CN102174187B - Synthetic method of targeted pegylated lipid medicinal material - Google Patents
Synthetic method of targeted pegylated lipid medicinal material Download PDFInfo
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- CN102174187B CN102174187B CN2011100476137A CN201110047613A CN102174187B CN 102174187 B CN102174187 B CN 102174187B CN 2011100476137 A CN2011100476137 A CN 2011100476137A CN 201110047613 A CN201110047613 A CN 201110047613A CN 102174187 B CN102174187 B CN 102174187B
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- Prior art keywords
- lipid
- targeted molecular
- pegylation
- hydroxyl
- deal
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- 239000000463 material Substances 0.000 title claims abstract description 82
- 238000010189 synthetic method Methods 0.000 title abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 98
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- Polyethers (AREA)
Abstract
The invention relates to a synthetic method of a targeted pegylated lipid medicinal material, belonging to the technical field of synthesis of medicinal lipid materials. According to the synthetic method, lipid containing hydroxy is used as an initiating agent to directly induce polymerization of an epoxyethane monomer by an anionic polymerization method; by controlling the ratio of the epoxyethane monomer to the initiating agent, the pegylated lipid medicinal material with controllable molecular weight and molecular weight distribution is obtained by acidification and purification; the medicinal carrier material can realize long circulation in vivo; and targeted molecules can also be coupled by further modification, thus realizing a targeting functional in vivo. The medicinal lipid material obtained in the invention has the advantages of stable structure, simple synthesis processing steps, mild reaction conditions, low cost and easy realization of functional targeting ability.
Description
Technical field
The present invention relates to a kind of synthetic technology of axunge material, particularly a kind of compound method of targeting poly terepthaloyl moietie lipid medicinal materials belongs to axunge material synthesis technical field.
Background technology
In recent years; Under the promotion of biomaterial and polymer chemistry high speed development; The macromolecular material of various functions continues to bring out, and impels the research develop rapidly of pharmaceutical prepn and formulation, and gets into drug delivery system (Drug delivery system; DDS) epoch, make novel drug delivery systems such as development is long-acting, efficient, target property become the direction of pharmaceutics researchdevelopment.
Polyoxyethylene glycol (PEG) has characteristics such as good water-solubility, biocompatibility, no antigen, toxicity be little.Be commonly used to decorated phospholipid phatidylcholine and lipid acid auxiliary material, after this auxiliary material is modified the lipid carrier surface, can increase the wetting ability of lipid carrier and sterically hindered as preparation emulsion or liposome; Can also avoid it by reticuloendothelial system phagocytic in the body; And can improve the stability of lipid carrier, make lipid carrier have the longer body-internal-circulation time, higher Plasma Concentration is assembled; Make and better bring into play curative effect, and can alleviate toxic side effect at diseased region.The other end at PEG connects targeted molecular; Adorned matrix material; Also have characteristics such as excellent biological compatibility, no antigen, toxicity be little, as pharmaceutical carrier, its advantage comprises with it: be used for the clinical pharmaceutical carrier target property of giving; Can improve the drug level of target tissue, increase the therapeutic index of medicine and enlarge clinical application etc.
It is that 200610150050.3 application for a patent for invention discloses a kind of polyoxyethylene glycol and is connected through micromolecular lipid acid with SUV that number of patent application is arranged; Find that after deliberation this method process is complicated; What polyoxyethylene glycol linked to each other with SUV is that ester bond is connected; Instability, especially ester bond easy fracture under alkaline condition under the condition of soda acid.The length of its polyoxyethylene glycol (PEG) chain can not automatic control in reaction, and must in reaction, add the PEG chain of certain-length; It is 200610168130.1 application for a patent for invention that number of patent application is arranged again; Disclose PEG has been connected in sterol (ChoL) synthetic copolymer (PGC) with ehter bond through micromolecular compound; Find after deliberation; Though more stable with the ehter bond syndeton, the process that preparation sterol and polyoxyethylene glycol are connected with ehter bond is complicacy and cost height comparatively; And polyglycol chain also need be bought, its length can not be in reaction automatic control, must in reaction, add the PEG chain of certain-length; Also has document [Hyperbranched polyglycerol-based lipids via oxyanionic polymerization:toward multifunctional stealth liposomes.Biomacromolecules.2010; 11; 568-574] in only have only the preparation of the synthetic and blank liposome of negatively charged ion Pegylation SUV; The Pegylation that does not relate to other lipid compounds is not in addition to the end group modification further of PEG.More than the matrix material of several kinds of said method preparations not only exist the preparation process complicated, production cost is high, and all exists its structural stability poor, the length of PEG chain can not automatic control, carrier is defective such as target property initiatively not.
Summary of the invention
The object of the invention provides a kind of polyoxyethylene glycol (PEG) to change the compound method of lipid medicinal materials and a kind of targeting poly terepthaloyl moietie (PEG) change lipid medicinal materials just in order to overcome existing deficiency in the prior art; This method is to adopt anionic polymerization; Directly bring out the oxirane monomers polymerization by initiator; And obtain the good Pegylation matrix material of biocompatibility through acidifying and purifying, or further through chemical process with targeted molecular in the coupling of Pegylation matrix material, the Pegylation matrix material that will have a targeted molecular is during as medicinal materials; Can give the target property of pharmaceutical carrier, be used for the clinical drug level that improves target tissue.
For realizing the foregoing invention purpose, the technical scheme that the present invention adopts following technical measures to constitute realizes:
The compound method of targeting poly terepthaloyl moietie lipid medicinal materials of the present invention; According to the present invention, adopt anionic polymerization, with the lipid that has hydroxyl as initiator; Directly bring out the oxirane monomers polymerization; Through the ratio of control oxirane monomers and initiator, and behind acidifying and purifying, obtain Pegylation lipid medicinal materials; Or, promptly obtain having the Pegylation lipid medicinal materials of target function further through chemical process coupling targeted molecular; Comprise following process step:
(1) basic metal with 1～3 mole of deal shreds into bottle, and at room temperature, the protection of nitrogen or inert gas down, with naphthalene stirring reaction 4～48h in anhydrous tetrahydro furan (THF) of 1～3 mole of deal, generation basic metal naphthalene solution;
(2) lipid that contains hydroxyl that in basic metal naphthalene solution, adds 1 mole of deal is as initiator; Under nitrogen or inert gas protection, after reacting 1～12h under the room temperature, under the ice-water bath condition; The oxirane monomers that adds 4.5～900 moles of deals again; Behind stirring reaction 12～48h, the absolute alcohol termination reaction with 3～10 moles of deals obtains the Pegylation lipid soln;
(3) with the Pegylation lipid soln in the step (2) behind acidifying and purifying, the end that can obtain the polyoxyethylene glycol chain length and be 200～20000Da is the Pegylation matrix material of hydroxyl;
(4) be that the Pegylation matrix material of hydroxyl adopts targeted molecular in three kinds of coupling method couplings with the end in the step (3), purified again after, can obtain targeting poly terepthaloyl moietie lipid medicinal materials.
In the technique scheme, described basic metal is sodium or potassium.
In the technique scheme, described absolute alcohol is a methyl alcohol, or ethanol, or glycerine, or propyl carbinol, or one or more mixing in the Virahol are used; Said acidifying acid comprises organic acid and mineral acid; Wherein, organic acid is a formic acid, or acetate, or Citric Acid; Mineral acid is a hydrochloric acid, or sulfuric acid, or phosphoric acid, or one or more mixing in the boric acid are used.
In the technique scheme, the described lipid initiator that contains hydroxyl is the phospholipids compounds that contains hydroxyl, or phytosterin compound, or 1,2-stearoyl-SN-glycerine.
In the technique scheme, the described phospholipids compounds that contains hydroxyl is Val or distearyl POPG or DOPG or two palmityl POPGs or two lauryl POPGs or two certain herbaceous plants with big flowers acyl phosphatide glycerine.
In the technique scheme, described phytosterin compound is SUV or vitamin D2 or Vitamin D3 500,000 I.U/GM or 7-dehydrocholesterol or ergot SUV.
The compound method of targeting poly terepthaloyl moietie lipid medicinal materials of the present invention; It is characterized in that with end be targeted molecular in the Pegylation lipid coupling of hydroxyl; Its method one is about to Pegylation lipid terminal hydroxyl and the coupling of targeted molecular esterification, comprises following process step:
(i) the targeted molecular folic acid or the vitamin H of 0.1～0.4 mole of deal or the magnetic ball that contains carboxyl are dissolved in the anhydrous dimethyl sulphoxide (DMSO); Under the protection and magnetic agitation of nitrogen or rare gas element; Slowly be added dropwise to 0.2～1.0 mole of deal N-hydroxy-succinamide (NHS) and 0.2～1.0 mole of deal 1; 3-NSC 57182 (DCC) stirs 0.5～2h, obtains the targeted molecular solution of activated carboxylic;
(ii) 0.1 mole of deal end is dissolved among the DMSO for the Pegylation matrix material of hydroxyl; And be added dropwise to lentamente in the targeted molecular solution of activated carboxylic, esterification 12～48h is purified under the room temperature; Vacuum-drying must contain the Pegylation lipid medicinal materials of targeted molecular.
The compound method of targeting poly terepthaloyl moietie lipid medicinal materials of the present invention; It is characterized in that with end be targeted molecular in the Pegylation lipid coupling of hydroxyl; Its method two be about to the terminal hydroxyl of Pegylation lipid carboxylated after; Targeted molecular in the coupling again comprises following process step:
(i) 0.5 mole of deal end is dissolved in the anhydrous organic solvent for the Pegylation matrix material of hydroxyl; Under nitrogen or protection of inert gas and ice-water bath; Under the magnetic agitation, add the 4-Dimethylamino pyridine (DMAP) of 0.5～2.5 mole of deal, reaction 0.5～2h; Slowly add the triethylamine of 0.5～2.5 mole of deal and the Succinic anhydried of 0.5～2.5 mole of deal, reaction 2～24h, purified, vacuum-drying must contain the Pegylation matrix material of carboxyl;
The Pegylation lipid that (ii) 0.1 mole of deal is contained carboxyl is dissolved among the anhydrous DMSO; Under the protection and magnetic agitation of nitrogen or rare gas element; Slowly be added dropwise to 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCL) of 0.1～0.5 mole of deal and the N-hydroxy-succinamide (NHS) of 0.1～0.5 mole of deal and stir 0.5～2h, obtain the Pegylation lipid soln of activated carboxylic;
(iii) with the targeted molecular semi-lactosi or the RGD of 0.1～0.4 mole of deal or contain amino magnetic ball and be dissolved among the anhydrous DMSO; Slowly be added dropwise in the Pegylation lipid soln of activated carboxylic; Room temperature reaction 12～48h; Purifying, vacuum-drying obtains containing the Pegylation lipid medicinal materials of targeted molecular.
The compound method of targeting poly terepthaloyl moietie lipid medicinal materials of the present invention; It is characterized in that with end be targeted molecular in the Pegylation lipid coupling of hydroxyl; After its method three is about to the terminal hydroxyl aminoization of Pegylation lipid; Targeted molecular in the coupling again comprises following process step:
(i) be that the Pegylation matrix material of hydroxyl is dissolved in the anhydrous organic solvent with the end of 0.5 mole of deal; Under the protection and ice-water bath of nitrogen or rare gas element; The triethylamine of 1.0～5.0 moles of deals of agitation and dropping and the Methanesulfonyl chloride of 1.0～5.0 moles of deals; Again at ambient temperature, stirring reaction 4～12h; Purified, vacuum-drying obtains sulfonyloxy methyl polyethylene glycol matrix material;
(ii) the sulfonyloxy methyl polyethylene glycol lipid of 0.2 mole of deal is added in the ammoniacal liquor of 1.0～100.0ml25% and dissolve, at room temperature stirring reaction is 2～4 days, and is purified, and vacuum-drying obtains amidized Pegylation matrix material;
(iii) under nitrogen or protection of inert gas; The targeted molecular folic acid or the vitamin H of 0.1～0.4 mole of deal or the magnetic ball that contains carboxyl are dissolved among the anhydrous DMSO; Slowly be added dropwise to the EDCHCL of 0.2～1.0 mole of deal and the NHS of 0.2～1.0 mole of deal under the magnetic agitation; Stir 0.5～2h, obtain the targeted molecular solution of activated carboxylic;
The amination Pegylation lipid of 0.1 mole of deal is dissolved among the anhydrous DMSO in (iv) will (ii) going on foot, and is added dropwise to lentamente in the activated carboxylic targeted molecular solution that (iii) goes on foot, and carries out acid amides reaction 12～48h under the room temperature; Purified again, vacuum-drying obtains containing the Pegylation lipid medicinal materials of targeted molecular.
The Pegylation lipid medicinal materials that the above-mentioned arbitrary described compound method of the present invention obtains, or targeting poly terepthaloyl moietie lipid medicinal materials is characterized in that the chemical structural formula of said medicinal materials is following:
Wherein, R
1Be phospholipids compounds or phytosterin compound or 1 of containing hydroxyl, 2-stearoyl-SN-glycerine; R
2Be hydroxyl or carboxyl or amino; Or the targeted molecular of ester bond or amido linkage connection; N is the integer from 4～500, and promptly molecular weight polyethylene glycol is 200～20000Da.
The compound method of targeting poly terepthaloyl moietie lipid medicinal materials of the present invention has following characteristics and useful technique effect:
1, the prepared Pegylation lipid medicinal materials of compound method of the present invention; With the lipid that contains hydroxyl is initiator; Directly bringing out oxirane monomers is polymerized; Not linked reaction,, obtain the PEG chain of molecular weight and controllable molecular weight distribution through the ratio of control oxirane monomers and initiator.
2, the chemicalstability of the prepared Pegylation lipid medicinal materials of compound method of the present invention is good, and hydroxyl is arranged as terminal bioactive molecule, is easy to further coupling targeted molecular; And whole method for synthesizing and purifying is easy, and cost is low.
3, the pharmaceutical carrier that adopts synthetic Pegylation lipid medicinal materials of the present invention to be prepared into had both had good physical stability, size distribution homogeneous characteristics, again can favourable cytophagy, and reduce drug dose, and reduce the toxic side effect of medicine; Reduce clearance rate when using in vivo, improved Plasma Concentration.
When 4, being used as pharmaceutical carrier behind the targeted molecular in the synthetic Pegylation matrix material of the present invention coupling; Targeted molecular can be discerned the special acceptor on the target cell membrane; The guide drugs carrier concentrates the target tissue organ; Thereby improved intracellular drug level, given the active Targeting Performance power of carrier.
Description of drawings
Fig. 1 embodiment of the invention 10 adopts nuclear-magnetisms to identify terminal the be structure of the polyoxyethylene glycol of hydroxyl (600Da) change SUV and the nuclear-magnetism figure of polyoxyethylene glycol chain length (deuterium is a solvent for DMSO) wherein;
Fig. 2 is that the embodiment of the invention 10 adopts the terminal infrared figure of structure that changes SUV for the polyoxyethylene glycol of hydroxyl (600Da) of infrared identification;
Fig. 3 is the characteristic absorbance that the embodiment of the invention 10 adopts ultraviolet detection folic acid, is respectively that folic acid targeting poly terepthaloyl moietie (600Da) is changed cholesterol ester material, folic acid, amination polyoxyethylene glycol (600Da) change cholesterol ester material ultraviolet characteristic absorbance figure from top to bottom;
Fig. 4 is that the embodiment of the invention 12 adopts GPC to identify the terminal polyoxyethylene glycol of hydroxyl (2000Da) the change SUV chain distribution curve that is;
Fig. 5 is that the embodiment of the invention 12 adopts nuclear-magnetisms to identify terminal the be structure of the polyoxyethylene glycol of hydroxyl (2000Da) change SUV and the nuclear-magnetism figure of polyoxyethylene glycol chain length (deuterochloroform is a solvent) wherein;
Fig. 6 is that the embodiment of the invention 12 adopts the terminal infrared figure of structure that changes SUV for the polyoxyethylene glycol of hydroxyl (2000Da) of infrared identification.
Embodiment
Below in conjunction with specific embodiment the present invention is described further, to help understanding content of the present invention.
The compound method of targeting poly terepthaloyl moietie lipid medicinal materials of the present invention is carried out according to the process step of compound method noted earlier.
Used instrument: magnetic stirring apparatus, vacuum pump, two mouthfuls of flasks;
Agents useful for same: DMSO, methylene dichloride, trichloromethane, THF, methyl alcohol, ethanol, propyl carbinol, Virahol, glycerine, sherwood oil, DCC, EDCHCL, NHS, DMAP;
Material therefor: Val or distearyl POPG or DOPG or two palmityl POPGs or two lauryl POPGs or two certain herbaceous plants with big flowers acyl POPGs, SUV, vitamin D2, Vitamin D3 500,000 I.U/GM, 7-dehydrocholesterol, ergot SUV, 1, contain carboxyl magnetic ball, RGD, contain amino magnetic ball, Succinic anhydried, triethylamine, potassium, sodium and oxyethane 2-stearoyl-SN-glycerine, folic acid, vitamin H, semi-lactosi.
Preparation vitamin H targeted molecular polyoxyethylene glycol (2000Da) is changed the Val matrix material
(1) 2.0mmol sodium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 2.0mmol naphthalene added in the anhydrous THF of 25ml dissolve, magnetic agitation reaction 4h produces sodium naphthalene solution;
(2),, mix with sodium naphthalene solution with the dissolving of 1.0mmol initiator Val with the anhydrous THF solution of 40ml; 1h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 45.0mmol of-20 ℃ of preservations; Magnetic agitation reaction 12h; With 3.0mmol absolute ethyl alcohol termination reaction, filtering solution obtains polyoxyethylene glycol (2000Da) and changes the Val lipid soln;
(3) polyoxyethylene glycol (2000Da) being changed Val lipid soln use first acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns, dialysed two days, use ethyl alcohol recrystallization; Vacuum-drying obtains the terminal polyoxyethylene glycol of hydroxyl (2000Da) the change Val matrix material that is;
(4) be that the polyoxyethylene glycol (2000Da) of hydroxyl is changed vitamin H targeted molecular in the coupling of Val lipid with end, be about to polyoxyethylene glycol (2000Da) and change Val lipid terminal hydroxyl and pass through the esterification coupling that its operation steps is following with targeted molecular:
(i) the vitamin H targeted molecular with 0.1mmol is dissolved among the anhydrous DMSO, under protection of nitrogen gas, slowly is added dropwise to the NHS of 0.2mmol and the DCC of 0.2mmol under the magnetic agitation, stirs 0.5h, obtains the vitamin H targeted molecular solution of activated carboxylic;
Be that the polyoxyethylene glycol (2000Da) of hydroxyl is changed the Val matrix material and is dissolved among the anhydrous DMSO (ii), and slowly be added dropwise in the vitamin H targeted molecular solution of activated carboxylic, react 12h under the room temperature the end of 0.1mmol; Behind the reaction terminating, product filters, and filtrate water is washed twice; The water dialysis; Ethyl alcohol recrystallization twice, vacuum-drying, the polyoxyethylene glycol (2000Da) that obtains containing the vitamin H targeted molecular is changed Val matter fat material.
Embodiment 2
Preparation magnetic ball targeted molecular polyoxyethylene glycol (200Da) is changed the DOPG matrix material
(1) 3.0mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and nitrogen protection, the 3.0mmol naphthalene added in the anhydrous THF of 25ml dissolve, magnetic agitation reaction 48h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1.0mmol initiator DOPG with the anhydrous THF solution of 40ml; 12h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 9.0mmol of-20 ℃ of preservations; Magnetic agitation reaction 48h; With 3.0mmol anhydrous methanol termination reaction, filtering solution obtains polyoxyethylene glycol (200Da) and changes the DOPG lipid soln;
(3) polyoxyethylene glycol (200Da) being changed DOPG lipid soln use second acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns; Dialysed two days, and used ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (200Da) the change DOPG matrix material that is;
(4) be that the polyoxyethylene glycol (200Da) of hydroxyl is changed targeted molecular in the coupling of DOPG lipid with end; Be about to polyoxyethylene glycol (200Da) and change the DOPG terminal hydroxyl and contain carboxyl magnetic ball targeted molecular through the esterification coupling, its operation steps is following:
(i) the carboxyl magnetic ball targeted molecular that contains with 0.4mmol is dissolved among the anhydrous DMSO, under protection of nitrogen gas and magnetic agitation, slowly is added dropwise to the NHS of 1.0mmol and the DCC of 1.0mmol, stirs 0.5h, obtains the magnetic ball targeted molecular solution of activated carboxylic;
Be that the polyoxyethylene glycol (200Da) of hydroxyl is changed the DOPG matrix material and is dissolved among the anhydrous DMSO in addition (ii), and slowly be added dropwise in the magnetic ball targeted molecular targeted molecular solution of activated carboxylic, react 12h under the room temperature the end of 0.1mmol; Behind the reaction terminating, product filters, washing; Use ether sedimentation at last; Cross post, recrystallization is removed impurity, and the polyoxyethylene glycol (200Da) that obtains containing magnetic ball targeted molecular is changed the DOPG matrix material.
Embodiment 3
Preparation magnetic ball targeted molecular polyoxyethylene glycol (1000Da) is changed two palmityl POPG matrix materials
(1) 2.0mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and nitrogen protection, the 2.0mmol naphthalene added in the anhydrous THF of 25ml dissolve, magnetic agitation reaction 24h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1.0mmol initiator two palmityl POPGs with the anhydrous THF solution of 40ml; 6h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 45.0mmol of-20 ℃ of preservations; Magnetic agitation reaction 24h; With 6.0mmol anhydrous glycerol termination reaction, filtering solution obtains polyoxyethylene glycol (1000Da) and changes two palmityl POPG lipid solns;
(3) polyoxyethylene glycol (1000Da) being changed two palmityl POPG lipid solns use citron acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns; Dialysed two days, and used ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (1000Da) the change two palmityl POPG matrix materials that are;
(4) be that the polyoxyethylene glycol (1000Da) of hydroxyl is changed targeted molecular in the two palmityl POPG lipid couplings with end; Be about to polyoxyethylene glycol (1000Da) and change two palmityl POPG lipid terminal hydroxyls and contain carboxyl magnetic ball targeted molecular through the esterification coupling, its operation steps is following:
(i) the carboxyl magnetic ball targeted molecular that contains with 0.2mmol is dissolved among the anhydrous DMSO, under protection of nitrogen gas and magnetic agitation, slowly is added dropwise to the NHS of 0.5mmol and the DCC of 0.5mmol, stirs 1h, obtains the magnetic ball targeted molecular solution of activated carboxylic;
Be that the polyoxyethylene glycol (1000Da) of hydroxyl is changed two palmityl POPG matrix materials and is dissolved among the anhydrous DMSO in addition (ii), and be added dropwise to lentamente in the magnetic ball targeted molecular solution of activated carboxylic, react 24h under the room temperature the end of 0.1mmol; Behind the reaction terminating, product filters, washing; Use ether sedimentation at last; Cross post, recrystallization is removed impurity, and the polyoxyethylene glycol (1000Da) that obtains containing magnetic ball targeted molecular is changed two palmityl POPG matrix materials.
Embodiment 4
Preparation magnetic ball targeted molecular polyoxyethylene glycol (2000Da) is changed two lauryl POPG matrix materials
(1) 1.0mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 1.0mmol naphthalene added in the anhydrous THF of 25ml dissolve, magnetic agitation reaction 4h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1.0mmol initiator two lauryl POPGs with the anhydrous THF solution of 40ml; 1h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 90.0mmol of-20 ℃ of preservations; Stirring reaction 12h; With 10.0mmol anhydrous isopropyl alcohol termination reaction, filtering solution obtains polyoxyethylene glycol (2000Da) and changes two lauryl POPG lipid solns;
(3) polyoxyethylene glycol (2000Da) being changed two lauryl POPG lipid solns use salt acid for adjusting pH value is 4; With 1: 50 deposition of the ratio of its solution and ether three times, cross 200～300 purpose silicagel columns, dialysis two days, use ethyl alcohol recrystallization, obtaining terminal is the polyoxyethylene glycol of hydroxyl (2000Da) change two lauryl POPG matrix materials;
(4) be that the polyoxyethylene glycol (2000Da) of hydroxyl is changed targeted molecular in the two lauryl POPG lipid couplings with end; Be about to polyoxyethylene glycol (2000Da) and change two lauryl POPG lipid terminal hydroxyls and contain carboxyl magnetic ball targeted molecular through the esterification coupling, its operation steps is following:
(i) the carboxyl magnetic ball targeted molecular that contains with 0.1mmol is dissolved among the anhydrous DMSO, under the protection and magnetic agitation of argon gas, slowly is added dropwise to the NHS of 0.2mmol and the DCC of 0.2mmol, stirs 2h, obtains the magnetic ball targeted molecular solution of activated carboxylic;
Be that the polyoxyethylene glycol (2000Da) of hydroxyl is changed two lauryl POPG matrix materials and is dissolved among the DMSO in addition (ii), and slowly be added dropwise in the folic acid targeted molecular solution of activated carboxylic, react 48h under the room temperature the end of 0.1mmol; Behind the reaction terminating, product filters, washing; Use ether sedimentation at last; Cross post, recrystallization is removed impurity, and the polyoxyethylene glycol (2000Da) that obtains containing magnetic ball targeted molecular is changed two lauryl POPG matrix materials.
Embodiment 1-4 is under used processing condition and processing parameter same case, and only will contain carboxyl magnetic ball changes folic acid targeted molecular or vitamin H targeted molecular into, also can prepare corresponding matrix material.
Preparation semi-lactosi targeted molecular polyoxyethylene glycol (4000Da) is changed two certain herbaceous plants with big flowers acyl POPG matrix materials
(1) 3mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 1.5mmol naphthalene added in the anhydrous THF of 50ml dissolve, magnetic agitation reaction 48h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1mmol initiator two certain herbaceous plants with big flowers acyl POPGs with the anhydrous THF solution of 40ml; 12h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 180.0mmol of-20 ℃ of preservations; Magnetic agitation reaction 48h; With the anhydrous butanols termination reaction of 3.0mmol, filtering solution obtains polyoxyethylene glycol (4000Da) and changes two certain herbaceous plants with big flowers acyl POPG lipid solns;
(3) polyoxyethylene glycol (4000Da) being changed two certain herbaceous plants with big flowers acyl POPG lipid solns use sulphur acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns; Dialysed two days, and used ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (4000Da) the change two certain herbaceous plants with big flowers acyl POPG matrix materials that are;
(4) be that the polyoxyethylene glycol (4000Da) of hydroxyl is changed targeted molecular in the two certain herbaceous plants with big flowers acyl POPG couplings with end; After the hydroxyl of the two certain herbaceous plants with big flowers acyl POPG lipids of polyoxyethylene glycol (4000Da) change soon end is carboxylated; Semi-lactosi targeted molecular in the coupling again, its operation steps is following:
(i) be that the polyoxyethylene glycol (4000Da) of hydroxyl is changed two certain herbaceous plants with big flowers acyl POPG lipids and is dissolved among the anhydrous DMSO with the end of 0.5mmol, under protection of nitrogen gas and ice-water bath, slowly be added dropwise to 0.5h under the DMAP magnetic agitation of 2.5mmol; Slowly be added dropwise to the triethylamine of 1mmol and the Succinic anhydried of 2.5mmol again; Reaction times 2h, the filtering reaction product is removed impurity, washing; With the ratio of its solution and ether 1: 50; Deposition twice, ethanol carries out recrystallization twice, and the polyoxyethylene glycol (4000Da) that obtains containing carboxyl is changed two certain herbaceous plants with big flowers acyl POPGs;
(ii) under protection of nitrogen gas; The polyoxyethylene glycol that 0.1mmol is carboxylated (4000Da) is changed two certain herbaceous plants with big flowers acyl POPG matrix materials and is dissolved among the anhydrous DMSO; Under room temperature and the magnetic agitation; Slowly be added dropwise to the EDCHCL of 0.5mmol and the NHS of 0.5mmol and stir 0.5h, the polyoxyethylene glycol (4000Da) that obtains activated carboxylic is changed two certain herbaceous plants with big flowers acyl POPG lipid solns;
(iii) the semi-lactosi targeted molecular with 0.4mmol is dissolved among the DMSO, and the polyoxyethylene glycol (4000Da) that is added drop-wise to activated carboxylic is slowly changed in the two certain herbaceous plants with big flowers acyl POPG matrix material solution, at room temperature reacts 12h; Reaction product is filtered; Ether sedimentation is used in 1000 dialysis tubing dialysis two days at last, crosses 200～300 order silicagel columns; Ethyl alcohol recrystallization twice, the polyoxyethylene glycol (4000Da) that obtains containing the semi-lactosi targeted molecular is changed two certain herbaceous plants with big flowers acyl POPG matrix materials.
Embodiment 6
Preparation semi-lactosi targeted molecular polyoxyethylene glycol (10000Da) is changed ergot cholesterol ester material
(1) 2mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 1.5mmol naphthalene added in the anhydrous THF of 50ml dissolve, magnetic agitation reaction 24h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1mmol initiator ergot ergot SUV with the anhydrous THF solution of 40ml; 6h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 225mmol of-20 ℃ of preservations; Magnetic agitation reaction 24h; With 6.0mmol anhydrous normal butyl alcohol termination reaction, filtering solution obtains polyoxyethylene glycol (10000Da) and changes ergot SUV lipid solution;
(3) polyoxyethylene glycol (10000Da) being changed ergot SUV lipid solution use phosphorus acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns; Dialysed two days, and used ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (10000Da) the change ergot cholesterol ester material that is;
(4) be that the polyoxyethylene glycol (10000Da) of hydroxyl is changed targeted molecular in the coupling of ergot SUV with end, be about to polyoxyethylene glycol (10000Da) change the terminal hydroxyl of ergot SUV lipid carboxylated after, semi-lactosi targeted molecular in the coupling again, its operation steps is following:
(i) be that the polyoxyethylene glycol (10000Da) of hydroxyl is changed the ergot SUV and is dissolved in the anhydrous methylene chloride with the end of 0.5mmol, under the protection and ice-water bath of helium, slowly add 1h under the DMAP magnetic agitation of 1mmol; Slowly add the triethylamine of 1mmol and the Succinic anhydried of 1mmol again; Reaction times 1h, the filtering reaction product is removed impurity, washing; With the ratio of its solution and ether 1: 50; Deposition twice, ethanol carries out recrystallization twice, and the polyoxyethylene glycol (10000Da) that obtains containing carboxyl is changed ergot cholesterol ester material;
(ii) under protection of nitrogen gas; The PEGization ergot cholesterol ester material that 0.1mmol is carboxylated is dissolved among the anhydrous DMSO; Under room temperature and the magnetic agitation; Slowly be added dropwise to the EDCHCL of 0.2mmol and the NHS magnetic agitation 1h of 0.2mmol, the polyoxyethylene glycol (10000Da) that obtains activated carboxylic is changed ergot SUV lipid solution;
(iii) the semi-lactosi targeted molecular with 0.2mmol is dissolved among the DMSO, and the polyoxyethylene glycol (10000Da) that is added drop-wise to activated carboxylic is slowly changed in the ergot cholesterol ester material solution, at room temperature reacts 24h; Reaction product is filtered; Ether sedimentation is used in 5000 dialysis tubing dialysis two days at last, crosses 200～300 order silicagel columns; Ethyl alcohol recrystallization twice, the polyoxyethylene glycol (10000Da) that obtains containing the semi-lactosi targeted molecular is changed ergot cholesterol ester material.
Embodiment 7
Preparation semi-lactosi targeted molecular polyoxyethylene glycol (15000Da) is changed the vitamin D2 matrix material
(1) 1.0mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 1.0mmol naphthalene added in the anhydrous THF of 50ml dissolve, magnetic agitation reaction 12h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1mmol initiator vitamin D2 with the anhydrous THF solution of 40ml; 1h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 337.5mmol of-20 ℃ of preservations; Magnetic agitation reaction 12h; With 10.0mmol absolute ethyl alcohol termination reaction, filtering solution obtains polyoxyethylene glycol (15000Da) and changes the vitamin D2 lipid soln;
(3) polyoxyethylene glycol (15000Da) being changed vitamin D2 lipid soln use boron acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns; Dialysed two days, and used ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (15000Da) the change vitamin D2 matrix material that is;
(4) be that the polyoxyethylene glycol (15000Da) of hydroxyl is changed targeted molecular in the vitamin D2 coupling with end, be about to polyoxyethylene glycol (15000Da) change the terminal hydroxyl of vitamin D2 lipid carboxylated after, semi-lactosi targeted molecular in the coupling again, its operation steps is following:
(i) be that the polyoxyethylene glycol (15000Da) of hydroxyl is changed the vitamin D2 matrix material and is dissolved in the anhydrous trichloromethane with the end of 0.5mmol, under protection of nitrogen gas and ice-water bath, slowly add the DMAP of 0.5mmol; 2h under the magnetic agitation slowly adds the triethylamine of 0.5mmol and the Succinic anhydried of 0.5mmol, reaction times 2h again; The filtering reaction product is removed impurity; Washing with the ratio of its solution and ether 1: 50, precipitates twice; Ethanol carries out recrystallization twice, and the polyoxyethylene glycol (15000Da) that obtains containing carboxyl is changed the vitamin D2 matrix material;
(ii) under protection of nitrogen gas; The Pegylation vitamin D2 matrix material that 0.1mmol is carboxylated is dissolved among the anhydrous DMSO; Under room temperature and the magnetic agitation; Slowly be added dropwise to the EDCHCL of 0.5mmol and the NHS of 0.5mmol and stir 2h, the polyoxyethylene glycol (15000Da) that obtains activated carboxylic is changed the vitamin D2 lipid soln;
(iii) the semi-lactosi targeted molecular with 0.1mmol is dissolved among the DMSO, and the polyoxyethylene glycol (15000Da) that is added drop-wise to activated carboxylic is slowly changed in the vitamin D2 lipid soln, at room temperature reacts 48h; Reaction product is filtered; Ether sedimentation is used in 10000 dialysis tubing dialysis two days at last, crosses 200～300 order silicagel columns; Ethyl alcohol recrystallization twice, the polyoxyethylene glycol (15000Da) that obtains containing the semi-lactosi targeted molecular is changed the vitamin D2 matrix material.
Embodiment 5-7 only changes the semi-lactosi targeted molecular into and contains amino magnetic ball targeted molecular or RGD targeted molecular under used processing condition and processing parameter same case, also can prepare corresponding matrix material.
Preparation folic acid targeted molecular polyoxyethylene glycol (20000Da) is changed distearyl POPG matrix material
(1) 3.0mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 3.0mmol naphthalene is added dissolving in the anhydrous THF of 50ml (THF), magnetic agitation reaction 4h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1mmol initiator distearyl POPG with the anhydrous THF solution of 40ml; 1h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers monomer 900.0mmol of-20 ℃ of preservations; Magnetic agitation reaction 12h; With 3.0mmol absolute ethyl alcohol termination reaction, filtering solution obtains polyoxyethylene glycol (20000Da) and changes distearyl POPG lipid soln;
(3) polyoxyethylene glycol (20000Da) being changed distearyl POPG lipid soln use salt acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns; Dialysed two days, and used ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (20000Da) the change distearyl POPG matrix material that is;
(4) with end be polyoxyethylene glycol (20000Da) the change distearyl POPG coupling folic acid targeted molecular of hydroxyl; After being about to the terminal hydroxyl aminoization of terepthaloyl moietie (20000Da) change distearyl POPG lipid; Folic acid targeted molecular in the coupling again, its operation steps is following:
(i) be that the polyoxyethylene glycol (20000Da) of hydroxyl is changed distearyl POPG matrix material and is dissolved in the anhydrous methylene dichloride with the end of 0.5mmol; Under protection of nitrogen gas and ice-water bath, under the magnetic agitation, slowly drip the triethylamine of 1.0mmol and the Methanesulfonyl chloride of 1.0mmol; Stir 4h; Filtering reaction product, product carry out recrystallization in ethanol, obtain sulfonyloxy methyl polyethylene glycol (20000Da) and change distearyl POPG matrix material;
(ii) dissolve in other the ammoniacal liquor sulfonyloxy methyl polyethylene glycol (20000Da) the change distearyl POPG matrix material adding 10ml 25% of 0.2mmol; At room temperature reacted 2 days under the high-speed stirring; Solution extracts; Thick product carries out recrystallization twice in ethanol, obtain amidized polyoxyethylene glycol (20000Da) and change distearyl POPG matrix material;
(iii) under nitrogen protection, the folic acid targeted molecular of 0.1mmol is dissolved among the anhydrous DMSO, under room temperature and magnetic agitation, slowly be added dropwise to the EDCHCL of 0.2mmol and the NHS of 0.2mmol and stir 0.5h, obtain the folic acid targeted molecular solution of activated carboxylic;
(iv) at room temperature; The amination polyoxyethylene glycol (20000Da) of 0.1mmol is changed distearyl POPG matrix material be dissolved among the anhydrous DMSO, be added drop-wise to slowly in the folic acid targeted molecular solution of activated carboxylic, reaction 12h; The filtering reaction product; Recrystallization is carried out in the water dialysis, and the polyoxyethylene glycol (20000Da) that obtains containing the folic acid targeted molecular is changed distearyl POPG matrix material.
Embodiment 9
Preparation folic acid targeted molecular polyoxyethylene glycol (20000Da) is changed 7-dehydrocholesterol matrix material
(1) 3.0mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 3.0mmol naphthalene is added dissolving in the anhydrous THF of 50ml (THF), magnetic agitation reaction 4h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1mmol initiator 7-dehydrocholesterol with the anhydrous THF solution of 40ml; 1h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 450.0mmol of-20 ℃ of preservations; Magnetic agitation reaction 12h; With 3.0mmol absolute ethyl alcohol termination reaction, filtering solution obtains polyoxyethylene glycol (20000Da) and changes 7-dehydrocholesterol lipid soln;
(3) polyoxyethylene glycol (20000Da) being changed 7-dehydrocholesterol lipid soln use salt acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns; Dialysed two days, and used ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (20000Da) the change 7-dehydrocholesterol matrix material that is;
(4) be that the polyoxyethylene glycol (20000Da) of hydroxyl is changed 7-dehydrocholesterol coupling folic acid targeted molecular with end, after being about to terepthaloyl moietie (20000Da) and changing the terminal hydroxyl aminoization of 7-dehydrocholesterol lipid, folic acid targeted molecular in the coupling again, its operation steps is following:
(i) be that the polyoxyethylene glycol (20000Da) of hydroxyl is changed 7-dehydrocholesterol matrix material and is dissolved in the anhydrous trichloromethane with the end of 0.5mmol; Under protection of nitrogen gas and ice-water bath, under the magnetic agitation, slowly drip the triethylamine of 1.0mmol and the Methanesulfonyl chloride of 1.0mmol; Stir 4h; Filtering reaction product, product carry out recrystallization in ethanol, obtain sulfonyloxy methyl polyethylene glycol (20000Da) and change 7-dehydrocholesterol matrix material;
(ii) dissolve in other the ammoniacal liquor sulfonyloxy methyl polyethylene glycol (20000Da) the change 7-dehydrocholesterol matrix material adding 10ml 25% of 0.2mmol; At room temperature reacted 2 days under the high-speed stirring; Solution extracts; Thick product carries out recrystallization twice in ethanol, obtain amidized polyoxyethylene glycol (20000Da) and change 7-dehydrocholesterol matrix material;
(iii) under nitrogen protection, the folic acid targeted molecular of 0.1mmol is dissolved among the anhydrous DMSO, under room temperature and magnetic agitation, slowly be added dropwise to the EDCHCL of 0.2mmol and the NHS of 0.2mmol and stir 0.5h, obtain the folic acid targeted molecular solution of activated carboxylic;
(iv) at room temperature; The amination polyoxyethylene glycol (20000Da) of 0.1mmol is changed 7-dehydrocholesterol matrix material be dissolved among the anhydrous DMSO, be added drop-wise to slowly in the folic acid targeted molecular solution of activated carboxylic, reaction 12h; The filtering reaction product; Recrystallization is carried out in the water dialysis, and the polyoxyethylene glycol (20000Da) that obtains containing the folic acid targeted molecular is changed 7-dehydrocholesterol matrix material.
Preparation folic acid property targeted molecular polyoxyethylene glycol (600Da) is changed the cholesterol ester material
(1) 2mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 1.5mmol naphthalene is added dissolving in the anhydrous THF of 50ml (THF), magnetic agitation reaction 24h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1mmol initiator SUV with the anhydrous THF solution of 40ml; 6h under room temperature and the magnetic agitation under the ice-water bath condition, adds the oxirane monomers 13.5mmol of-20 ℃ of preservations; Magnetic agitation reaction 24h; With 6.0mmol absolute ethyl alcohol termination reaction, filtering solution obtains polyoxyethylene glycol (600Da) and changes SUV lipid solution;
(3) polyoxyethylene glycol (600Da) being changed SUV lipid solution use salt acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns, use ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (600Da) the change cholesterol ester material that is; Adopt nuclear-magnetism to identify terminal the be structure of the polyoxyethylene glycol of hydroxyl (600Da) change SUV and the nuclear-magnetism figure of polyoxyethylene glycol chain length wherein; (400MHz, d6-DMSO) d/ppm: δ 0.64ppm is unimodal to 1H NMR, is the hydrogen on 18 in the SUV; δ 3.36ppm is a multiplet, is the hydrogen on 3 in the SUV; δ 3.40-3.58ppm is the hydrogen on the polyoxyethylene glycol; δ 5.15ppm is unimodal, is the hydrogen on 6 of SUV; δ 2.49-2.51ppm is a solvent peak, and calculates according to integral area, obtains polyoxyethylene glycol chain portion molecular weight and is about 600Da.As shown in Figure 1; Adopting the infrared identification end is the structure of polyoxyethylene glycol (600Da) the change SUV of hydroxyl, on ir spectra, has both had the characteristic absorbance of SUV unsaturated double-bond: 1639cm in the product
-1(C=C), 2934 and 2868cm
-1(saturated vibration of C-H and the unsaturated vibration of C-H); Also has simultaneously the segmental characteristic absorbance of PEG: 1112cm
-1(C-O-C), 3000-2800cm
-1(C-H) and 3436cm
-1(O-H); This explains that resultant product is to cause the PEG oligopolymer that epoxyethane ring-expansion polymerization forms by SUV really, and is as shown in Figure 2;
(4) be that the polyoxyethylene glycol (600Da) of hydroxyl is changed SUV coupling folic acid targeted molecular with end, after being about to polyoxyethylene glycol (600Da) and changing the terminal hydroxyl aminoization of SUV lipid, folic acid targeted molecular in the coupling again, its operation steps is following:
(i) be that the polyoxyethylene glycol (600Da) of hydroxyl is changed the cholesterol ester material and is dissolved among the anhydrous DMSO with the end of 0.5mmol; Under protection of nitrogen gas and ice-water bath, under the magnetic agitation, slowly drip the triethylamine of 2.5mmol and the Methanesulfonyl chloride of 2.5mmol; Stir 8h; Filtering reaction product, product carry out recrystallization in ethanol, obtain sulfonyloxy methyl polyethylene glycol (600Da) and change the cholesterol ester material;
(ii) dissolve in other the ammoniacal liquor sulfonyloxy methyl polyethylene glycol (600Da) the change cholesterol ester material adding 50ml 25% of 0.2mmol; At room temperature reacted 3 days under the high-speed stirring; Solution extracts; Thick product carries out recrystallization twice in ethanol, dry under vacuum, obtains amidized polyoxyethylene glycol (600Da) and changes the cholesterol ester material;
(iii) under nitrogen protection, the folic acid targeted molecular of 0.2mmol is dissolved among the anhydrous DMSO, under room temperature and magnetic agitation, slowly be added dropwise to the EDCHCL of 0.5mmol and the NHS of 0.5mmol and stir 1h, obtain the folic acid targeted molecular solution of activated carboxylic;
(iv) at room temperature; The amination polyoxyethylene glycol (600Da) of 0.1mmol is changed the cholesterol ester material be dissolved among the anhydrous DMSO, be added drop-wise to slowly in the folic acid targeted molecular solution of activated carboxylic, reaction 24h; The filtering reaction product; Recrystallization is carried out in the water dialysis, and the polyoxyethylene glycol (600Da) that obtains containing the folic acid targeted molecular is changed the cholesterol ester material; Adopt ultraviolet detection folic acid target polyoxyethylene glycol (600Da) to change the cholesterol ester material; Detect folic acid targeted molecular characteristic absorbance; Employing DMSO is a solvent, and this figure can find out that folic acid target polyoxyethylene glycol (600Da) changes on the cholesterol ester material folic acid targeted molecular in the coupling, and is as shown in Figure 3.
Embodiment 11
Preparation folic acid targeted molecular polyoxyethylene glycol (2000Da) changes 1,2-stearoyl-SN-glyceride material
(1) 1mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 1mmol naphthalene is added dissolving in the anhydrous THF of 50ml (THF), magnetic agitation reaction 48h produces potassium naphthalene solution;
(2) with the anhydrous THF solution of 40ml, with 1mmol initiator 1,2-stearoyl-SN-glycerine dissolving; Mix with potassium naphthalene solution, 12h under room temperature and the magnetic agitation is under the ice-water bath condition; The oxirane monomers 45.0mmol that adds-20 ℃ of preservations, magnetic agitation reaction 48h is with 10.0mmol absolute ethyl alcohol termination reaction; Filtering solution obtains polyoxyethylene glycol (2000Da) and changes 1,2-stearoyl-SN-glycerine lipid soln;
(3) polyoxyethylene glycol (2000Da) is changed 1; It is 4 that 2-stearoyl-SN-glycerine lipid soln uses the citron acid for adjusting pH value, with 1: 50 deposition of the ratio of its solution and ether three times, and mistake 200～300 purpose silicagel columns; Dialysed two days; Use ethyl alcohol recrystallization, obtain terminal the be polyoxyethylene glycol of hydroxyl (2000Da) change 1,2-stearoyl-SN-glyceride material;
(4) with end be polyoxyethylene glycol (2000Da) change 1 of hydroxyl; 2-stearoyl-SN-glycerine coupling folic acid targeted molecular is about to polyoxyethylene glycol (2000Da) and changes 1, after the hydroxyl aminoization of 2-stearoyl-SN-glycerine lipid end; Folic acid targeted molecular in the coupling again, its operation steps is following:
(i) end with 0.5mmol is polyoxyethylene glycol (2000Da) change 1 of hydroxyl, and 2-stearoyl-SN-glyceride material is dissolved in the anhydrous methylene dichloride, under protection of nitrogen gas and ice-water bath; Under the magnetic agitation, slowly the triethylamine of Dropwise 5 .0mmol and the Methanesulfonyl chloride of 5.0mmol stir 12h; The filtering reaction product; Product carries out recrystallization in ethanol, sulfonyloxy methyl polyethylene glycol (2000Da) changes 1,2-stearoyl-SN-glyceride material;
(ii) in addition the sulfonyloxy methyl polyethylene glycol (2000Da) of 0.2mmol is changed 1; Dissolve in the ammoniacal liquor of 2-stearoyl-SN-glyceride material adding 100ml 25%, at room temperature reacted 4 days under the high-speed stirring, solution extracts; Thick product carries out recrystallization twice in ethanol; Dry under vacuum, obtain amidized polyoxyethylene glycol (2000Da) and change 1,2-stearoyl-SN-glyceride material;
(iii) under nitrogen protection, the folic acid targeted molecular of 0.4mmol is dissolved among the anhydrous DMSO, under room temperature and magnetic agitation, slowly be added dropwise to the EDCHCL of 1.0mmol and the NHS of 1.0mmol and stir 2h, obtain the folic acid targeted molecular solution of activated carboxylic;
(iv) at room temperature, the amination polyoxyethylene glycol (2000Da) of 0.1mmol is changed 1,2-stearoyl-SN-glyceride material is dissolved among the anhydrous DMSO; Be added drop-wise in the folic acid targeted molecular solution of activated carboxylic reaction 48h, filtering reaction product slowly; The water dialysis; Carry out recrystallization, the polyoxyethylene glycol (2000Da) that obtains containing the folic acid targeted molecular changes 1,2-stearoyl-SN-glyceride material.
Preparation folic acid targeted molecular polyoxyethylene glycol (2000Da) is changed the cholesterol ester material
(1) 2mmol potassium is shredded under the 50ml sherwood oil be transferred in the two-mouth bottle, remove sherwood oil, under room temperature and the nitrogen protection, the 1.5mmol naphthalene is added dissolving in the anhydrous THF of 50ml (THF), magnetic agitation reaction 24h produces potassium naphthalene solution;
(2),, mix with potassium naphthalene solution with the dissolving of 1mmol initiator SUV with the anhydrous THF solution of 40ml; 6h under room temperature and the magnetic agitation; Under the ice-water bath condition, add the oxirane monomers 45.0mmol of-20 ℃ of preservations, 24h is with 6.0mmol absolute ethyl alcohol termination reaction in the magnetic agitation reaction; Filtering solution obtains polyoxyethylene glycol (2000Da) and changes SUV lipid solution;
(3) polyoxyethylene glycol (2000Da) being changed SUV lipid solution use salt acid for adjusting pH value is 4; The ratio of its solution and ether is precipitated three time at 1: 50; Cross 200～300 purpose silicagel columns; Dialysed two days, and used ethyl alcohol recrystallization, obtain the terminal polyoxyethylene glycol of hydroxyl (2000Da) the change cholesterol ester material that is; Adopt GPC to identify the terminal polyoxyethylene glycol of hydroxyl (2000Da) the change SUV chain distribution curve that is, its MWD is narrower, and is shown in Figure 4; Adopt nuclear-magnetism to identify terminal the be structure of the polyoxyethylene glycol of hydroxyl (2000Da) change SUV and the nuclear-magnetism figure of polyoxyethylene glycol chain length wherein, (400MHz, CDCL3) d/ppm: δ 0.67ppm is unimodal to 1H NMR, is the hydrogen on 18 in the SUV; The multiplet of δ 3.18ppm is the hydrogen on 3 of SUV; δ 3.46-3.82ppm is the hydrogen on the polyoxyethylene glycol; δ 5.15ppm is unimodal, is the hydrogen on 6 in the SUV, and calculates according to integral area, obtains polyoxyethylene glycol chain portion molecular weight and is about 2000Da.As shown in Figure 5; Adopting the infrared identification end is the structure of polyoxyethylene glycol (2000Da) the change SUV of hydroxyl, on ir spectra, has both had the characteristic absorbance of SUV unsaturated double-bond: 1630cm in the product
-1(C=C), 3100 and 2800cm
-1(saturated vibration of C-H and the unsaturated vibration of C-H); Also has simultaneously the segmental characteristic absorbance of PEG: 1114cm
-1(C-O-C), 3000-2800cm
-1(C-H) and 3434cm
-1(O-H); This explains that resultant product is to cause the PEG oligopolymer that epoxyethane ring-expansion polymerization forms by SUV really, and is as shown in Figure 6;
(4) be that the polyoxyethylene glycol (2000Da) of hydroxyl is changed SUV coupling folic acid targeted molecular with end, after being about to polyoxyethylene glycol (2000Da) and changing the terminal hydroxyl aminoization of SUV lipid, folic acid targeted molecular in the coupling again, its operation steps is following:
(i) be that the polyoxyethylene glycol (2000Da) of hydroxyl is changed the cholesterol ester material and is dissolved in the anhydrous methylene dichloride with the end of 0.5mmol; Under protection of nitrogen gas and ice-water bath; Stir and slowly drip the triethylamine of 2.5mmol and the Methanesulfonyl chloride of 2.5mmol down, stir 8h, the filtering reaction product; Product carries out recrystallization in ethanol, obtain sulfonyloxy methyl polyethylene glycol (2000Da) and change the cholesterol ester material;
(ii) dissolve in other the ammoniacal liquor sulfonyloxy methyl polyethylene glycol (2000Da) the change cholesterol ester material adding 50ml25% of 0.2mmol; Reaction is 3 days under room temperature and high-speed stirring; Solution extracts, and thick product carries out recrystallization twice in ethanol, and the product that purifying is crossed is collected; Dry under vacuum, obtain amidized polyoxyethylene glycol (2000Da) and change the cholesterol ester material;
(iii) under nitrogen protection, the folic acid targeted molecular of 0.2mmol is dissolved among the anhydrous DMSO, under room temperature and magnetic agitation, slowly be added dropwise to the EDCHCL of 0.5mmol and the NHS magnetic agitation 1h of 0.5mmol, obtain the folic acid targeted molecular solution of activated carboxylic;
(iv) at room temperature; Amination polyoxyethylene glycol (2000Da) the cholesterol ester material of 0.1mmol is dissolved among the anhydrous DMSO, is added drop-wise in the folic acid targeted molecular solution of activated carboxylic reaction times 24h slowly; The filtering reaction product; Recrystallization is carried out in the water dialysis, and the polyoxyethylene glycol (2000Da) that obtains containing the folic acid targeted molecular is changed the SUV material.
Embodiment 8-12 only changes the folic acid targeted molecular into the vitamin H targeted molecular, or contains the magnetic ball targeted molecular of carboxyl under used processing condition and processing parameter same case, also can prepare corresponding matrix material.
Claims (9)
1. the compound method of a targeting poly terepthaloyl moietie lipid medicinal materials; It is characterized in that adopting anionic polymerization, as initiator, directly bring out the oxirane monomers polymerization with the lipid that has hydroxyl; Ratio through control oxirane monomers and initiator; And behind acidifying and purifying, further through chemical process coupling targeted molecular, promptly obtain having the Pegylation lipid medicinal materials of target sexual function again; Comprise following process step:
(1) basic metal with 1～3 mole of deal shreds into bottle, and at room temperature, the protection of nitrogen or inert gas down, with naphthalene stirring reaction 4～48h in anhydrous tetrahydro furan (THF) of 1～3 mole of deal, generation basic metal naphthalene solution;
(2) lipid that contains hydroxyl that in basic metal naphthalene solution, adds 1 mole of deal is as initiator; Under nitrogen or inert gas protection, after reacting 1～12h under the room temperature, under the ice-water bath condition; The oxirane monomers that adds 4.5～900 moles of deals again; Behind stirring reaction 12～48h, the absolute alcohol termination reaction with 3～10 moles of deals obtains the Pegylation lipid soln;
(3) with the Pegylation lipid soln in the step (2) behind acidifying and purifying, the end that promptly obtains the polyoxyethylene glycol chain length and be 200～20000Da is the Pegylation matrix material of hydroxyl;
(4) be that the Pegylation matrix material of hydroxyl adopts targeted molecular in three kinds of coupling method couplings with the end in the step (3); Be about to Pegylation lipid terminal hydroxyl and the coupling of targeted molecular esterification; Or the hydroxyl that the Pegylation lipid is terminal carboxylated after targeted molecular in the coupling again, or targeted molecular in the coupling again after the hydroxyl aminoization that the Pegylation lipid is terminal; After purified again, promptly obtain targeting poly terepthaloyl moietie lipid medicinal materials.
2. the compound method of targeting poly terepthaloyl moietie lipid medicinal materials according to claim 1 is characterized in that said basic metal is sodium or potassium.
3. the compound method of targeting poly terepthaloyl moietie lipid medicinal materials according to claim 1 and 2 is characterized in that said absolute alcohol is a methyl alcohol, or ethanol, or glycerine, or propyl carbinol, or one or more mixing in the Virahol are used; Said acidifying acid comprises organic acid and mineral acid; Wherein, organic acid is a formic acid, or acetate, or Citric Acid; Mineral acid is a hydrochloric acid, or sulfuric acid, or phosphoric acid, or one or more mixing in the boric acid are used.
4. the compound method of targeting poly terepthaloyl moietie lipid medicinal materials according to claim 1 and 2; It is characterized in that the described lipid initiator that contains hydroxyl is the phospholipids compounds that contains hydroxyl; Or phytosterin compound, or 1,2-stearoyl-SN-glycerine.
5. the compound method of targeting poly terepthaloyl moietie lipid medicinal materials according to claim 4 is characterized in that
The described phospholipids compounds that contains hydroxyl is Val or distearyl POPG or DOPG or two palmityl POPGs or two lauryl POPGs or two caprinoyl POPGs.
6. the compound method of targeting poly terepthaloyl moietie lipid medicinal materials according to claim 4 is characterized in that described phytosterin compound is SUV or vitamin D2 or Vitamin D3 500,000 I.U/GM or 7-dehydrocholesterol or ergosterol.
7. the compound method of targeting poly terepthaloyl moietie matrix material according to claim 1; It is characterized in that with end be targeted molecular in the Pegylation lipid coupling of hydroxyl; Its method one is about to Pegylation lipid terminal hydroxyl and the coupling of targeted molecular esterification, comprises following process step:
(ⅰ) the targeted molecular leaf of 0.1～0.4 mole of deal acid ﹑ or the magnetic ball of giving birth to the plain ﹑ of thing or containing carboxyl are dissolved in the anhydrous dimethyl sulphoxide (DMSO); Under the protection and magnetic agitation of nitrogen or rare gas element; Slowly be added dropwise to 0.2～1.0 mole of deal N-hydroxy-succinamide (NHS) and 0.2～1.0 mole of deal 1; 3-NSC 57182 (DCC) stirs 0.5～2h, obtains the targeted molecular solution of activated carboxylic;
(ⅱ) 0.1 mole of deal end is dissolved among the DMSO for the Pegylation matrix material of hydroxyl; And be added dropwise to lentamente in the targeted molecular solution of activated carboxylic, esterification 12～48h is purified under the room temperature; Vacuum-drying must contain the Pegylation lipid medicinal materials of targeted molecular.
8. the compound method of targeting poly terepthaloyl moietie lipid medicinal materials according to claim 1; It is characterized in that with end be targeted molecular in the Pegylation lipid coupling of hydroxyl; Its method two be about to the terminal hydroxyl of Pegylation lipid carboxylated after; Targeted molecular in the coupling again comprises following process step:
(ⅰ) 0.5 mole of deal end is dissolved in the anhydrous organic solvent for the Pegylation matrix material of hydroxyl; Under nitrogen or protection of inert gas and ice-water bath; Under the magnetic agitation, add the 4-Dimethylamino pyridine (DMAP) of 0.5～2.5 mole of deal, reaction 0.5～2h; Slowly add the triethylamine of 0.5～2.5 mole of deal and the Succinic anhydried of 0.5～2.5 mole of deal, reaction 2～24h, purified, vacuum-drying must contain the Pegylation matrix material of carboxyl;
The Pegylation lipid that (ⅱ) 0.1 mole of deal is contained carboxyl is dissolved among the anhydrous DMSO; Under the protection and magnetic agitation of nitrogen or rare gas element; Slowly be added dropwise to 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) of 0.1～0.5 mole of deal and the N-hydroxy-succinamide (NHS) of 0.1～0.5 mole of deal and stir 0.5～2h, obtain the Pegylation lipid soln of activated carboxylic;
(ⅲ) with the targeted molecular of 0.1～0.4 mole of deal half newborn sugared ﹑ or RGD or contain amino magnetic ball and be dissolved among the anhydrous DMSO; Slowly be added dropwise in the Pegylation lipid soln of activated carboxylic; Room temperature reaction 12～48h; Purifying, vacuum-drying obtains containing the Pegylation lipid medicinal materials of targeted molecular.
9. the compound method of targeting poly terepthaloyl moietie lipid medicinal materials according to claim 1; It is characterized in that with end be targeted molecular in the Pegylation lipid coupling of hydroxyl; After its method three is about to the terminal hydroxyl aminoization of Pegylation lipid; Targeted molecular in the coupling again comprises following process step:
Be that the Pegylation matrix material of hydroxyl is dissolved in the anhydrous organic solvent (ⅰ) with the end of 0.5 mole of deal; Under the protection and ice-water bath of nitrogen or rare gas element; The triethylamine of 1.0～5.0 moles of deals of agitation and dropping and the Methanesulfonyl chloride of 1.0～5.0 moles of deals; Again at ambient temperature, stirring reaction 4～12h; Purified, vacuum-drying obtains sulfonyloxy methyl polyethylene glycol matrix material;
(ⅱ) the sulfonyloxy methyl polyethylene glycol lipid with 0.2 mole of deal adds 1.0～100.0ml, dissolves in 25% the ammoniacal liquor, and at room temperature stirring reaction is 2～4 days, and is purified, and vacuum-drying obtains amidized Pegylation matrix material;
(ⅲ) under nitrogen or protection of inert gas; The targeted molecular leaf of 0.1～0.4 mole of deal acid ﹑ or the magnetic ball of giving birth to the plain ﹑ of thing or containing carboxyl are dissolved among the anhydrous DMSO; Slowly be added dropwise to the EDCHCl of 0.2～1.0 mole of deal and the NHS of 0.2～1.0 mole of deal under the magnetic agitation; Stir 0.5～2h, obtain the targeted molecular solution of activated carboxylic;
(ⅳ) the amination Pegylation lipid with 0.1 mole of deal in (ⅱ) step is dissolved among the anhydrous DMSO, is added dropwise to lentamente in (ⅲ) the activated carboxylic targeted molecular solution in step, carries out acid amides reaction 12～48h under the room temperature; Purified again, vacuum-drying obtains containing the Pegylation lipid medicinal materials of targeted molecular.
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| WO2013014073A1 (en) * | 2011-07-22 | 2013-01-31 | Universite De Strasbourg | Phospholipid-detergent conjugates and uses thereof |
| CN103263388B (en) * | 2012-12-18 | 2016-03-23 | 苏州大学 | Stealthy vesicle of a kind of modified with folic acid norcantharidin and preparation method thereof |
| CN103965463B (en) * | 2014-04-28 | 2016-09-21 | 苏州岸谷纳米材料科技有限公司 | A kind of preparation method of mPEG2000-DSPE |
| CN104892918B (en) * | 2015-05-29 | 2017-08-25 | 吕常海 | Phosphatidyl-ethanolamine hydroxyl polyethyleneglycol derivative and preparation method, liposome contrast agent and treatment oncolipid body diagnosis and treatment medicine |
| CN107337787A (en) * | 2017-08-11 | 2017-11-10 | 湖南华腾制药有限公司 | A kind of preparation method of Amino End Group polyethylene glycol hydroxyl |
| CN109364026A (en) * | 2018-11-26 | 2019-02-22 | 四川大学 | The preparation and application of the breast cancer targeting lipids material of biotin modification |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1543931A (en) * | 2003-11-27 | 2004-11-10 | 西安力邦医药科技有限责任公司 | Method for preparing brain targeting liposome pharmaceutical |
| CN1962683A (en) * | 2006-12-18 | 2007-05-16 | 张文芳 | Polyethylene glycol modified sterol copolymer and its uses |
| CN1986600A (en) * | 2006-07-07 | 2007-06-27 | 张文芳 | PEG modified cholesterol copolymer and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543931A (en) * | 2003-11-27 | 2004-11-10 | 西安力邦医药科技有限责任公司 | Method for preparing brain targeting liposome pharmaceutical |
| CN1986600A (en) * | 2006-07-07 | 2007-06-27 | 张文芳 | PEG modified cholesterol copolymer and its application |
| CN1962683A (en) * | 2006-12-18 | 2007-05-16 | 张文芳 | Polyethylene glycol modified sterol copolymer and its uses |
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