CN101684177A - Folate-conjugated polyethylene glycol polyalkylcyanoacrylate, preparation method and application thereof - Google Patents
Folate-conjugated polyethylene glycol polyalkylcyanoacrylate, preparation method and application thereof Download PDFInfo
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- CN101684177A CN101684177A CN200910011746A CN200910011746A CN101684177A CN 101684177 A CN101684177 A CN 101684177A CN 200910011746 A CN200910011746 A CN 200910011746A CN 200910011746 A CN200910011746 A CN 200910011746A CN 101684177 A CN101684177 A CN 101684177A
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Abstract
The invention discloses synthesis and application of a type of folate (FA)-conjugated polyethylene glycol polycyanoacrylate (PEG - PHDCA) (FA-PEG-PHDCA for short). The type of polymer is an amphiphilic block copolymer obtained through the Michael addition reaction of folate-polyethylene glycolcyano acetate and alkyl cyanoacetate in the presence of formaldehyde and dimethylamine. The type of polymer can be self-assembled into nano-particles or micelles in water, wherein hydrophobic alkyl segments are aggregated to a core, while hydrophilic polyethylene glycol segments form a hydrophilic shell.Meanwhile, due to excellent surface activity of the polymer and the tumor targeting property of folate, the polymer can also be applied to the modification of solid lipid nano-particles, liposomes, submicroemulsion and other nano-particle preparations. The polymer can be used for intravascular administration, intramuscular injection and oral administration, and is applicable to water-soluble and water-insoluble medicaments. The preparation method has the advantages of mature process and suitability for large-scale continuous production.
Description
Technical field
The invention belongs to medical technical field, relate to the method for making and the application thereof of medicinal polymer folate-conjugated polyethylene glycol polyalkylcyanoacryla,e (FA-PEG-PHDCA), belong to segmented copolymer.
Background technology
Nanoparticle is the solid colloid particle, particle diameter is 1～1000nm, it has characteristics such as small-size effect, quantum size effect, surface effects and macro quanta tunnel effect, can be organized and the cell absorption, thereby make it may become good drug delivery system.There are shortcoming separately in widely used low molecule and macromolecular drug at present: (1) low-molecule drug is by oral or drug administration by injection, and drug level far surpasses the actual demand amount in the short period of time endosome, and lacks the selectivity that enters human body; Metabolism is fast, the transformation period short, the very fast reduction of bulk concentration and affecting the treatment, thus the heavy dose of administration of needs, and too high drug level can strengthen Side effects of pharmaceutical drugs; (2) biopharmaceutical macromolecular drug is in vivo easily by enzyme liberating or inactivation, and biological half-life is short, needs repeat administration; Also receive restriction as immunity system, tissue, cytolemma etc., most being difficult for by these biological barriers, thereby the bioavailability of macromolecular drug is lower.In recent years; drug-carrying nanometer particle is as novel medicament transmission and Controlled Release System; be subjected to the extensive concern of Chinese scholars; it can protect medicine to exempt from destruction; be woven with special affinity with some groups of cells again; can concentrate on the target area and progressively discharge medicine by the reticuloendothelial system of organ-tissue institute endocytosis (engulf, pinocytosis) or by cytogamy.The research of nanoparticle aspect pharmacy is used has very outstanding meaning.
The material of preparation nanoparticle is more, be broadly divided into polymkeric substance and matrix material, the nanoparticle that the former makes is called polymer nanoparticle (polymeric nanoparticles), the latter be called solid lipid nanoparticle (solid lipid nanoparticles, SLN).Because the SLN encapsulation rate of water soluble drug is low, and biopharmaceutical macromolecular drug SLN faces the deactivation of gastroenteric environment factor, makes the application of SLN be restricted, and degradable biological section bar material to be the polymer nanoparticle of carrier receive increasing concern.
In the past few years, developing into the Biodegradable polymeric nanoparticle efficiently, drug delivery system has caused people's extensive interest, wherein with PLGA, PLA, the PCL polymkeric substance is the most commonly used, the drug-carrying nanometer particle of its preparation has not only kept pharmaceutical activity, improve medicine stability, reduce toxicity, also embodied significant slow release effect, but in fact, the intravascular injection nanoparticle generally is difficult to active role in target position, still can from blood vessel, remove rapidly and by reticuloendothelial system (RES) picked-up, for the RES diseases associated be favourable, but numerous diseases is not in this system.Therefore how research reduces the problem that RES takes in the concern that is the investigator.Research tendency is that nanoparticulate carriers is modified recently, and polyoxyethylene glycol (PEG) has many advantages and obtains FDA to be ratified to can be used in the human body.In view of this, in recent years, have in a large number to show about the research report that PEG is introduced nanoparticulate carriers as hydrophilic component, the nanoparticle that wetting ability PEG modifies, when being used for intravenously administrable, blood is removed and the RES picked-up significantly reduces.And PEG introduces the biological degradation behavior that can influence nanoparticle, regulates the release mode.Analyze from the pharmaceutical activity angle, thisly form microenvironment by PEG, also will help medicine store and the administration process in its activity of maintenance.
The polymkeric substance that PEG modifies is its synthesizing water-solubility segmented copolymer or graft copolymer that target is arranged, make it possess hydrophilic property group and hydrophobic group simultaneously, dissolving back spontaneous formation macromolecule micelle (polymeric micelles) in water, finish solubilising and parcel to medicine, because possess hydrophilic property shell and hydrophobic cores, be suitable for carrying medicine of different nature, make itself and surrounding medium isolated in order to avoid too fast degraded, and release of active agent when needed, and its hydrophilic shell also possesses the characteristics of " stealth ".In addition, polymer nanoparticle has good storage stability and biocompatibility.In recent years, biodegradable polymkeric substance is made nanoparticle, but the nanoparticle controlled release drug of this polymkeric substance is avoided drug degradation or leakage, improve medicine stability and curative effect, reduce untoward reaction.Medicine wraps into and can reduce toxic reason in the nanoparticle 2 points are arranged: (1) medicine is positioned at the nanoparticle kernel, reduce medicine and contact with the direct of cell, and hydrophilic PEG shell can reduce to reach between nanoparticle and the cell between the nanoparticle and acts on.(2) medicine lasting characteristic that discharges from the copolymer nano particle that PEG modifies helps the survival of cell.Peracchia etc. find that PHDCA toxicity after PEG modifies reduces.Cultivate through nanoparticle, the 50% huge monocyte survival of biting, and the PHDCA nanoparticle of not modifying through PEG is cultivated, and has only the 20% huge monocyte survival of biting.This explanation more helps reducing cytotoxicity through the copolymer nano particle that PEG modifies.
Lot of documents shows that folacin receptor (FR) is a kind ofly glycoprotein on film by glycan-phosphatidylinositol (GPI) anchor, to folic acid (folic acid, FA) has high affinity, it is less to distribute in healthy tissues, and in the malignant tumour in the ovarian cancer more than 90% and many epithelial cells and myelocyte source overexpression is arranged.FR has high affinity equally to folacin coupled medicine, and this lays a good foundation in the research of tumour cell for FR mediation drug targeting.The cyanoacrylate polymkeric substance is the bioadhesive polymer of domestic and international widespread use, such carrier has characteristics such as excellent biological compatibility, biodegradable, and the major advantage of such carrier nanoparticle has slowly-releasing, reduces drug toxicity, prevents drug degradation, increases medicine to biomembranous permeability, prolong drug transformation period etc.PEG-PHDCA originally as a long circulation auxiliary material, can obtain the polymkeric substance of different outside surface FA fraction of coverage by the ratio of adjusting FA, has long circulation passive targeting and make final product promptly have the active target.
Summary of the invention
The object of the present invention is to provide the synthetic and application of class folic acid (FA) link coupled polyethylene glycol polyalkylcyanoacryla,e (PEG-PHDCA) (being called for short FA-PEG-PHDCA).This base polymer can be self-assembled into nanoparticle or micella in water, wherein hydrophobic alkyl section is assembled nucleation, and hydrophilic polyoxyethylene glycol section forms hydrophilic shell; Simultaneously, this polymkeric substance is because the tumor-targeting of its good surfactivity and folic acid can also be applied to modify Nanoparticulate formulations such as solid lipid nanoparticle, liposome, submicron emulsion.
FA-PEG-PHDCA multipolymer of the present invention has structure shown in the formula (1), and its molecular weight is 1.0 * 10
3-1.0 * 10
6PEG content is 1-98%) Q and K are O or N atom in the formula, x, m, n is positive integer.The x scope is 1-1000, and the m scope is 1-1000000000, and the n scope is 1-1000000000.
The used PEG of preparation FA-PEG-PHDCA multipolymer has structure shown in formula (II), (III), (IV):
(its molecular weight is 1.0 * 10
2-1.0 * 10
6) n is positive integer in the formula.
With above-mentioned PEG, hexadecanol, cyanoacetic acid, folic acid is synthetic materials, and folic acid-polyoxyethylene glycol cyan-acetic ester and hexadecyl cyan-acetic ester are formed with the cyanoacetic acid dehydrating condensation respectively by above-mentioned PEG and hexadecanol.With polyoxyethylene glycol cyan-acetic ester and the hexadecyl cyan-acetic ester (mol ratio 1: 1-1: 100) in the presence of formaldehyde and dimethylamine that obtains, after the Michael addition reaction, the crude product that obtains extracts repeatedly with methylene dichloride, organic phase is with anhydrous magnesium sulfate or anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated into thick, and the room temperature decompression is placed and solidified, and obtains faint yellow folic acid-pure product of polyethylene glycol-alkyl cyanoacrylate (FA-PEG-PHDCA).
FA-PEG-PHDCA is dissolved in the organic solvent (one of chloroform, methylene dichloride, acetone, tetrahydrofuran (THF) or arbitrary composition) of certain volume; under agitation be added dropwise to and contain 0.01-50% emulsifying agent (phospholipid, the smooth class of lipid acid sorb, poly yamanashi esters, poloxalkol class, polyoxyethylene fatty acid ester class, polyoxyethylene aliphatic alcohol ether class and arbitrary combination thereof); stir volatilization and remove organic solvent, obtain nanoparticle or micella water dispersion.Particle diameter 5-1000nm.
Polymkeric substance of the present invention can be used for intravascular administration, administered intramuscular and oral administration, is applicable to that water-soluble and water-insoluble medicine can be applied to modify simultaneously Nanoparticulate formulations such as solid lipid nanoparticle, liposome, submicron emulsion.
The present invention is folacin coupled novel amphiphilic auxiliary material---folate-conjugated polyethylene glycol polyalkylcyanoacryla,e (FA-PEG-PHDCA).This polymkeric substance has the hydrophobic end, thereby can be easy to combine with hydrophobic particles such as lipid nanoparticle or structured lipid carriers, and it has water-wet side simultaneously, this make be connected on it the target group---folic acid can be exposed on the outermost layer of nanoparticle, the targeting that performance is maximum; FA-PEG-PHDCA is a more satisfactory solid support material, and its principal feature is that the polymerization degree is controlled, and toxicity is littler, and degradation speed is slow; Because the long circulation characteristics that PEG chain possess hydrophilic property, flexible characteristics have been given copolymer nano particle; Because the tumour taxis of FA group makes polymkeric substance have tumor-targeting, thereby changed by pharmacokinetics behavior in the body of bag medicine carrying thing.This polymkeric substance can be used for intravascular administration, administered intramuscular and oral administration, is applicable to water-soluble and water-insoluble medicine.Preparation method's technical maturity of the present invention is suitable for large scale continuous prod.
Description of drawings
Fig. 1 folic acid-polyoxyethylene glycol gathers alkyl cyano group acryllic acid ester infrared spectra
Fig. 2 folic acid-polyoxyethylene glycol gathers alkyl cyano group acryllic acid ester nucleus magnetic resonance
1The H spectrum
Fig. 3 folic acid-polyoxyethylene glycol gathers alkyl cyano group acryllic acid ester nucleus magnetic resonance
13The C spectrum
The nanoparticle particle diameter for preparing with the poly-alkyl cyano group acryllic acid ester of folic acid-polyoxyethylene glycol among Fig. 4 embodiment 1
The nanoparticle particle diameter for preparing with the poly-alkyl cyano group acryllic acid ester of folic acid-polyoxyethylene glycol among Fig. 5 embodiment 2
Embodiment
Below again with embodiment to the present invention's further instruction in addition.
Embodiment 1:
Synthesizing of folic acid-polyoxyethylene glycol cyanoacetate: monoamine polyoxyethylene glycol 5000 6mmol and cyanoacetic acid 12mmol put in the 250ml three-necked bottle, add methylene dichloride 50ml, ultrasonic dissolution.Stir and add condensing agent DCC 12mmol and a small amount of DMAP down, stirring at room 12h under the feeding condition of nitrogen gas.Add normal hexane 30ml, filter, filter cake is with washed with dichloromethane (15ml * 3), merging filtrate and washing lotion, be evaporated to thick, solidify under the room temperature faint yellow waxy solid, add folic acid 6mmol, add methylene dichloride 50ml.Stir and add condensing agent DCC 12mmol and a small amount of DMAP down, stirring at room 12h under the feeding condition of nitrogen gas.Add normal hexane 30ml, filter, filter cake is with washed with dichloromethane (15ml * 3), merging filtrate and washing lotion, be evaporated to thick, solidify under the room temperature faint yellow waxy solid.
Hexadecyl cyanoacetate synthetic: feed intake with hexadecanol 5.5mmol and cyanoacetic acid 11mmol, operate the samely, obtain Off-white solid.
Synthesizing of FA-PEG-PHDCA polymkeric substance: precision takes by weighing hexadecyl cyanoacetate 6mmol, adds folic acid-polyoxyethylene glycol cyanoacetate 2mmol, adds ethanol-methylene dichloride (1: 1) mixing solutions 60ml, ultrasonic dissolution.Add 37% formaldehyde solution 20mmol and 33% dimethylamine solution 20mmol, room temperature reaction 12h under the nitrogen protection.Concentrating under reduced pressure, in the residuum impouring water, with dichloromethane extraction (15ml * 3), organic phase is filtered with anhydrous sulphur sodium drying, and filtrate decompression is concentrated into thick, and the room temperature decompression is placed down and is solidified, and gets faint yellow waxy solid polymkeric substance.
The preparation of nanoparticle: FA-PEG-PHDCA 200mg is dissolved in the 2ml methylene dichloride, under agitation is added dropwise in the water that contains 1%poloxamer188, stir volatilization and remove organic solvent, obtain the nanoparticle water dispersion.Particle diameter 129nm.
Embodiment 2:
Synthesizing of folic acid-polyoxyethylene glycol cyanoacetate: Macrogol 2000 6mmol and cyanoacetic acid 12mmol put in the 250ml three-necked bottle, add methylene dichloride 50ml, ultrasonic dissolution.Stir and add condensing agent DCC 12mmol and a small amount of DMAP down, stirring at room 12h under the feeding condition of nitrogen gas.Add normal hexane 30ml, filter, filter cake is with washed with dichloromethane (15ml * 3), merging filtrate and washing lotion, be evaporated to thick, solidify under the room temperature faint yellow waxy solid, add folic acid 6mmol, add methylene dichloride 50ml.Stir and add condensing agent DCC 12mmol and a small amount of DMAP down, stirring at room 12h under the feeding condition of nitrogen gas.Add normal hexane 30ml, filter, filter cake is with washed with dichloromethane (15ml * 3), merging filtrate and washing lotion, be evaporated to thick, solidify under the room temperature faint yellow waxy solid.
Hexadecyl cyanoacetate synthetic: feed intake with hexadecanol 5.5mmol and cyanoacetic acid 11mmol, operate the samely, obtain Off-white solid.
Synthesizing of FA-PEG-PHDCA polymkeric substance: precision takes by weighing hexadecyl cyanoacetate 3mmol, adds folic acid-polyoxyethylene glycol cyanoacetate 3mmol, adds ethanol-methylene dichloride (1: 1) mixing solutions 60ml, ultrasonic dissolution.Add 37% formaldehyde solution 20mmol and 33% dimethylamine solution 20mmol, room temperature reaction 12h under the nitrogen protection.Concentrating under reduced pressure, in the residuum impouring water, with dichloromethane extraction (15ml * 3), organic phase is filtered with anhydrous sulphur sodium drying, and filtrate decompression is concentrated into thick, and the room temperature decompression is placed down and is solidified, and gets faint yellow waxy solid polymkeric substance.
Modify solid lipid nanoparticle: glyceryl monostearate 300mg, FA-PEG-PHDCA 60mg are dissolved in the 2mL ethanol, and low-grade fever forms organic phase.Soybean phospholipid 50mg and tween-8010mg that other gets recipe quantity are dissolved in about 8mL water, constitute water.At high-speed stirring (1000r.min
-1) under organic phase is injected aqueous phase with syringe needle, whole process keeps 75 ± 2 ℃ of temperature, concentrates volume to original about 1/2.The translucent system of gained is mixed fast in another 0-2 ℃ 10mL aqueous phase, continue to stir 2 hours, 0.8 μ m filtering with microporous membrane promptly gets the solid lipid nanoparticle that FA-PEG-PHDCA modifies.Particle diameter 126nm.
Claims (8)
1, a kind of folate-conjugated polyethylene glycol polyalkylcyanoacryla,e is characterized in that: this base polymer has the structure shown in the formula (I):
Its molecular weight is 1.0 * 10
3-1.0 * 10
6PEG content is 1-98%, and Q and K are O or N atom in the formula, x, and m, n is positive integer, and the x scope is 1-1000, and the m scope is 1-1000000000, and the n scope is 1-1000000000.
2, folate-conjugated polyethylene glycol polyalkylcyanoacryla,e according to claim 1 is characterized in that: described polyoxyethylene glycol has structure shown in formula (II), (III), (IV):
Its molecular weight is 1.0 * 10
2-1.0 * 10
6, n is positive integer in the formula.
3, a kind of method for preparing the described folate-conjugated polyethylene glycol polyalkylcyanoacryla,e of claim 1 is characterized in that: with PEG, hexadecanol, cyanoacetic acid, folic acid is synthetic materials, by the following method preparation:
(1) folic acid-polyoxyethylene glycol cyan-acetic ester and hexadecyl cyan-acetic ester are formed with the cyanoacetic acid dehydrating condensation respectively by PEG and hexadecanol;
(2) be 1 with the mol ratio that obtains: 1-1: 100 polyoxyethylene glycol cyan-acetic ester and hexadecyl cyan-acetic ester are in the presence of formaldehyde and dimethylamine, by the Michael addition reaction;
(3) crude product that step (2) is obtained extracts repeatedly with methylene dichloride, organic phase is filtered with anhydrous magnesium sulfate or anhydrous sodium sulfate drying, and filtrate decompression is concentrated into thick, the room temperature decompression is placed and is solidified, and obtains faint yellow folic acid-pure product of polyethylene glycol-alkyl cyanoacrylate.
4, method according to claim 3 is characterized in that: described formaldehyde and dimethylamine are coupling agent.
5, folate-conjugated polyethylene glycol polyalkylcyanoacryla,e according to claim 1 is characterized in that: this polymkeric substance can self-assembly form nanoparticle or micella in water; Folate-conjugated polyethylene glycol polyalkylcyanoacryla,e is dissolved in the organic solvent of certain volume, under agitation is added dropwise to and contains the 0.01-50% emulsifying agent, stir volatilization and remove organic solvent, obtain nanoparticle or micella water dispersion, particle diameter 5-1000nm.
6, folate-conjugated polyethylene glycol polyalkylcyanoacryla,e according to claim 5 is characterized in that: described organic solvent is a kind of or arbitrary composition in chloroform, methylene dichloride, acetone, the tetrahydrofuran (THF); Described emulsifying agent is phospholipid, the smooth class of lipid acid sorb, poly yamanashi esters, poloxalkol class, polyoxyethylene fatty acid ester class, polyoxyethylene aliphatic alcohol ether class and arbitrary combination thereof.
7, sour conjugated polyethylene glycol polyalkylcyanoacryla,e according to claim 1, it is characterized in that: this polymkeric substance can be used for intravascular administration, administered intramuscular and oral administration, is applicable to water-soluble and water-insoluble medicine.
8, sour conjugated polyethylene glycol polyalkylcyanoacryla,e according to claim 1, it is characterized in that: this polymkeric substance is used to modify Nanoparticulate formulations such as solid lipid nanoparticle, liposome, submicron emulsion.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013084208A2 (en) | 2011-12-07 | 2013-06-13 | Universidade Do Minho | Liposomes and method for producing the same |
| CN107595805A (en) * | 2017-08-09 | 2018-01-19 | 杭州市萧山区第人民医院 | PEG6000-PHDCA loads the preparation method of adriamycin nano-particles |
| CN104394891B (en) * | 2012-03-16 | 2019-04-16 | 约翰霍普金斯大学 | For delivering non-linear segmented copolymer-drug conjugates of activating agent |
-
2009
- 2009-05-27 CN CN200910011746A patent/CN101684177A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013084208A2 (en) | 2011-12-07 | 2013-06-13 | Universidade Do Minho | Liposomes and method for producing the same |
| CN104394891B (en) * | 2012-03-16 | 2019-04-16 | 约翰霍普金斯大学 | For delivering non-linear segmented copolymer-drug conjugates of activating agent |
| CN107595805A (en) * | 2017-08-09 | 2018-01-19 | 杭州市萧山区第人民医院 | PEG6000-PHDCA loads the preparation method of adriamycin nano-particles |
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Application publication date: 20100331 |