CN101538312A - Preparation and applications of RGD-fatty amine series compound as tumor targeting vector material - Google Patents
Preparation and applications of RGD-fatty amine series compound as tumor targeting vector material Download PDFInfo
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- CN101538312A CN101538312A CN200910136619A CN200910136619A CN101538312A CN 101538312 A CN101538312 A CN 101538312A CN 200910136619 A CN200910136619 A CN 200910136619A CN 200910136619 A CN200910136619 A CN 200910136619A CN 101538312 A CN101538312 A CN 101538312A
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Abstract
The invention relates to the preparation and applications of RGD-fatty amine series compound as tumor targeting vector material, and the compound has a structure as the right formula.
Description
Technical field
The present invention relates to the preparation of targeted carrier material, relate in particular to construction process, the invention still further relates to the application of pharmaceutical carrier in the preparation targeting drug administration preparation, belong to biomedicine field at fat-soluble medicine target administration system.
Background technology
The growth of malignant tumour and transfer are the processes of the rapid too many levels of multistep of a complexity, and all change relevant with plain abnormal expression of integration or molecular structure mostly.Integrating element is class transmembrane protein extended familys, constitutes heterodimer by two kinds of subunits of α, β.Find that at present α has 18 kinds approximately, β has 8 kinds approximately, has the integration prime form of 24 kinds of heterodimers at least.Integrate plain progress in tumour and may have duality: 1) tumour takes place in early days, weakens but integrate the plain adhesive attraction that reduces tumorigenic cell and basilar membrane or ECM composition of expressing, thereby helps tumour in local growth and diffusion; 2) after oncocyte enters circulation of blood, integrate plain express to increase help oncocyte and adhere to blood vessel endothelium, location propagation then.It is admitted facts that the plain expression at tumor cell surface of integration is higher than normal cell.
The arginine-glycine-aspartic acid tripeptide sequence (Arg-Gly-Asp is to integrate plain specific recognition sequence fragment RGD), RGD tripeptides and modifier by with integrate plain specific combination, have the tumour cell of prevention location propagation, anti-tumor neovascularization nucleus formation.Wherein, α v β 3 integrates elements and can combine with various kinds of cell epimatrix molecule, brings into play corresponding biological action comprising fibronectin, Fibrinogen and vitreum are connected albumen etc.And integrin alpha 1, α 6, β 1, β 4 subunits are relevant with the formation of tumour in the expression decreased of breast epithelium tissue.
Nano medicament carrying system is the ball-type double-layer of lipoid of diameter 50～1000nm, and moiety is flexible, can make kind, size, broad variety that surface characteristic is different, as effective transport agent of biologically active substance.
Common nano medicament carrying system does not have target.Can be at nano level drug-loading system surface bonding antibody, part, utilize the antigen of tumour cell and normal cell surface expression or the difference of acceptor, increase the active target of liposome by the specific effect of antigen, antibody and acceptor, part, thereby improve therapeutic index.
The active target preparation of antitumor drug will be a new trend of improving anti-tumor medicinal preparation.In order to make carrier system have the specific target tropism, various active substances can be coupled to carrier surface.Receptor-mediated target strategy is one of resolved vector system target approach.The carrier system that is loaded with various antitumor drugs can be targeted to organ, tissue or the cell that contains specific receptors by this specific specificity interaction; Acceptor combines with part and can promote that drug release is in cell in the carrier system simultaneously.
Summary of the invention
One of purpose of the present invention provides a kind of amphipathic integrin receptor target anchor point compound and preparation method thereof that has;
Two of purpose of the present invention provides a kind of target medicine carrier that contains above-mentioned anchor point compound and preparation method thereof;
Three of purpose of the present invention is that above-mentioned target medicine carrier is applied to load fat-soluble antitumor drug, prepares the initiatively anti-tumor medicinal preparation composition of target.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of have an amphipathic integrin receptor target anchor point series compound, and structure is as follows
Its molecular formula is: Arg-Gly-Asp-NHC
nH
2n+1, wherein, n represents the carbon number of different long-chain fat amine, is respectively 8,10,12,14,16.
Arg-Gly-Asp is puted together with different alkyl fatty chains respectively, promptly prepare above-mentioned series compound.
The preparation method of compound of the present invention may further comprise the steps:
(1) meets the synthetic respectively RGD of peptide technology according to conventional liquid phase;
(2) with the Arg-Gly-Asp of protecting group protection respectively with CH
3(CH
2)
6CH
2NH
2, CH
3(CH
2)
8CH
2NH
2, CH
3(CH
2)
10CH
2NH
2, CH
3(CH
2)
12CH
2NH
2, CH
3(CH
2)
14CH
2MH
2Protecting group is sloughed in coupling, promptly.
The target medicine carrier that contains the anchor point compound of the present invention is selected from liposome, nanoparticle or micro emulsion.Preferred liposome.
The pharmaceutical preparations composition that contains target medicine carrier of the present invention, wherein said medicine is selected from fat-soluble medicine.Preferred Docetaxel.
Pharmaceutical composition of the present invention, preferred liposome Docetaxel preparation.
Pharmaceutical preparations composition of the present invention, it consists of fat-soluble medicine and accounts for molar percentage 0.5-30%; The mixture of common drug carrier and anchor point compound accounts for molar percentage 70-99.5%, and in this mixture, the common drug carrier accounts for molar percentage 80-99%, and the anchor point compound accounts for molar percentage 1-20%.
Target medicine carrier of the present invention (as liposome); Be made up of general solid support material and anchor point compound of the present invention, wherein preferred, each component is formed according to different molar percentages: general solid support material 80-99%, integrin receptor target anchor point compound 1-20%.
Anti-tumor medicinal preparation composition of the present invention, (for example: antitumor drug Docetaxel etc.) be prepared (for example antitumor drug Docetaxel target liposomes) according to different preparation techniques be with general solid support material, integrin receptor target anchor point compound with fat-soluble medicine; Preferably, to account for the molar content of target medicine carrier (natural phosphatidyl choline and integrin receptor target anchor point compound) be 0.5-30% to fat-soluble medicine.
Preferably, a kind of method for preparing the antitumor drug targeting preparation comprises:
(1) gets each component by following molar percentage: antitumor drug 0.5-30%; The common drug carrier is (as phosphatide, cholesterol etc.) and the mixture 70-99.5% of integrin receptor target anchor point compound of the present invention, in this mixture, common drug carrier (as Yelkin TTS) 80-99% (molar percentage), integrin receptor target anchor point compound 1-20% of the present invention (molar percentage);
(2) above-mentioned each component is pressed the ordinary method preparation of pharmaceutical preparation, obtain the anti-tumor medicinal preparation composition.
The particle diameter of prepared targeted drug preparation is 20-1000nm, and Zeta potential is-70～70mV.
The above antitumor drug is selected from:
Docetaxel
The common drug solid support material is selected from:
Yelkin TTS
Anchor point compound of the present invention has outstanding Targeting Performance, introduces the anchor point compound in drug delivery system, can be with the drug targeting tumor by local.Integrate plain molecule mainly come between the mediated cell by identification RGD tripeptide sequence and cell and extracellular matrix between stick reaction.Shortcomings such as but the RGD peptide exists easily by enzymolysis, and the transformation period is short.In order to overcome these shortcomings, the present invention puts together different carbon number alkyl fatty chains mutually with RGD peptide section, it is carried out hydrophobically modified, has synthesized and possesses amphipathic different alkyl fatty chains and RGD peptide conjugate, that is: RGD-NH (CH
2)
7CH
3, RGD-NH (CH
2)
9CH
3, RGD-NH (CH
2)
11CH
3, RGD-NH (CH
2)
13CH
3And RGD-NH (CH
2)
13CH
3This conjugate stability is strong, is difficult for by enzyme liberating.
The Docetaxel antitumor curative effect is remarkable, but it is water-soluble low, and oral administration biaavailability is poor, and existing docetaxel injection easily causes allergic reaction.Because the conjugate of different carbon number alkyl fatty chains and RGD peptide section has the hydrophobic aliphatic chain, can insert on the plasma membrane, and pharmaceutical carrier is modified, and makes target medicine carrier.Therefore the present invention introduces the drug delivery system that contains antitumor drug (as Docetaxel) with amphipathic RGD conjugate and prepares Docetaxel targeting preparation (as the Docetaxel target liposomes).This targeting preparation system can increase antitumor drug also can reduce its toxic side effect at non-target site in the concentration of target site, improves the therapeutic index of medicine.
The present invention is a model with lotus sarcoma S180 mouse, adopt after kind of the knurl 1,3,5, the treatment plan of 7 days tail intravenously administrables has been estimated the anti-tumor activity of the prepared Docetaxel targeted liposome preparation of the present invention, and the result shows that the Docetaxel target liposomes has more excellent anti-tumor activity than each control group.
Compound of the present invention is compared with prior art and is had the following advantages:
Have now the RGD tripeptides has been carried out structural modification, but its synthesis step is loaded down with trivial details, this is integrated on the basis of plain specific recognition sequence fragment keeping the RGD tripeptides in the present invention, carries out the transformation of hydrophobic structure, and it is amphiphilic that it is had.So not only simplify the structure, reduced cost, also have good target effect simultaneously.
Embodiment:
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment 1 Boc-Arg (NO
2The preparation of)-Gly-OMe
With 1.595g (5.0mmol) Boc-Arg (NO
2)-OH is dissolved in the 20ml dry DMF, under the condition of ice bath, adds 0.675g (5mmol) N-hydroxy benzo triazole (HOBt), and makes dissolving fully.Add 1.236g (6mmol) dicyclohexyl carbonyl diimine (DCC) after 10 minutes.Obtain reaction solution (I), stand-by.The following 0.628g of ice bath (5.0mmol) HCLGly-OMe (5mmol) is dissolved among the 20mlTHF, adds 1ml N-methylmorpholine (NMM) then, transfers pH 8-9.Stirred 35 minutes, and obtained reaction solution (II), stand-by.The following reaction solution of ice bath (I) adds in the reaction solution (II), and first ice bath stirs 1h down, stirring at room 12h again, and TLC (chloroform/methanol, 10: 1) shows Boc-Arg (NO
2)-OH disappears.Filtering dicyclohexylurea (DCU) (DCU), filtrate is blown away DMF.Residue 50ml acetic acid ethyl dissolution.The solution that obtains is used 5%NaHCO successively
3The aqueous solution is washed, the saturated NaCl aqueous solution is washed, 5%KHSO
4The aqueous solution is washed, the saturated NaCl aqueous solution is washed, 5%NaHCO
3The aqueous solution is washed with the saturated NaCl aqueous solution and is washed.The ethyl acetate layer anhydrous Na
2SO
4Drying, filtration, filtrate decompression are concentrated into dried, obtain 2.948g (100%) crude product, are the beige solid.Get the white pure title compound of 1.405g (72.1%) behind the silicagel column purifying.(ESI-MS(m/z)：391.6[M]
+)
Embodiment 2 Boc-Arg (NO
2The preparation of)-Gly-OH
With 0.780g (2.0mmol) Boc-Arg (NO
2)-Gly-OMe is dissolved in 10ml methyl alcohol.Ice bath is transferred pH to 10-11 and is stirred 4h with NaOH (2N) aqueous solution down, and TLC (chloroform/methanol, 10: 1) shows Boc-Arg (NO
2)-Gly-OMe disappears.The saturated KHSO of reaction mixture
4Transfer pH to 7, concentrating under reduced pressure removes methyl alcohol.The saturated KHSO of residue
4Transfer pH to 2, use ethyl acetate extraction (30ml * 3).The ethyl acetate phase that merges is washed till neutrality, anhydrous Na with the saturated NaCl aqueous solution
2SO
4Dry.Filter, filtrate decompression is concentrated into dried, gets 0.591g (78.7%) title compound, is white solid.(ESI-MS(m/z)：375.3[M]
-)
Embodiment 3
1) Boc-Asp (OBzl)-NHCH
2(CH
2)
6CH
3Preparation
According to Boc-Arg (NO
2) preparation method, 1.615g (5mmol) Boc-Asp (OBzl)-OH and 0.541g (4.5mmol) CH of Gly-OMe
3(CH
2)
6CH
2NH
2Make 1.918g (98.2%) beige solid crude product, the silicagel column purifying gets 1192g (61.0%) title compound, is white solid.(ESI-MS(m/z)：435.7[M]
+)
2) HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3Preparation
With 0.868g (2.0mmol) Boc-Asp (OBzl)-NHCH
2(CH
2)
6CH
3Be dissolved in 10ml 4mol/l hydrogenchloride-ethyl acetate solution, stirring at room 4 hours, TLC (chloroform/methanol, 5: 1) shows that raw material point disappears, and concentrating under reduced pressure is removed ethyl acetate, and residue adds a small amount of ether repeatedly and carries out decompressing and extracting to remove hydrogen chloride gas.Add a small amount of ether at last residue is ground to form 0.632g (94.7%) title compound, be the white solid powder, be directly used in next step reaction.(ESI-MS(m/z)：335.5[M]
+)
3) Boc-Arg (NO2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
6CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe, 0.752g (2.0mmol) Boc-Arg (NO
2)-Gly-OH and 0.601g (1.8mmol) HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3Make 1.204g (96.7%) crude product, be the beige solid, behind the silicagel column purifying the 0.387g title compound, for white solid (ESI-MS (m/z): 693.5[M]
+)
4) Boc-Arg-Gly-Asp-NH-CH
2(CH
2)
6CH
3Preparation
With 0.138g (0.2mmol) Boc-Arg (NO
2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
6CH places the 50ml eggplant-shape bottle, with an amount of dissolve with ethanol, add 28mgPd/C (5%), logical H
2(0.02Mba), stirring at room to raw material point disappears.Filtering Pd/C, filtrate decompression are concentrated into dried, and residue grinds with sherwood oil repeatedly, get 0.104g (94.0%) title compound, are colorless oil.(ESI-MS(m/z)：558.4[M]
+)
5) HClArg-Gly-Asp-NHCH
2(CH
2)
6CH
3Preparation
According to HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3The preparation method, from 0.104g (0.2mmol) Boc-Arg-Gly-NH-CH
2(CH
2)
6CH
3Make 0.087g (96%) title compound, be faint yellow solid.ESI-MS(m/z)：458.3[M]
-，?Mp.85.7～86..8℃，[α]
D 20＝+6.67(c＝1，CH
3OH)。
Embodiment 4
1) Boc-Asp (OBzl)-NHCH
2(CH
2)
8CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe is by 1.595g (5mmol) Boc-Asp (Bzl)-OH and 0.708g (4.5mmol) CH
3(CH
2)
8CH
2NH
2Make 1.887g (100%) faint yellow solid, get 1.135g (64.7%) title compound, be the white solid powder through the silicagel column purifying.(ESI-MS(m/z)：463.7[M]
+)
2) HClAsp (OBzl)-NHCH
2(CH
2)
8CH
3Preparation
According to HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3The preparation method from 0.780g (2.0mmol) Boc-Asp (OBzl)-NHCH
2(CH
2)
8CH
3Make 0.701g (96.9%) title compound, be the white powder solid.(ESI-MS(m/z)：363.6[M]
+)
3) Boc-Arg (NO2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
8CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe is by 0.752g (2.0mmol) Boc-Arg (NO
2)-Gly-OH and 0.724g (2.0mmol) HClAsp (OBzl)-NHCH
2(CH
2)
8CH
3Make the faint yellow oily crude product of 1.44g (100%), get 0.658g (47%) title compound, be colorless oil through the silicagel column purifying.(ESI-MS(m/z)：721.4[M]
+)
4) Boc-Arg-Gly-Asp-NHCH
2(CH
2)
8CH
3Preparation
According to Boc-Arg-Gly-Asp-NHCH
2(CH
2)
6CH
3The preparation method, 0.150g (0.2mmol) Boc-Arg (NO
2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
8CH
3Make 0.114g (93.5%) title compound, be colorless oil.(ESI-MS(m/z)：586.3[M]
+)
5) HClArg-Gly-Asp-NHCH
2(CH
2)
8CH
3Preparation
According to HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3The preparation method, from 0.114g (0.2mmol) Boc-Arg-Gly-NHCH
2(CH
2)
8CH
3Make 0.094g (97%) title compound, be the beige solid.ESI-MS(m/z)：486.3[M]
+，Mp.90.1～91.3℃，[α]
D 20＝+17.11(c＝1，CH
3OH)。
Embodiment 5
1) Boc-Asp (OBzl)-NHCH
2(CH
2)
10CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe is by 1.595g (5mmol) Boc-Asp (OBzl)-OH and 0.834g (4.5mmol) CH
3(CH
2)
10CH
2NH
2Make 2.790g (100%) crude product, be faint yellow solid.Get 1.67g (68.2%) title compound through the silicagel column purifying.(ESI-MS(m/z)：491.5[M]
+)
2) HClAsp (OBzl)-NHCH
2(CH
2)
10CH
3Preparation
According to HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3The preparation method from 0.98g (2.0mmol) Boc-Asp (OBzl)-NHCH
2(CH
2)
10CH
3Make 0.764g (98%) title compound, be the white powder solid.(ESI-MS(m/z)：391.6[M]
+)
3) Boc-Arg (NO2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
10CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe is by 0.78g (2.0mmol) Boc-Arg (NO
2)-Gly-OH and 0.764gHClAsp (OBzl)-NHCH
2(CH
2)
10CH
3Make 1.336g (91%) crude product, get 0.671g (46%) title compound, be colorless oil through the silicagel column purifying.(ESI-MS(m/z)：749.5[M]
+)
4) Boc-Arg-Gly-Asp-NHCH
2(CH
2)
10CH
3Preparation
According to Boc-Arg-Gly-Asp-NHCH
2(CH
2)
6CH
3The preparation method, 0.150g (0.196mmol) Boc-Arg (NO
2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
10CH
3Make 0.106g (88%) title compound, be colorless oil.(ESI-MS(m/z)：614.4[M]
+)
5) HClArg (NO
2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
10CH
3Preparation
According to HClAsp (OBzl)-MHCH
2(CH
2)
6CH
3The preparation method, from 0.106g (0.17mmol) Boc-Arg-Gly-NHCH
2(CH
2)
10CH
3Make 0.081g (93%) title compound, be the beige solid.ESI-MS(m/z)：514.4[M]
+，Mp.96.7～98.7℃，[α]
D 20＝+14.62(c＝1，CH
3OH)。
Embodiment 6
1) Boc-Asp (OBzl)-NHCH
2(CH
2)
12CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe is by 1.595g (5mmol) Boc-Asp (OBzl)-OH and 0.960g (4.5mmol) CH
3(CH
2)
12CH
2NH
2Make 2.596g (100%) crude product, be faint yellow solid.Get 1.65g (71%) title compound through the silicagel column purifying, be the white solid powder.(ESI-MS(m/z)：519.8[M]
+)
2) HClAsp (OBzl)-NHCH
2(CH
2)
12CH
3Preparation
According to HClAsp (OBzl)-MHCH
2(CH
2)
6CH
3The preparation method from 1.038g (2.0mmol) Boc-Asp (OBzl)-NHCH
2(CH
2)
12CH
3Make 0.879g (96.1%) title compound, be the white powder solid.(ESI-MS(m/z)：419.7[M]
+)
3) Boc-Arg (NO2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
12CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe, 0.750g (2.0mmol) Boc-Arg (NO
2)-Gly-OH and 0.836g (2.0mmol) HClAsp (OBzl)-NHCH
2(CH
2)
12CH
3Make 1.583g (100%) crude product, be faint yellow oily thing, get 0.667 (43%) g title compound, be colorless oil through the silicagel column purifying.(ESI-MS(m/z)：777.9[M]
+)
4) Boc-Arg-Gly-Asp-NHCH
2(CH
2)
12CH
3Preparation
According to Boc-Arg-Gly-Asp-NHCH
2(CH
2)
6CH
3The preparation method, 0.150g (0.19mmol) Boc-Arg (NO
2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
12CH
3Make 0.111g (92.0%) title compound, be colorless oil.(ESI-MS(m/z)：642.5[M]
+)
5) HClArg (NO
2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
12CH
3Preparation
According to HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3The preparation method, 0.111g (0.17mmol) Boc-Arg-Gly-NHCH
2(CH
2)
12CH
3Make 0.087g (94.4%) title compound, be the beige solid.ESI-MS(m/z)：542.5[M]
-，Mp.125.3～127.1℃，[α]
D 20＝+18.22(c＝1，CH
3OH)。
Embodiment 7
1) Boc-Asp (OBzl)-NHCH
2(CH
2)
14CH
3Preparation
According to Boc-Arg (NO
2) preparation method, 1.595g (5mmol) Boc-Asp (OBzl)-OH and 1.085g (4.5mmol) CH of Gly-OMe
3(CH
2)
14CH
2NH
2Make 2.300g (93.6%) crude product, be yellow solid.Get 1.69g (69%) title compound through the silicagel column purifying, be colorless oil.(ESI-MS(m/z)：547.6[M]
+)
2) HClAsp (OBzl)-NHCH
2(CH
2)
14CH
3Preparation
According to HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3The preparation method, 1.092g (2.0mmol) Boc-Asp (OBzl)-NHCH
2(CH
2)
14CH
3Make 0.871g (97.7%) title compound, be the white solid powder.(ESI-MS(m/z)：447.6[M]
+)
3) Boc-Arg (NO2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
14CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe is by, 0.750g (2.0mmol) Boc-Arg (NO
2)-Gly-OH and 0.803g (1.8mmol) HClAsp (OBzl)-NHCH
2(CH
2)
14CH
3Make 1.57g (100%) crude product, be faint yellow oily thing, get 0.680g (47%) title compound through the silicagel column purifying, for colorless oil (ESI-MS (m/z): 806.2[M]
+)
4) Boc-Arg-Gly-Asp-NHCH
2(CH
2)
14CH
3Preparation
According to Boc-Arg-Gly-Asp-NHCH
2(CH
2)
6CH
3The preparation method, 0.150g (0.19mmol) Boc-Arg (NO
2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
14CH
3Make 0.121g (95.6%) title compound, be colorless oil.(ESI-MS(m/z)：670.8[M]
+)
5) HClArg (NO
2)-Gly-Asp (OBzl)-NHCH
2(CH
2)
14CH
3Preparation
According to HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3The preparation method, 0.121g (0.18mmol) Boc-Arg-Gly-NHCH
2(CH
2)
14CH
3Make 0.099g (97.2%) title compound, be the beige solid.ESI-MS(m/z)：570.7[M]
+，Mp.131.6～133.9℃，[α]
D 20＝+7.27(c＝1，CH
3OH)。
Embodiment 8
1) preparation of Boc-Gly-Gly-OH
0.875g (5mmol) Boc-Gly is dissolved in anhydrous THF, add 0.810g (5.5mmol) N-hydroxy-succinamide (HOSu), add 1.34gDCC under the ice bath, behind the reaction 12h, filter DCU, THF is removed in decompression, use the 50ml acetic acid ethyl dissolution, the saturated NaHCO3 aqueous solution is washed, and the saturated NaCl aqueous solution is washed, anhydrous Na SO4 drying.Filter NaSO4, ethyl acetate is removed in decompression, dissolves with THF.0.377g (5mmol) Gly is dissolved in 10ml distilled water, is added dropwise in the THF reaction solution, NMM transfers pH to 8-9, and reaction is spent the night.THF is removed in decompression, and saturated KHSO4 transfers pH to 2, and ethyl acetate extraction (30ml * 3), saturated NaCl solution are subsequently washed anhydrous Na SO4 dried overnight 3 times.Filter, ethyl acetate is removed in decompression, makes 0.650g (56.0%) title compound, is the white powder solid.(ESI-MS(m/z)：231.1[M]
-)
3) Boc-Gly-Gly-Asp (OBzl)-NHCH
2(CH
2)
L0CH
3Preparation
According to Boc-Arg (NO
2) preparation method of Gly-OMe is by 0.464g (2.0mmol) Boc-Gly-Gly-OH and 0.702g (2.0mmol) HClAsp (OBzl)-NHCH
2(CH
2)
12CH
3Make 1.021g (93.9%) crude product, get 0.576g (54%) title compound, be colorless oil through the silicagel column purifying.(ESI-MS(m/z)605.2[M]
+)
4) Boc-Gly-Gly-Asp-NHCH
2(CH
2)
12CH
3Preparation
According to Boc-Arg-Gly-Asp-NHCH
2(CH
2)
6CH
3The preparation method by 0.150g (0.25mmol) Boc-Gly-Gly-Asp (OBzl)-NHCH
2(CH
2)
12CH
3Make 0.123g (95.5%) title compound, be colorless oil.(ESI-MS(m/z)515.4[M]
-)
5) HClGly-Gly-Asp-NHCH
2(CH
2)
10CH
3Preparation
According to HClAsp (OBzl)-NHCH
2(CH
2)
6CH
3The preparation method, 0.123g (0.24mmol) Boc-Gly-Gly-Asp-NH-CH
2(CH
2)
10CH
3Make 0.092g (93.4%) title compound, be the beige solid.ESI-MS(m/z)：415.2[M]
+，Mp.99.7～101.2℃，[α]
D 20＝+8.89(c＝1，CH
3OH)。
Embodiment 9 contains RGD-NHCH
2(CH
2)
14CH
3The preparation of liposome (D)
Film dispersion method preparation, get phosphatide (80-99%, n/n) and required RGD conjugate RGD-NHCH
2(CH
2)
14CH
3(1-20% n/n) dissolves with chloroform to round-bottomed flask, and rotary evaporation is removed solvent, forms the dry transparent plasma membrane of one deck at the bottle wall, adds the PBS phosphate buffered saline buffer (0.01mol/L) of aequum, 30 ℃ of ultra-sonic dispersion 20min.Get the opalescent liposome solutions of tool, particle diameter 100～300nm, Zeta-Potential-20～-25mV.
Embodiment 10 contains the preparation of Docetaxel liposome (F)
The film dispersion method preparation, get phosphatide (80-99%, n/n) and required Docetaxel (0.5-30%, n/n) to round-bottomed flask, dissolve with chloroform, rotary evaporation is removed solvent, form the dry transparent plasma membrane of one deck at the bottle wall, add the PBS phosphate buffered saline buffer (0.01mol/L) of aequum, 30 ℃ of ultra-sonic dispersion 20min.Get the opalescent liposome solutions of tool, particle diameter 100～200nm, Zeta-Potential-25～-60mV.
Embodiment 11 contains RGD-NHCH
2(CH
2)
6CH
3Preparation with Docetaxel liposome (G)
The consumption of each component: Docetaxel 0.5-30%; Natural phosphatidyl choline and RGD-NHCH
2(CH
2)
6CH
3Mixture 70-99.5%, in this mixture, natural phosphatidyl choline 80-99% (molar percentage), integrin receptor target anchor point compound 1-20% (molar percentage);
With reference to the preparation method of embodiment 1, get phosphatide and RGD-NHCH
2(CH
2)
6CH
3Reach required Docetaxel and dissolve with chloroform to round-bottomed flask, rotary evaporation is removed solvent, forms the dry transparent plasma membrane of one deck, the PBS phosphate buffered saline buffer (0.01mol/L) of adding aequum, 30 ℃ of ultra-sonic dispersion 20min at the bottle wall.Get the opalescent liposome solutions of tool, particle diameter 100～250nm, Zeta-Potential-10～-70mV.
Embodiment 12 contains RGD-NHCH
2(CH
2)
8CH
3Preparation with Docetaxel liposome (H)
The consumption of each component: Docetaxel 0.5-30%; Natural phosphatidyl choline and RGD-NHCH
2(CH
2)
8CH
3Mixture 70-99.5%, in this mixture, natural phosphatidyl choline 80-99% (molar percentage), integrin receptor target anchor point compound 1-20% (molar percentage);
With reference to the preparation method of embodiment 1, get phosphatide, Docetaxel and RGD-NHCH
2(CH
2)
8CH
3Dissolve with chloroform to round-bottomed flask, rotary evaporation is removed solvent, forms the dry transparent plasma membrane of one deck at the bottle wall, adds the PBS phosphate buffered saline buffer (0.01mol/L) of aequum, 30 ℃ of ultra-sonic dispersion 20min.Get the opalescent liposome solutions of tool, particle diameter 100～250nm, Zeta-Potential-10～-70mV.
Embodiment 13 contains RGD-NHCH
2(CH
2)
10CH
3Preparation with Docetaxel liposome (I)
The consumption of each component: Docetaxel 0.5-30%; Natural phosphatidyl choline and RGD-NHCH
2(CH
2)
10CH
3Mixture 70-99.5%, in this mixture, natural phosphatidyl choline 80-99% (molar percentage), integrin receptor target anchor point compound 1-20% (molar percentage);
Phosphatide, Docetaxel and RGD-NHCH are got in the film dispersion method preparation
2(CH
2)
10CH
3Dissolve with chloroform to round-bottomed flask, rotary evaporation is removed solvent, forms the dry transparent plasma membrane of one deck at the bottle wall, adds the PBS phosphate buffered saline buffer (0.01mol/L) of aequum, 30 ℃ of ultra-sonic dispersion 20min.Get the opalescent liposome solutions of tool, particle diameter 100～250nm, Zeta-Potential-10～-70mV.
Experimental example 14 contains RGD-NHCH
2(CH
2)
12CH
3Preparation with Docetaxel liposome (J)
The consumption of each component: Docetaxel 0.5-30%; Natural phosphatidyl choline and RGD-NHCH
2(CH
2)
12CH
3Mixture 70-99.5%, in this mixture, natural phosphatidyl choline 80-99% (molar percentage), integrin receptor target anchor point compound 1-20% (molar percentage);
Phosphatide, Docetaxel and RGD-NHCH are got in the film dispersion method preparation
2(CH
2)
12CH
3Dissolve with chloroform to round-bottomed flask, rotary evaporation is removed solvent, forms the dry transparent plasma membrane of one deck at the bottle wall, adds the PBS phosphate buffered saline buffer (0.01mol/L) of aequum, 30 ℃ of ultra-sonic dispersion 20min.Get the opalescent liposome solutions of tool, particle diameter 100～250nm, Zeta-Potential-10～-70mV.
Experimental example 15 contains RGD-NHCH
2(CH
2)
14CH
3Preparation with Docetaxel liposome (K)
The consumption of each component: Docetaxel 0.5-30%; Natural phosphatidyl choline and RGD-NHCH
2(CH
2)
14CH
3Mixture 70-99.5%, in this mixture, natural phosphatidyl choline 80-99% (molar percentage), integrin receptor target anchor point compound 1-20% (molar percentage);
Phosphatide, Docetaxel and RGD-NHCH are got in the film dispersion method preparation
2(CH
2)
14CH
3Dissolve with chloroform to round-bottomed flask, rotary evaporation is removed solvent, forms the dry transparent plasma membrane of one deck at the bottle wall, adds the PBS phosphate buffered saline buffer (0.01mol/L) of aequum, 30 ℃ of ultra-sonic dispersion 20min.Get the opalescent liposome solutions of tool, particle diameter 100～250nm, Zeta-Potential-10～-70mV.
Embodiment 16 contains GGD-NHCH
2(CH
2)
10CH
3Preparation with Docetaxel liposome (L)
The consumption of each component: Docetaxel 0.5-30%; Natural phosphatidyl choline and GGD-NHCH
2(CH
2)
10CH
3Mixture 70-99.5%, in this mixture, natural phosphatidyl choline 80-99% (molar percentage), integrin receptor target anchor point compound 1-20% (molar percentage);
Phosphatide, Docetaxel and GGD-NHCH are got in the film dispersion method preparation
2(CH
2)
10CH
3Dissolve with chloroform to round-bottomed flask, rotary evaporation is removed solvent, forms the dry transparent plasma membrane of one deck at the bottle wall, adds the PBS phosphate buffered saline buffer (0.01mol/L) of aequum, 30 ℃ of ultra-sonic dispersion 20min.Get the opalescent liposome solutions of tool, particle diameter 100～250nm, Zeta-Potential-10～-70mV.
Embodiment 17 contains RGD-NHCH
2(CH
2)
10CH
3, long circulation film material DSPE and Docetaxel liposome (O) preparation
The consumption of each component: Docetaxel 0.5-30%; Natural phosphatidyl choline, RGD-NHCH
2(CH
2)
10CH
3With the mixture 70-99.5% of DSPE-mPEG2000, in this mixture, natural phosphatidyl choline 80-99% (molar percentage), integrin receptor target anchor point compound 1-20% (molar percentage);
Phosphatide, Docetaxel and RGD-NHCH are got in the film dispersion method preparation
2(CH
2)
10CH
3Dissolve with chloroform to round-bottomed flask, rotary evaporation is removed solvent, forms the dry transparent plasma membrane of one deck at the bottle wall, adds the PBS phosphate buffered saline buffer (0.01mol/L) of aequum, 30 ℃ of ultra-sonic dispersion 20min.Get the opalescent liposome solutions of tool, particle diameter 100～250nm, Zeta-Potential-10～-70mV.
Experimental example 18 contains RGD-NHC
nH
2n+1The therapeutic action to S180 ascites mouse of (n=8,10,12,14,16) and Docetaxel liposome
Get abdominal cavity inoculation S
180One of the 8th day ICR kind mouse of ascitic tumor takes off cervical vertebra and puts to death, and is placed in the super clean bench with 75% alcohol disinfecting, picks up skin that the belly center line takes over and cuts an osculum to as seen oyster white ascites outflow with little scissors with tweezers.Suction pipe is inserted abdominal cavity sucking-off ascites gently by opening part.Inhale ascites be added in the centrifuge tube of the 15ml that about 3ml sterile saline is housed, make volume increase to about 10ml.Blow gently with suction pipe, make ascites and physiological saline mixing.Test tube is added a cover, and 1000 rev/mins centrifugal 5 minutes.After the abandoning supernatant, add the 9ml sterile saline, blow gently with suction pipe, oncocyte is evenly floated, test tube is added a cover, 1000 rev/mins centrifugal 5 minutes, abandoning supernatant.The milky jelly that the test tube bottom has.In the oyster white jelly of test tube bottom, add the 9ml sterile saline, blow gently, oncocyte is evenly floated with suction pipe.Get 100 these suspension of μ l and add in the 9.9ml sterile saline, mixing gets 100 times of diluents, and mixing is added a cover, and it is stand-by to put into ice.Get the above-mentioned oncocyte diluent of 100 μ l and insert in the Eppendoff tubule, add 100 μ l platforms and expect blue dye liquor, mixing.Get a little this mixing liquid and add in the counting cell of tally, calculate in 4 big lattice by the number of the survival oncocyte of colors blue in microscopically.Survival oncocyte in the stoste is diluted to 2.0 * 10
7Individual/ml, be used for inoculation.Under aseptic condition,, sterilize in oxter, male mice in kunming right side with 2% tincture of iodine cotton balls and 75% cotton ball soaked in alcohol with 1ml ascitic tumor cell inoculation liquid.And inject 0.2ml oncocyte liquid, slowly extract syringe needle out.According to said method give every batch of Kunming mouse inoculation, random packet is put into animal housing and is raised.
The medicine preparation: this experiment is established 14 groups altogether: A.PBS solution group; B.0.5M the PBS of CMC-Na organizes C. blank liposome group; D. the blank liposome group (embodiment 9 is prepared) that contains RGD; E. Docetaxel suspension group; F. Docetaxel liposome (embodiment 10 is prepared) is organized; G. contain RGD-NH (CH in the film material
2)
7CH
3Docetaxel liposome (embodiment 11 is prepared) group; H. contain RGD-NH (CH in the film material
2)
9CH
3Docetaxel liposome (embodiment 12 is prepared) group; I. contain RGD-NH (CH in the film material
2)
11CH
3Docetaxel liposome (embodiment 13 is prepared) group; J. contain RGD-NH (CH in the film material
2)
13CH
3Docetaxel liposome (embodiment 14 is prepared) group; K. contain RGD-NH (CH in the film material
2)
15CH
3Docetaxel liposome (embodiment 15 is prepared) group; L. contain GGD-NH (CH in the film material
2)
11CH
3Docetaxel liposome (embodiment 16 is prepared) group; M. contain RGD-NH (CH in the film material
2)
11CH
3Low dose of Docetaxel liposome (embodiment 12 is prepared) group; N. contain low dose of RGD-NH (CH in the film material
2)
11CH
3Docetaxel liposome (embodiment 12 is prepared) group.O. contain RGD-NH (CH in the film material
2)
11CH
3And Docetaxel liposome (embodiment 17 the is prepared) group of long circulation film material DSPE.
Drug suspension preparation: take by weighing medicine and grind, it is wetting to add two tween 80s, makes suspension with 0.5%CMC-Na then.The dispersion system of liposome is the PBS buffered soln behind the autoclave sterilization, and positive control is the liposome of Docetaxel, and negative control is a blank liposome.Each is organized medicine and removes the M group and (contain RGD-NH (CH in the film material
2)
11CH
3Low dose of Docetaxel medicine fat body group) with outside the 0.25mg/ml preparation, all the other are all prepared with 0.5mg/mL.
Experimental technique: tranquillization is raised two days mouse, behind oxter, the right side inoculation ascitic tumor, be divided into 15 groups at random, 10 every group.After the inoculation, in the 1st, 3,5,7 days tail intravenously administrables, the above-mentioned medicine 0.2ml that respectively organizes of tail vein injection every day.After 7 days each group tumor-bearing mice is put to death, it is heavy with knurl to weigh, and calculates tumour inhibiting rate by tumour inhibiting rate=[the average knurl of (it is heavy that average knurl is organized in the average knurl weight-treatment of negative control group)/negative control group is heavy] * 100%.The data that obtain are with (X ± SD) expression, and do the t check.
The results are shown in Table 1.The result shows that the Docetaxel liposome that contains the RGD peptide conjugate has superior anti-tumor activity.Can find out wherein G by interpretation of result, H, I, J, K group antitumor action is higher than Docetaxel liposome group F, J wherein, the K group has utmost point significant difference (P＜0.01), H, the I group has significant difference (P＜0.05).The antitumor action that contains low dose of Docetaxel liposome group (M) is higher than Docetaxel liposome group F, but not statistically significant; Though M group anti-tumor activity has certain difference with the J group, not statistically significant has had good antitumor activity when Docetaxel target liposomes dosage 0.25mg/kg is described.Though N group anti-tumor activity is suitable with the F group, not statistically significant illustrates that RGD film material content is lower than certain level and just can not reaches good result of treatment.The average knurl of D group heavy with the C group quite, but and not statistically significant prove that simple RGD film material can not play the effect of knurl, and actual what work is to be the target effect that the film material is reached with RGD.O group antitumor action is higher than Docetaxel liposome group F, and utmost point significant difference (P＜0.01) is arranged, illustrate that the targeting preparation with long circulation film material has good result of treatment, and compare there was no significant difference with the I group, the ratio that shows long circulation film material is influential to its curative effect, also needs further to explore.G, H, I, J, L, the anti-tumor activity of M group all is higher than the L group, J wherein, L, the M group has utmost point significant difference (P＜0.01), H, the I group has significant difference (P＜0.05), and L group and F group no difference of science of statistics show that liposome L does not have target, and the necessity of RGD peptide conjugate as integrin receptor anchor point compound is described.
Table 1 Docetaxel targeting preparation is to the effect of lotus sarcoma S180 mouse
*Ining contrast to Docetaxel liposome control group has significance meaning (P＜0.05),
*In contrast to Docetaxel liposome group utmost point significance meaning (P＜0.01) is arranged.
Claims (10)
1, the amphipathic target anchor point compound of tool following formula structure,
Wherein, n represents 8,10, and 12,14,16.
2, the preparation method of the described compound of claim 1 may further comprise the steps:
(1) meets the synthetic respectively RGD of peptide technology according to conventional liquid phase;
(2) with the Arg-Gly-Asp of protecting group protection respectively with CH
3(CH
2)
6CH
2NH
2, CH
3(CH
2)
8CH
2NH
2, CH
3(CH
2)
10CH
2NH
2, CH
3(CH
2)
12CH
2NH
2, CH
3(CH
2)
14CH
2MH
2Protecting group is sloughed in coupling, promptly.
3, the target medicine carrier that contains the anchor point compound of claim 1.
4, the target medicine carrier of claim 3 is selected from nanometer formulations such as liposome, nanoparticle or micro emulsion.
5, the target medicine carrier of claim 3 is liposomes.
6, the pharmaceutical preparations composition that contains the target medicine carrier of claim 3.
7, the pharmaceutical preparations composition of claim 6, wherein said medicine is selected from antitumor drug.
8, the pharmaceutical preparations composition of claim 7, wherein said antitumor drug is selected from Docetaxel.
9, the pharmaceutical preparations composition of claim 6 is the liposome drug combinations that contain phosphatide, and its Chinese traditional medicine is selected from Docetaxel.
10, the pharmaceutical preparations composition of claim 9, it consists of antitumor drug and accounts for molar percentage 0.5-30%; The mixture of common drug carrier and anchor point compound accounts for molar percentage 70-99.5%, and in this mixture, the common drug carrier accounts for molar percentage 80-99%, and the anchor point compound accounts for molar percentage 1-20%.
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