EP2044141A1 - Procédé de fabrication de dérivés de polyglycérol linéaires et méthylés et leur utilisation pour la fonctionnalisation de surfaces - Google Patents

Procédé de fabrication de dérivés de polyglycérol linéaires et méthylés et leur utilisation pour la fonctionnalisation de surfaces

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Publication number
EP2044141A1
EP2044141A1 EP07729876A EP07729876A EP2044141A1 EP 2044141 A1 EP2044141 A1 EP 2044141A1 EP 07729876 A EP07729876 A EP 07729876A EP 07729876 A EP07729876 A EP 07729876A EP 2044141 A1 EP2044141 A1 EP 2044141A1
Authority
EP
European Patent Office
Prior art keywords
polyglycerols
linear
methylated
polymerization
protein
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07729876A
Other languages
German (de)
English (en)
Inventor
Monika Wyszogrodzka
Rainer Haag
Heidemarie Weinhart
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Freie Universitaet Berlin
Original Assignee
Freie Universitaet Berlin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Freie Universitaet Berlin filed Critical Freie Universitaet Berlin
Publication of EP2044141A1 publication Critical patent/EP2044141A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds

Definitions

  • the invention relates to a process for the preparation of defined linear, methylated polyglycerol derivatives on Giycidylmethyletherbasis having a degree of polymerization of 1 to 1000 with narrow molecular weight distributions determined by GPC (Gel Permeation Chromatography) and polydispersities less than 2, preferably less than 1.1 (PS standard), by ring-opening anionic polymerization of the glycidyl methyl ether in the presence of a hydrogen-active starter compound under basic catalysis.
  • the invention relates to polymers of the general forms! 1.
  • the invention also relates to the use of these linear, methylated Polyglcerolderivate for the functionalization of any surfaces.
  • surfaces that have a coating with the new polyglycerol derivatives have excellent protein-resistant properties.
  • Protei nresistente Oberfi Stahlenbe Anlagenungen play z. B. in medical technology a large Roile.
  • medical implants are made of different materials, which are selected according to the specific biochemical and mechanical properties. These include z. As surgical or orthopedic screws, plates, joint prostheses, artificial heart valves, vascular prostheses, stents or implantable drug depots. The materials must be suitable for permanent use in the body, but they have z. T. significant disadvantages in terms of their biocompatibility. Also in the field of medical devices or biosensors protein-repellent materials are indispensable to suppress biofilm formation by non-specific adsorption of biological species such as bacteria, cells or even viruses at solid-liquid interfaces. In addition, z. B.
  • PEG polyethylene glycol derivatives
  • DE 103 11 163 A1 discloses protein-repellent compounds based on hyperbranched and dendritic polymer films for surface modification.
  • These polymers are glycerol-derived ethers and / or ether alcohols which have at least one thioctic acid group for immobilization.
  • the large number of free OH groups in the hyperbranched and dendritic polyglycerols represents a potential that allows the compounds to mimic sugars and glycoproteins, thus leading to long-term biocompatibility problems.
  • the authors also found that fully methylated polyglycerol with a thioctic acid group could not confer protein repellency to immobilize a gold surface.
  • the invention therefore an object of the invention to find other materials for coating surfaces that show good protein resistance and on the other hand are easy and inexpensive to produce.
  • defined linear, methylated Pofyglycerole having a degree of polymerization of 1 to 1000 with narrow molecular weight distributions determined by GPC and polydispersities less than 2, preferably less than 1.1 (PS standard) have protein resistance and in comparison to the highly branched and dendritic polyglycerols DE 103 11 163 A1 even have improved protein-resistant properties.
  • these defined linear, linearized methylated polyglycerols are easy to prepare when poiymerized glycidyl methyl ether by means of ring-opening anionic polymerization in the presence of a starter compound under basic catalysis.
  • the epoxide ring is opened by base catalysis, preferably at the unsubstituted end, and the linear, methylated polymers are formed.
  • the invention therefore preferably linear, methylated polyglycerols of the general formula I.
  • X C 1 to C 20 -alkyl, aryl, OH, NH 2 or SH 1 where the groups OH, NH 2 or SH can also be provided with a protective group
  • An aryl radical is understood to mean a substituted or unsubstituted phenyl or naphthyl radical or a heterocyclo. The radicals may be substituted by OH, NH 2 , CH 3 and halogen.
  • Aryl is preferably a phenyl radical.
  • Heterocycles are 5- and 6-membered heterocycles containing heteroatoms of at least one other element, preferably nitrogen, oxygen or sulfur.
  • halogen is meant in particular F, Cl, Br and J.
  • Preferred compounds according to the invention are those polyglycerols of the general formula I in which X is NH 2 .
  • Y is OH.
  • m is preferably 1 to 10, more preferably 1 to 5.
  • the number n more preferably means 1 to 30, most preferably 5 to 20, especially preferably 10 to 20.
  • Anionic polymerization is known to the person skilled in the art.
  • the peculiarity of the anionic polymerization is that there is virtually no chain transfer and no termination reactions, so that the chain reaction can continue while there are still monomers, unless one adds substances to the chain termination. Since it is a so-called living polymerization, the molecular weight of a desired oligo- or polymers on the ratio of monomer to initiator can be very well adjusted.
  • Examples include: Methanol, ethanol, n-, sec-, tert-butanol,
  • Phenol, benzyl alcohol, diols such as. B. monoethylene glycol, 1,3-propylene glycol, 1, 4-ButyIendiol, hexamethylene glycol,
  • Aminoalkanols preferably Ami ⁇ opropanols, in particular 3-aminopropano! et al homologous
  • Preferred Schutz devis ⁇ for the OH, NH 2 or SH group are, for. B. Trimethyisilyl (TMS) ethers, benzyl groups and tert-Butoxycarbonyi (BOC) and 4-methoxybenzyl or triphenylmethyl.
  • TMS Trimethyisilyl
  • BOC tert-Butoxycarbonyi
  • the starter compounds II are first partially deprotonated by a strong base, preferably with an alkali metal, preferably potassium or a alkali metal hydroxide or alkoxide, preferably potassium hydroxide or tert-butoxide.
  • a strong base preferably with an alkali metal, preferably potassium or a alkali metal hydroxide or alkoxide, preferably potassium hydroxide or tert-butoxide.
  • the basic initiator system is dissolved or dispersed, preferably under inert gas (eg N 2 , Ar) 1 in an inert solvent such as diethylene glycol dimethyl ether (Diglyme®), dioxane or dimethoxyethane (DME).
  • inert gas eg N 2 , Ar
  • an inert solvent such as diethylene glycol dimethyl ether (Diglyme®), dioxane or dimethoxyethane (DME).
  • the compounds of the general formula I are prepared by bringing an alcohol derivative of the general formula II into contact with the strong base in diethylene glycol dimethyl ether, then adding the glycidyl methyl ether (the monomer) and polymerizing to the target compound I.
  • the monomer solution is preferably metered in under inert gas (eg N 2 , Ar) to the initiator mixture.
  • the reaction temperatures are usually 4O 0 C to 150 0 C, preferably 70 to 120 0 C. In general, the reaction is carried out under atmospheric pressure.
  • the workup of the polymer is preferably carried out by treatment with an acidic ion exchanger.
  • an acidic ion exchanger Preference is given to a sulfonated polystyrene resin in Methanoi used to terminate the polymerization, particularly preferably Lewatit K1131 (Bayer AG).
  • Methanoi used to terminate the polymerization, particularly preferably Lewatit K1131 (Bayer AG).
  • filtration of the ion exchanger and distilling off the solvent optionally further purification of the polymer follows and the polymer is z. B. freed of solvent residues in vacuo.
  • protecting groups for X are removed by final cleavage according to techniques known per se. So z. B. the removal of benzyl groups, preferably with H 2 in the presence of Pd / C.
  • the present inventive synthesis is simple and allows the preparation of decorative compounds I from non-toxic starting compounds.
  • the simple procedure allows a yield in the multi-gram scale.
  • the new compounds thus prepared are due to their reactive end groups capable of any surfaces such. As glass, metals and polymers, preferably by forming kovIERer bonds to functionalize.
  • the compounds I according to the invention exhibit good protein-resistant properties which correspond to or are even superior to those of PEG-coated surfaces.
  • the surfaces which are coated with the linear, methylated polyglycerols according to the invention are substantially more oxidation-resistant.
  • the new compounds have the advantage that it can not come in the long term to biocompatibility problems, since they have no free OH groups, which can imitate sugar or glycoproteins in comparison with the known highly branched and dendritic polyglycerols except a possible terminal OH group.
  • this terminal OH group additionally offers the possibility of attaching further functional groups or also suitable linker groups which are able to selectively and specifically immobilize proteins.
  • the compounds I are also highly versatile polymeric intermediates which can be used in a variety of ways, which - open up a wide range of variation and offer a wide range of possible applications through the targeted control of the degree of polymerization and the degree of functionalization.
  • the invention therefore also relates to the use of the polyglycerol derivatives of the general formula according to the invention! for coating surfaces of any materials.
  • they are used for coating medical devices, devices or biosensors intended for contact with body fluids, e.g.
  • in vivo sensors or medical implants such as, for example, surgical or orthopedic screws, plates, joint prostheses, artificial heart valves, vascular prostheses, stents or impla ⁇ tierbare drug depots.
  • products of the optical industry, such. B in contact lenses can be coated with the polyglycerol derivatives according to the invention.
  • the protein-resistant coating is applied to prevent nonspecific protein adsorption from biofluids, which is typically the first step in surface biofifing formation.
  • polyglycerol derivatives according to the invention are suitable as filter materials or for coating materials in filtration technology.
  • Correspondingly modified surfaces can in a further preferred embodiment for the coupling of ligands to the terminal functional Group of the polymer and used to produce specific protein interaction with simultaneous suppression of non-specific adsorption.
  • the solvents were purchased in reagent grade and before the
  • Resin with suifonic acid groups was supplied by Lanxesstechnik GmbH.
  • the mass spectroscopic data were obtained either on a Var / a spectrometer CH6 (EI-MS) or a Va ⁇ an spectrometer CH5-DF (FAB-MS) using m-nitrobenzyl alcohol (mNBA) as standard or on a Bruker Ultraflex II Instrument (Maidi-TOF) using ⁇ -hydroxycinnamic acid (HCCA) as matrix material. Elemental analyzes were performed on a Vario EL Ili elemental analyzer. Analytical GPC measurements were performed on an Agilent 1100 Series instrument with UV detector (254 nm) and refractive index detector (35 ° C.).
  • Polystyrene standards were used for calibration, and calculations were made with the PSS W / n-GPC software. Measurements were made in THF as eluent (1 ml / min, 25 ° C) using three PLgel 5 ⁇ mm / xec / C columns (7.5 x 300 mm in length / l of D.) at one pressure of 93 bar (column pressure). The FT-IR measurements were taken with sodium bromide plates on a Nicolet Avator 320 FT-! R instrument operating at 4000 nm to 400 nm and analyzed using the EZ OMNIC ESP 5.2 software program.
  • the precipitated hydrobromide salt from TEA was filtered off, which became filtrate concentrated under reduced pressure, and the resulting yellow liquid was mixed with water (10O mI).
  • the aqueous phase was extracted with diethyl ether (3 x 50 ml), the combined organic layers were dried (Na 2 SO 4) and concentrated in vacuo.
  • the crude product was filtered through silica gel (ethyl acetate / hexane 8: 1) to give, after drying under high vacuum, the title compound (21.7 g, 81%) as a colorless liquid.
  • the respective monomer is added to the deprotonated starter compound 5 under Ar atmosphere, and the molecular weight of the polymer is adjusted via the monomer / initiator ratio.
  • the polymerization runs for 20 hours. After cooling to RT, the reaction is driven by adding methanol and Lewatit ® K1131 to a standstill and stirred for an additional hour. The solution will be filtered from the Lewatit, and the polymer solution is concentrated under reduced pressure. To purify Saizen, the resulting polymer is dissolved in diethyl ether and centrifuged. Subsequently, the upper clear liquid layer is decanted from insoluble salts at the bottom of the vessel, and the solvent is evaporated under reduced pressure to give the desired polymer, which is dried under high vacuum.
  • Polymers 6b and 6c were prepared in the same manner, taking into account each monomer / initiator ratio, and showed the same NMR data.
  • the acetal-protected linear polyglycerol 7 a (2 g) was dissolved in THF (20 ml). Hydrochloric acid (12M, 1ml) was added and the mixture was stirred at room temperature for two hours to precipitate the deprotected polymer 7b. Then the THF was decanted and the polymer was washed with THF (10 ml) and acetone (3 x 20 ml) and purified by repeated dissolution in methanol and precipitation in acetone. The desired polymer 7b was obtained as a colorless viscous oil with a yield of 87% (1, 0 g).
  • the initiator solution at 110 0 C with 2.13 ml (23.7 mmoi, 14äq.) Freshly distilled, dry Glycidylmethyiether and stirred for a further 15h under argon, with a reddish brown coloration of the solution is observed.
  • the polymerization has ended by addition of 1 g of acidic ion exchanger Lewatit K1131 in 10 ml of methanol at room temperature and stirred for 1 h, the ion exchanger is filtered off and the solvent is distilled off.
  • the orange-colored oligomer obtained is dissolved in chloroform for further purification, filtered off from any remaining insoluble potassium salts and the solvent is distilled off in vacuo.
  • Lysozyme (chicken protein, E.C. 3.2.1.17, L6876) and pepsin (muscle, E.C.
  • Phosphate-buffered saline (PBS, 10X concentrated, 900 g / L NaCl, 79.5 g / L Na2HPO4 and 14.4 g / L KH2PO4, pH 7.4) was purchased from Cambrex. 11-
  • SAM self-aggregating
  • the chip now having concatenated carboxylic acid anhydride groups on the SAM, was immediately placed in a flask with a freshly prepared solution of each amine (10 mM in anhydrous NMP) which was to couple to the surface. After 30-40 minutes, the goid chip was rinsed with ethanol for 30 seconds and dried under an argon stream. All chips were used directly for contact angle measurements and SPR experiments
  • SPR Surface Plasmon Resonance Spectroscopic
  • Example 2 Surface modification and assay for protein adsorption
  • a glass substrate to which a thin gold film (50 nm) was vapor-deposited was exposed to a 1 M solution of the derivative in methanol for 18 hours.
  • protein adsorption was performed to the modified glass surface by SPR (Surface Plasmon Resonance) spectroscopy according to the instructions of Whitesides et al. (Langmuir 2001, 17, 1225).
  • the respective surfaces were treated with a protein solution of 1 mg / ml fibrinogen in PBS immediately after their preparation and with a protein solution of 2 mg / ml fibrinogen in PBS after a 2-week storage at 4 ° C in PBS.
  • the flow rate was 10 ⁇ l / min in all tests, the exposure time was 25 minutes.
  • the reference layer showed 100% protein adsorption after 25 minutes.
  • the fibrinogen treatment of both the surface coated with the inventive linear methylated polymer and the surface coated with the hyperbranched polyglycerol via a thioctic acid linker did not result in protein adsorption.
  • Figure 1 shows the SPR sensogram of adsorption of fibrinogen to a gold surface modified by polymers 1 and 3 and mono-amino-functionalized PEG compared to HDT, the insert showing amplification of the critical part of the plot.
  • Table 1 summarizes the molecular weights of the compounds measured (M), the number of repeating units of polymers (n), the specific contact angles of the surfaces after immobilization ( ⁇ ) and the various amounts of adsorbed proteins in% HDT.
  • M molecular weight
  • n number of repeating units of polymers
  • ⁇ specific contact angles of the surfaces after immobilization
  • ⁇ specific contact angles of the surfaces after immobilization
  • ⁇ specific contact angles of the surfaces after immobilization
  • Tab. 1 Amount of adsorbed fibrinogen, pepsin, albumin and lysozyme in% HDT, contact angle of the corresponding surface
  • Scheme 1 shows the synthesis of the terminal mono-amino-functionalized linear poly (methylglycerol) 1 and linear polyglycerin 3 according to the invention and a schematic illustration of the subsequent surface immobilization of 1, 3 and monoamino-functionalized PEG according to the "anhydride method" (reference 3).
  • Fig. 2 also demonstrates surface immobilization with the compounds of the invention.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Polyethers (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un procédé de fabrication de dérivés de polyglycérol linéaires et méthylés à base de glycidylméthyléther constitués de façon définie avec un degré de polymérisation de 1 à 1 000, avec une distribution étroite de masses molaires, déterminée par GPC (chromatographie d'exclusion diffusion) et une polydispersité inférieure à 2, de préférence inférieure à 1,1 (Étalon PS), par polymérisation anionique par ouverture de cycle du glycidylméthyléther en présence d'un composé de départ à hydrogène actif sous catalyse basique. L'invention concerne notamment des polymères de formule générale I. L'invention concerne également l'utilisation de ces dérivés de polyglycérol linéaires et méthylés pour la fonctionnalisation de surfaces quelconques. Les surfaces munies d'un revêtement des nouveaux dérivés de polyglycérol présentent d'excellentes propriétés de résistance aux protéines.
EP07729876A 2006-06-02 2007-06-04 Procédé de fabrication de dérivés de polyglycérol linéaires et méthylés et leur utilisation pour la fonctionnalisation de surfaces Withdrawn EP2044141A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE200610027125 DE102006027125A1 (de) 2006-06-02 2006-06-02 Verfahren zur Herstellung von linearen, methylierten Polyglycerolderivaten und ihre Verwendung zur Funktionalisierung von Oberflächen
PCT/EP2007/055489 WO2007141248A1 (fr) 2006-06-02 2007-06-04 Procédé de fabrication de dérivés de polyglycérol linéaires et méthylés et leur utilisation pour la fonctionnalisation de surfaces

Publications (1)

Publication Number Publication Date
EP2044141A1 true EP2044141A1 (fr) 2009-04-08

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Application Number Title Priority Date Filing Date
EP07729876A Withdrawn EP2044141A1 (fr) 2006-06-02 2007-06-04 Procédé de fabrication de dérivés de polyglycérol linéaires et méthylés et leur utilisation pour la fonctionnalisation de surfaces

Country Status (3)

Country Link
EP (1) EP2044141A1 (fr)
DE (1) DE102006027125A1 (fr)
WO (1) WO2007141248A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102011081260B4 (de) 2011-08-19 2013-05-29 PolyAn Gesellschaft zur Herstellung von Polymeren für spezielle Anwendungen und Analytik mbH Verfahren zur Herstellung von beschichteten Glasoberflächen und Glasgefäßen zur Handhabung von Biomolekülen oder biologischen Materialien sowie die entsprechenden Glasgefäße
EP3048130A1 (fr) 2015-01-20 2016-07-27 Freie Universität Berlin Dérivés de polyglycérol linéaires anioniques, procédé de fabrication et applications
DE102018009655A1 (de) 2018-12-08 2020-06-10 Heinrich Jehle Verfahren zur Oberflächenbeschichtung
WO2023166477A1 (fr) * 2022-03-04 2023-09-07 Università Degli Studi Di Bari Aldo Moro Agents tensioactifs dérivés de polyglycérol linéaire

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL67705C (fr) * 1946-09-30
AU2003281208A1 (en) * 2002-07-05 2004-01-23 Asahi Kasei Kabushiki Kaisha Resin compatible with body fluid and living tissue
DE10311163A1 (de) * 2003-03-12 2004-09-23 Albert-Ludwigs-Universität Freiburg, vertreten durch den Rektor Proteinabweisende Oberflächen auf der Basis dendritischer Polymerfilme

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007141248A1 *

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WO2007141248A1 (fr) 2007-12-13
DE102006027125A1 (de) 2007-12-06

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