × 10
6the right hind that the suspension of individual KBv cell is expelled to male balb/c nude mice is subcutaneous, treats that tumor grows to 50-100mm
3(being denoted as 0 day), with drug level 10mgkg
-1dosage, give normal saline, DOX, Taxol, Taxol+DOX, FP-DP and RGD-FP-DP respectively.In tail vein injection administration on the the 0th, 3,6, put to death mice on 10th, separate tumor and weigh, calculate tumour inhibiting rate, result shows, and the KBv tumor tumour inhibiting rate of RGD-FP-DP, apparently higher than FP-DP and each free drug group, produces the drug effect of good treatment resistant tumors in vivo.
Claims (4)
1. the associating carrier micelle of a targeted integration element receptor, it is characterized in that, be made up of the component of following mass percent: hydrophobic antitumor drug 0.1%-20%, the RGD peptide with integrin receptor target modify amphipathic copolymer, be 80-99.9% with the block copolymer of medicine copolymerization and the mixture of common block copolymer, the amphipathic copolymer that in this mixture, RGD peptide is modified is 1%-20%, be 10%-60% with the block copolymer of medicine copolymerization, common block copolymer is 89%-20%; Be water solublity or hydrophobic drug with the medicine of copolymerization on the block copolymer of medicine copolymerization, be selected from amycin, doxorubicin hydrochloride, epirubicin, paclitaxel, Docetaxel, vincristine, vincristine sulfate, methotrexate or 9-nitrocamptothecin one or both or two or more; Associating medicine carrying mode is carried and copolymerization for wrapping.
2., by the associating carrier micelle of targeted integration element receptor according to claim 1, it is characterized in that, the described amphipathic nature block polymer with active group carboxyl, its molecular formula is Pluronic-COOH; Common block copolymer Pluronic, wherein, Pluronic represents various Pluronic model, comprises PluronicL35, L43, L44, L61, L62, L64, F68, L81, P84, P85, F87, F88, L92, F98, L101, P103, P104, P105, F108, L121, P123 and F127.
3. by the associating carrier micelle of targeted integration element receptor according to claim 1, it is characterized in that, its molecular formula of amphipathic copolymer that the described RGD peptide with integrin receptor target is modified is: RGD-X-PF-DP, wherein, RGD-X is the polymer of linear RGD peptide, ring-type RGD peptide and RGD peptide containing Arg-Gly-Asp sequence.
4. prepare a method for the associating carrier micelle of targeted integration according to claim 1 element receptor, it is characterized in that, it comprises: by described each component with organic solvent dissolution, adopts thin film/aquation legal system for targeting micelle.
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| CN106913881A (en) * | 2015-12-24 | 2017-07-04 | 冬青（天津）生物科技有限公司 | A kind of anti-human epidermal growth factor acceptor 2 monoclonal antibody combination nano-micelle and preparation method and application |
| CN106169033A (en) * | 2016-03-22 | 2016-11-30 | 烟台大学 | A kind of ring-type RGD peptide and virtual screening method thereof |
| CN106860873A (en) * | 2017-01-09 | 2017-06-20 | 王喆 | A kind of cancer target discharges controllable combination medicine delivery system and preparation method thereof |
| CN113616593A (en) * | 2021-08-23 | 2021-11-09 | 嘉兴学院 | Application of nano-targeting polymer micelle in preparation of targeting drug delivery system |
| CN114288417B (en) * | 2021-11-22 | 2023-04-21 | 四川大学华西医院 | Double-targeting nano drug-loaded micelle and preparation method and application thereof |
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| CN102626521A (en) * | 2012-04-26 | 2012-08-08 | 山东大学 | Segmented copolymer - docetaxel combination, preparation thereof and preparation method thereof |
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