WO2009054814A1 - Thiophène ponté poly(3, 4-alkylène) (pabt) fonctionnalisé - Google Patents

Thiophène ponté poly(3, 4-alkylène) (pabt) fonctionnalisé Download PDF

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WO2009054814A1
WO2009054814A1 PCT/SG2008/000412 SG2008000412W WO2009054814A1 WO 2009054814 A1 WO2009054814 A1 WO 2009054814A1 SG 2008000412 W SG2008000412 W SG 2008000412W WO 2009054814 A1 WO2009054814 A1 WO 2009054814A1
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edot
formula
polymer
poly
functionalized
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WO2009054814A8 (fr
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Jackie Y. Ying
Hsiao-Hua Yu
Shyh-Chyang Luo
Hong Xie
Eric Assen B. Kantchev
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Agency For Science, Technology And Research
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    • 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
    • C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G61/12—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule
    • C08G61/122—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides
    • C08G61/123—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides derived from five-membered heterocyclic compounds
    • C08G61/126—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides derived from five-membered heterocyclic compounds with a five-membered ring containing one sulfur atom in the ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/28—Compounds of silicon
    • C09C1/30—Silicic acid
    • C09C1/3072—Treatment with macro-molecular organic compounds
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    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C3/00—Treatment in general of inorganic materials, other than fibrous fillers, to enhance their pigmenting or filling properties
    • C09C3/10—Treatment with macromolecular organic compounds
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54346—Nanoparticles
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/61—Micrometer sized, i.e. from 1-100 micrometer
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/62—Submicrometer sized, i.e. from 0.1-1 micrometer
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer

Definitions

  • the invention generally relates to functionalized poly (3, 4-alkylenebridgedthiophene) (PABT) polymers, a method for their preparation and uses thereof.
  • PABT functionalized poly (3, 4-alkylenebridgedthiophene)
  • biointerface can determine the biocompatibility of the foreign objects and the efficiency of the targeted function (Prime, K. L. ; G. M.
  • Poly (3, 4-ethylenedioxythiophene) (PEDOT) is a known conducting polymer due to its electrical properties, long-term stability, and transparency to visible light at its doping state (Heywang, G.; F. Jonas, Adv. Mater. 1992, 4, 111; Pei, B.; G. Zuccarello, M. Ahlskog, 0. Inganas, Polymer 1994, 35, 1347; Groenendaal, B. L.; F. Jonas, D. Freitag, H. Pielartzik, J. R. Reynolds, Adv. Mater. 2000, 12, 481) . It has been used for various electronic products such as antistatic coatings for cathode ray tubes (Jonas, F.; W.
  • the present invention relates to functionalized poly (3, 4-alkylenebridgedthiopene) (PABT) polymers and a method of depositing PABT polymer coatings on a non- conducting support matrix or a nanoparticle .
  • PABT functionalized poly
  • the invention relates to a polymer comprising "n" subunits of formula (I) :
  • Ai is a bridging alkylene chain, optionally substituted, having 2, 3, 4, 5 or 6 carbon atoms;
  • Yi and Y 2 are, independently, 0, S or N-R 2 , and wherein R 2 is hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl, an aryl or a heterocycle; and
  • Ri is a functional chain attached to the bridging alkylene chain
  • n is an integer of 2 or more.
  • the sulphur (S) of the thiophene ring may be replaced by 0, N-R 2 or another similarly functioning atom or group, as would be recognized by an artisan. Further, such a replacement could be made to all aspects of the invention.
  • the polymer is, for example and without limitation, a co-polymer comprising ⁇ m" sub-units of formula (I) and "p" sub-units of Formula (II)
  • Ai and A 2 are independently a bridging alkylene chain, optionally substituted, having 2, 3, 4, 5 or 6 carbon atoms, and, "m” and “p” independently are integers of 2 or more, and Yi, Y 2 and Ri are as defined above.
  • the co-polymer may have, predominantly, the sub- unit of formula (I) and some quantity of sub-unit of formula (II) .
  • the ratio of the sub- unit of formula (I) to formula (II) can range from 0.01 to 99.99%, 10 to 90%, 20 to 80%, 40 to 60%, 60% to 40%, 80% to 20% or 90% to 10%.
  • about 5% of the units of the co-polymer described above are sub-unit of formula (II).
  • the molecular weight of the polymer can range from 1000 - 1,000,000.
  • Ai and A 2 are identical and are part of a glycol chain forming a five-membered ring with dioxythiophene.
  • Ri is a non-adhesive chain, wherein the non-adhesive chain is a phospholipid chain, an oligo- ethylene glycol or a poly-ethylene glycol. In another embodiment, Ri is an oligo-ethylene glycol having 2, 4, 6 or 8 carbon atoms.
  • the invention relates to a method of preparation of a compound of formula (III), as described above, the method comprising:
  • Formula (IV) Formula (V) wherein A 2 is a bridging alkylene chain, optionally substituted, having 2, 3, 4, 5 or 6 carbon atoms;
  • the invention relates to a bionanointerface for controlled adhesion of a biological molecule, the bionanointerface comprising:
  • the adhesive region having a biologically adhesive agent for releasably binding the biological molecule
  • the adhesive agent is, without limitation and for the purpose of illustration, a functionalized poly (EDOT-OH) or poly (EDOT-
  • the polymer of formula (I), without limitation and for the purpose of illustration is a functionalized poly (PED0T-EG3- OH) polymer.
  • the polymer of formula (I), without limitation and for the purpose of illustration is a co-polymer functionalized poly (PEDOT-EG3-OH) and poly (PEDOT-OH) .
  • the nanobiointerface is formed by layer-by-layer electropolymerization.
  • the invention relates to a method of depositing functionalized poly (3,4- alkylenebridgedthiopene) (PABT) polymer coatings on a non- conductive support matrix or nanoparticle, the method comprising the steps of:
  • PABT functionalized poly (3,4- alkylenebridgedthiopene)
  • ABT 3,4- alkylenebridgedthiophene
  • the polymerization is an oxidative chemical polymerization reaction.
  • the monomer is a monomer having low solubility in water and which can be dissolved by sonicating.
  • the non- conductive support matrix or nanoparticle is silica, a polystyrene nanoparticle, a metal oxide particle, nylon fibers, cellulose, a siliceous MCF or a chitosan alignate fiber.
  • the functionalized PABT polymer coating is poly (EDOT-OH) or poly (EDOT-COOH) .
  • the method is used for the preparation of functionalized PABT nanostructures .
  • the nanostructure is a hollow poly (PEDOT-OH) sphere having a thickness of at least about 15nm.
  • the functionalized poly PABT is a poly (EDOT-OH) deposited on the non-conducting support matrix or nanoparticle having a layer thickness of 5-7 nm.
  • QCM quartz crystal microbalance
  • QCM quartz crystal microbalance
  • Figure 2 displays, according to an invention embodiment, the amperometric response of various functionalized PEDOT nanobiointerfaces in the presence of 40 mM of glucose upon non-specific adsorption of GOX and osmium-containing electroactive hydrogels.
  • Figure 3(A) displays, according to an invention embodiment, amperometric response of glucose at different concentrations on poly (EDOT-OH) -coated platinum electrode after adsorbing GOX on the surface of the electrode.
  • Figure 3 (B) displays, according to an invention embodiment, amperometric response as a function of glucose concentration ( ⁇ ) , and polynomial curve fit.
  • Figure 5 displays, and according to an invention embodiment, the proliferation of NIH3T3 cells after (a) 2 h, (b) 15 h, and (c) 39 h of incubation on adhesive poly (EDOT-OH) biointerface, in sections (a) , (b) and (c) , respectively.
  • adhesive poly EDOT-OH
  • Figure 6 shows a multi-layer PEDOT structure, according to an invention embodiment, where section (a) is legends of monomer composition of layered PEDOT nanobiointerfaces, and sections (b)-(g) are controlled cell adhesion from alternating layer-by-layer deposition of PEDOT nanobiointerfaces with adhesive and non-adhesive properties.
  • Figure 7 shows the contact angles of PEDOT nanobiointerfaces from layer-by-layer deposition, according to an invention embodiment.
  • the legends for the composition of PEDOT nanobiointerfaces are as shown in Figure 9.
  • Figure 8 shows the controlled cell adhesion on poly (EDOT-OH) patterned on co-poly (EDOT-OH) -poly (ED0T-EG3-0H) surface, according to an invention embodiment.
  • Section (a) is top and side views of the device patterned by selective electropolymerization using PDMS mask, and magnified microscopic images of selective cell adhesion on the patterned surface are shown in sections (b) and (c) .
  • Figure 9 illustrates a method for the coating of various substrates with functionalized PEDOT, according to an invention embodiment.
  • Figure 10 (A) shows a transmission Electron Microscopy (TEM) micrograph of poly (EDOT-OH) -coated silica nanoparticles .
  • Figure 10 (B) shows an energy Dispersive X-ray spectroscopy (EDX) results of poly (EDOT-OH) -coated silica nanoparticles.
  • EDX energy Dispersive X-ray spectroscopy
  • Figure 11 displays in sections (a) , (b) , (c) and (d) , a
  • Figure 12 displays in sections (a) , (b) , (c) and (d) , the structure and morphology of PEDOT-OH-coated PS beads after removal of the PS cores by toluene, where in section (a) TEM and in section (b) SEM micrographs of hollow beads obtained from 200-nm PS beads coated with thin poly (EDOT-OH) layers ( ⁇ 5 nm) are shown, and in section (c) TEM and in section (d) SEM micrographs of hollow beads obtained from 500-nm PS beads coated with thick poly (EDOT-OH) layers (> 15 nm) are shown.
  • Figure 13 displays the N 2 adsorption-desorption isotherms of siliceous MGF (•) , poly (EDOT-OH) -coated MCF after chemical polymerization for ( ⁇ ) 4 h and (A) 16 h, and a (inset) TEM micrograph of MCF after 4-h coating of poly (EDOT-OH) .
  • Figure 14 displays in sections (a) , (b) and (c) , the SEM and
  • the invention relates to functionalized poly (3,4- alkylenebridgedthiophene) (PABT) polymers, methods for their preparation and their use in the preparation of, for example and without limitation, biointerfaces having regions with adhesive (fouling) and non-adhesive (non-fouling) surfaces, where the adhesive surface may bind to a biological target.
  • PABT functionalized poly (3,4- alkylenebridgedthiophene)
  • the term 'functionalized' in 'functionalized PABT ⁇ polymer' is not limited and can be any atom or chain that imparts the desired characteristics of adhesiveness or non- adhesiveness due to the functional chain.
  • the adhesiveness and non-adhesiveness properties are towards adhesive and non-adhesive interaction with a target, such as, a biological target, which includes, without limitation and for the purposes of illustration, a cell or a protein.
  • the functionalized PABT polymers of the invention may be obtained by polymerization of the appropriate functionalized ABT monomers, as would be understood by the skilled person.
  • the invention relates to a polymer comprising ⁇ n" subunits of formula (I) :
  • Ai is a bridging alkylene chain, optionally substituted, having 2, 3, 4, 5 or 6 carbon atoms;
  • Yi and Y 2 are, independently, 0, S or N-R 2 , and wherein R 2 is hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl, an aryl or a heterocycle; and
  • Ri is a functional chain attached to the bridging- alkylene chain
  • n is an integer of 2 or more.
  • the polymer is, for example and without limitation, a co-polymer comprising "m" sub-units of formula (I) and "p" sub-units of Formula (II)
  • Ai and A 2 are independently, and optionally substituted, a bridging alkylene chain of 2, 3, 4, 5 or 6 carbon atoms, and, "m” and “p” independently are integers of 2 or more, and Yi, Y 2 and Ri are as defined above.
  • a co-polymer is generally considered to be a polymer derived from two (or more) monomeric species.
  • n can be in the range of 2 or more.
  • the length of the polymer may be dependent on the application, which can be assessed through routine experimentation.
  • the molecular weight of the polymer can range from 1000-1000000.
  • the number of ⁇ n' , ⁇ m' or ⁇ p' subunits can range from 10 to 10000, 100 to 9000, 1000 to 8000, 2000 to
  • a bridging alkylene chain that may be substituted or unsubstituted, for example, and without limitation, include any straight or branched alkylene, for example, methylene, ethylene, n-propylene, i-propylene, sec- propylene, n-butylene, i-butylene, sec-butylene, t-butylene, n-pentylene, i-pentylene, sec-pentylene, t-pentylene, n- hexylene, i-hexylene, 1, 2-dimethylpropylene, 2- ethylpropylene, l-methyl-2-ethylpropylene, l-ethyl-2- methylpropylene, 1, 1, 2-trimethylpropylene, 1,1- dimethylbutylene, 2, 2-dimethylbutylene, 2-ethylbutylene, 1, 3-dimethylbutylene, 2-methylpentylene, 3-
  • Substitution on the bridging alkylene chain include, without limitation and for the purpose of illustration, one or more substituents which are the same or different, and may be, for example, and without limitation, a halogen atom, a hydroxyl group, an amine group, a thiol group, a nitro group, a nitrile group or a cyano group.
  • substituents which are the same or different, and may be, for example, and without limitation, a halogen atom, a hydroxyl group, an amine group, a thiol group, a nitro group, a nitrile group or a cyano group.
  • One example of the substituted bridging alkylene chain, as disclosed herein, is a glycerol derivative.
  • an alkyl group which may be substituted, may be, for example, and without limitation, any straight or branched alkyl, for example, methyl, ethyl, n-propyl, i-propyl, sec-propyl, n- butyl, i butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec- pentyl, t-pentyl, n-hexyl, i-hexyl, 1, 2-dimethylpropyl, 2- ethylpropyl, l-methyl-2-ethylpropyl, l-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1, 2-triethylpropyl, 1,1- dimethylbutyl, 2, 2-dimethylbutyl, 2-ethylbutyl
  • an alkenyl group which may be substituted, may be, for example, and without limitation, any straight or branched alkenyl, for example, vinyl, allyl, isopropenyl, 1-propene-
  • the C2-6 alkenyl group may be, for example, and without limitation, interrupted by one or more heteroatoms which are independently nitrogen, sulfur or oxygen.
  • an alkynyl group which may be substituted, may be, for example, and without limitation, any straight or branched alkynyl, for example, ethynyl, propynyl, butynyl, pentynyl or hexynyl .
  • the C 2 - 6 alkynyl group may be, for example, and without limitation, interrupted by one or more heteroatoms which are independently nitrogen, sulfur or oxygen.
  • a cycloalkyl group which may be substituted, may be, for example, and without limitation, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl or cycloheptanyl .
  • an aryl group which may be substituted, may be, for example, and without limitation, phenyl, pentalenyl, indenyl, naphthyl, azulenyl, heptalenyl, benzocyclooctenyl or phenanthrenyl .
  • a non- aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen of the heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen and which group may be substituted may contain, for example, and without limitation, from 1 to 4 heteroatoms which are independently nitrogen, sulfur or oxygen.
  • the non-aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen may be, for example, and without limitation, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolydinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, phthalimide or succinimide.
  • an aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen of the aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen and which group may be substituted may contain, for example, and without limitation, from 1 to 4 heteroatoms which are independently nitrogen, sulfur or oxygen.
  • the aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen may be, for example, and without limitation, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pirazinyl, imidazolyl, thiazolyl or oxazolyl.
  • Each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, non-aromatic heterocylic and aromatic heterocyclic groups may be substituted with one or more substituents which are the same or different.
  • each of the above- mentioned groups may be substituted with, for example, and without limitation, one to three substituents.
  • the one or more substituents for each of the above-mentioned groups may be, for example, and without limitation, a halogen atom, a hydroxyl group, an amine group, a thiol group, a nitro group, a nitrile group or a cyano group.
  • the Ri functional chain is not limited and can be, for 'example, substituted or unsubstituted, alkyl, alkenyl, alkynyl, cycloalkyl, cycoalkenyl, aryl, arylalkyl, arylalkenyl or a heterocycle, each of which may have one or more heteroatoms and/or organic functional groups within the functional chain, and additionally, may also be cationic, anionic or zwitterionic.
  • the functional chain is selected based on the interaction desired with a target, such as, a biological cell or protein. It can be either adhesive
  • substituted alkyl chains having heteroatoms within the chain include oligoethylene glycol, polyethyleneglycol and an amine- substituted alkyl-phosphate.
  • the molecular weight of ' the oligoethylene glycol can be, for example, up to about 1000 g/mol and the molecular weight of polyethylene glycol can, for example, range from about 1000 to about 40,000 g/mol.
  • the functional chain can have and further be, different functional groups, such as, alcohols, ketones, aldehydes, carboxylic acid, esters, ethers, amide, amines, imine, phosphodiester, sulphide, thioether, sulfone, sulfoxide or thiols.
  • the functional chain can be selected based on the design and properties desired for the synthesized polymer. It can be selected, such that the functional group can adhesively (fouling) bind to a target cell or protein or has a non-adhesive (non-fouling) interaction with the target cell or protein.
  • the bridging alkylene chain is a glycerol derivative linking oxygen atoms of a 3, 4-dioxythiophene to form a five-membered ring, and resulting in 3, 4-ethylenedioxythiophene (EDOT) monomers having a methylene-hydroxy group for attachment to the functional chain.
  • the functional chain is a oligo or poly-ethylene glycol (OEG or PEG) , a phospholipid or an acetic acid.
  • Ai and Ri are the same as described above.
  • a compound of formula (IV) or a derivative thereof, is reacted with a compound of formula (V) .
  • R 2 is a derivative of Ai, such as, the protonated form of a hydroxyl group.
  • the reaction may be performed by nucleophilic substitution reaction using the compound of formula (IV), or derivative thereof, having a nucleophilic atom on the bridging alkylene chain for nucleophilic substitution on an electrophilic atom on Ri, and where LG is a suitable leaving group.
  • a nucleophilic atom is generally considered, without limitation, as an atom that forms a bond with an electrophile by donating a pair of electrons for forming the bond.
  • Suitable examples include, oxygen, nitrogen and sulphur atoms.
  • an electrophilic atom is generally considered, without limitation, as an atom that accepts a pair of electrons from the nucleophilic atom, and can include, without being limited to, carbon atoms bearing a strong electron withdrawing groups, phosphorous atoms and halides.
  • a leaving group is generally considered, without limitation, as an atom or group of atoms that detaches itself from the electrophile. Generally, the lower the pK a of .the conjugate acid, the better the leaving group. Suitable leaving groups include, without being limited to, halides, triflates or mesylate.
  • the nucleophilic atom is the oxygen atom on a hydroxyl group and the electrophile is a derivatized oligoethylene glycol or a phospholane reagent having a leaving group, such as, chloride, iodide or mesylate.
  • PABT functionalized poly (3, 4-alkylenebridgedthiophene)
  • Suitable non-conductive support matrix include, without being limited to, colloidal silica, polystyrene beads, metal oxide particle, nylon fiber, cellulose, siliceous MCF or chitosan-alignate fibers.
  • a nanoparticle is generally understood as an object that behaves as a whole unit in terms of its transport and properties. It is normally classified based on size, ranging from about 1 to about 2500 nm, for example, and without limitation.
  • the coating is carried out by oxidative chemical polymerization.
  • the monomer is a monomer having low solubility in water, and which can be dissolved by sonicating in an aqueous medium.
  • An oxidative chemical polymerization is generally understood as, for example, a polymerization reaction that results in oxidation of the monomers used in the reaction.
  • Solubility is generally understood as, for example, the amount of a substance that can be dissolved in a given amount of solvent, and a compound having low solubility, would be generally understood as, for example, one that is sparingly soluble.
  • An aqueous medium is generally considered as a medium containing water and includes a medium that is predominantly water.
  • the invention relates to a bionanointerface for controlled adhesion of a biological molecule, the bionanointerface comprising:
  • the adhesive region having a biologically adhesive agent for releasably binding the biological molecule
  • a biologically adhesive agent is understood to be an agent that would bind adhesively (fouling) to a biological target, such as, and without limitation, a cell or protein.
  • the binding of the agent is generally, without limitation, reversible, such that under appropriate conditions, the biological target can be released from the biologically adhesive agent.
  • the biologically adhesive agent would comprise a poly (EDOT-OH) or a poly (EDOT-COOH) .
  • the preparation of the non- adhesive functionalized PABT polymers was performed using oligoethylene glycol tethered EDOT monomers. It has been observed that the non-fouling properties of polyethylene glycol (PEG) and oligoethylene (OEG) grafted self-assembled monolayer (SAM) are dependent on the polymer molecular weight and graft density. Therefore, new monomer synthesis was performed for controlling the composition of PEDOT nanobiointerfaces . For example, triethylene glycol tethered EDOT monomer (ED0T-EG3-0H) was synthesized from 2- [2- (2- chloroethoxy) ethoxy] ethanol .
  • THP0-EG3-I The -OH group of the starting material was first protected by tetrahydrofuran, followed by transhalogenation reaction to yield THP0-EG3-I (Scheme 1) .
  • the desired product EDOT- EG3-0H was obtained after the THP group was deprotected using acidic resin.
  • the total yield over four steps was 30%, and the structure of ED0T-EG3-0H was confirmed by spectroscopic methods (NMR, infrared (IR) and mass spectrometry (MS) ) .
  • ⁇ rt' stands for room temperature.
  • the dissolution of the deposited blue polymer was observed, which was most likely due to the increased water solubility of both the monomer and the polymer, due to the tethering hydrophilic ethylene glycol groups.
  • the solubility of the polymer was reduced when EDOT-EG3-OH was copolymerized with another less soluble monomer.
  • about a minimum of 5% EDOT-OH in the monomer mixture enhanced the polymer deposition.
  • Atomic force microscopy (AFM) images confirmed that the new PEDOT nanobiointerfaces containing ED0T-EG3-0H side chains displayed preferable smoothness (R rms ⁇ 5 nm) .
  • the functionalized PEDOT films were thin (about ⁇ 100 nm in thickness) , ultrasmooth (R r ms about ⁇ 5 nm) and non-cytotoxic.
  • non-adhesive functionalized PABT polymers were prepared using phospholipid tethered EDOT monomers. Post-polymerization functionalization of poly (EDOT-OH) surface was performed
  • PoIy(EDOT-OH) showed the strongest binding to GOX ( Figure 1(A)) .
  • the binding of GOX decreased as the ratio of ED0T-EG3-0H in copolymers increased. This indicated that the triethylene glycol functional groups on PABT thin films reduced non- specific binding, and that poly (ED0T-EG3-0H) formed a non- adhesive surface.
  • the binding of BSA on poly (EDOT-OH) and co-poly (EDOT-OH) -poly (ED0T-EG3-0H) also indicates " the same trend ( Figure 1(B)) .
  • poly (EDOT-COOH) demonstrated a very weak binding to GOX, but a strong binding to BSA.
  • carboxyl groups on PEDOT thin films played a role for enzyme binding.
  • the carboxyl groups tend to dissociate into H + cations and carboxylate in aqueous solution, which leads to a negative charge on PEDOT surface. Therefore, the binding property for poly (EDOT-COOH) thin films is determined by the Coulombic force between the functional groups on the enzyme surface and the negatively charged RCOO " anions.
  • the strong binding of BSA indicates the existence of positively charged functional groups on BSA surface, and these functional groups have strong interactions with carboxyl groups.
  • Controlling the interfaces between cells and solid substrates can be of concern for cell-based biosensors and biochips .
  • the interaction between cells and functionalized PABT substrates are illustrated by the cell adhesion on different functionalized PABT thin films.
  • Cells were allowed to attach to PABT surfaces for 2 h under serum-free conditions. After 2 h of incubation, unattached and loosely attached cells were gently removed by washing three times with PBS. Substrates were then further incubated in full medium with 10% FBS overnight. As shown in Figure 4, both NIH3T3 and KB cells were selectively attached to polyEDOT and poly (EDOT-OH) surfaces.
  • PABT surface electropolymerized from a mixture of 10% EDOT-OH and 90% EDOT-EG3-OH were cell- resistant, while the PEDOT-COOH surface characteristics were dependent on the cell type. Cell adhesion and proliferation were observed on poly (EDOT-OH) surface, as shown in Figure 5. These results support the possibility of engineering the surface "cell-adhesiveness” or "cell-resistance” through layer-by-layer deposition.
  • multilayer PABT structures were constructed by electropolymerization of alternative layer of co-poly (EDOT-OH) -poly (EDOT-EG3-OH) and poly (EDOT-OH) from their respective monomer solutions
  • the non-adhesive PABT biointerfaces were also applied towards cell patterning by first covering the ITO- coated glass slides with non-adhesive co-poly (EDOT-OH) - poly (ED0T-EG3-0H) surface. Patterned, adhesive poly (EDOT-OH) was then electropolymerized using a PDMS mask to create the device configuration shown in Figure 8. After cell attachment and washing, cells were observed only on the poly (EDOT-OH) -covered regions, since the remaining regions were non-adhesive.
  • EDOT-OH non-adhesive co-poly
  • E0T-EG3-0H non-adhesive co-poly
  • EDOT-OH adhesive poly
  • PABT nanobiointerface may be designed to have different properties, such as: (1) thin and smooth films are deposited with ⁇ 100 nm in thickness and ⁇ 5 nm in roughness
  • the functionalized PABT monomers were initially polymerized by acid-catalyzed microemulsion electropolymerization.
  • electropolymerization offers a convenient way to deposit films, the variety of substrates on which such deposits can be made are limited, and there is a need to develop an alternate route, such as, chemical polymerization in an aqueous media, for depositing functionalized PEDOT coatings on non-conductive supporting matrix or nanoparticle.
  • chemical polymerization is generally performed in organic solutions or aqueous microemulsions for improved polymer formation.
  • EDOT monomers Due to the low solubility of functionalized EDOT monomers in water, sonication was performed to prepare an aqueous solution of EDOT monomers with a high concentration (generally > 10 mM) . After adding the substrates to the monomer solutions, oxidants were added to initiate the reaction. HCl was used to lower the oxidation potential of EDOT, and Cl " also served as dopants. After PEDOT was formed, it favored precipitation and adsorption onto the substrates due to its low solubility in water. Little side-products of homo-PEDOT clusters were observed in the reaction mixture. The degree of chemical polymerization was controlled by the monomer composition, concentration, and reaction time. Therefore, the thickness of PEDOT layers on the substrates could be varied by these three parameters.
  • Siliceous MCF with well-defined, ultralarge open pores of 30-50 nm is an attractive new material as catalyst support and separation medium, while chitosan-alginate fibers have been created as a new scaffold material for cell proliferation and tissue engineering.
  • Deposition of functionalized PABT on the surface of siliceous MCF and chitosan-alginate fibers provides for three-dimensional conductive systems for applications, such as advanced tissue engineering scaffolds and biofuel cells.
  • the various types of substrates all turned blue in color after polymerization, indicating the formation of functionalized PEDOT on their surface.
  • the Transmission Electron Microscopy (TEM) micrograph of poly (EDOT-OH) -coated silica nanoparticles is shown in Figure 10 (A) .
  • the poly (EDOT-OH) layer on silica nanoparticles was not so clear in the image, possibly due to the thin poly (EDOT-OH) layer and the poor contrast between the coating and the silica nanoparticle.
  • Energy dispersive X-ray analysis (EDX) confirmed the presence of sulfur peak after the poly (EDOT-OH) coating
  • Figure 11 shows the scanning electron microscopy (SEM) micrographs before and after the coating of poly (EDOT- OH) layers.
  • SEM scanning electron microscopy
  • the surface of poly (EDOT-OH) -coated beads was examined with various bead sizes and coating thicknesses. Formation of poly (EDOT-OH) layers on the surface of PS beads was clearly observed after the chemical polymerization process. Rougher surface was obtained from thicker poly (EDOT-OH) coatings ( ⁇ 20 nm) ( Figure ll(section (c) ) ) . Similar surface roughness was noted when the polymerization was performed on larger beads ( Figure 11 (section (d) ) ) .
  • FIG 12 shows the structure and morphology of poly (EDOT-OH) nanostructures after the PS core was removed. Hollow poly (EDOT-OH) spheres were clearly observed. The spherical structures collapsed after the removal of the PS cores in the case of thin poly (EDOT-OH) layers ( ⁇ 5 nm) (see Figure 12 (section (b) ) ) . For the thick poly (EDOT-OH) layers (> 15 nm) , hollow and spherical particles were obtained.
  • FIG. 14 shows the chitosan-alginate fibers before poly (EDOT-OH) coating. They were white in color with a smooth surface. After the fibers was immersed in EDOT-OH solution in the presence of ammonium persulfate (APS) oxidants for 4 h, the fibers turned blue
  • EDOT-COOH was also successfully coated onto the different substrates described with similar results. Compared to poly (EDOT-OH) coatings, the poly (EDOT- COOH) coatings of the same thickness generally required a longer polymerization period at the same monomer concentration. The poly (EDOT-COOH) coatings were also more uniform according to SEM and TEM observations.
  • Ethylenedioxythiophene (EDOT, Sigma- Aldrich) , lithium perchlorate (LiClO 4 , Fluka) , sodium dodecyl sulfate (SDS, Alfa Aesar) and D- (+) -glucose (Sigma) were used as received.
  • Hydroxymethyl-functionalized EDOT (EDOT-
  • EDOT-COOH was synthesized in the same way as described previously.
  • a phosphate-buffered saline (PBS) consisting of 137 mM of NaCl (sodium chloride), 2.7 mM of KCl (potassium chloride) , and 10 mM of phosphate buffer was used as the supporting electrolyte solution.
  • Glucose oxidase-avidin D (GOD-A, Vector Laboratories) was diluted in PBS by 100, 1000 and 5000 times in volume to produce 50 ⁇ g/mL, 5 ⁇ g/mL and 1 ⁇ g/mL solutions.
  • Indium tin oxide (ITO) coated glass (Delta- Technologies, Ltd.) was cleaned by standard procedure prior to use.
  • MCF silica
  • EDOT-OH (4.31 g, 25 mmol) was dissolved in dry dimethyl formamide (DMF) (50 mL) in a 250-mL round-bottomed flask under argon (Ar) .
  • Sodium hydride (NaH) (60% dispersion in mineral oil; 1.50 g, 37.5 mmol) was added slowly against a gentle stream of Ar, and the mixture was stirred under Ar for 15 min.
  • THPO-EG3-I (8.60 g, 25 mmol) was then added, and the mixture was stirred overnight and partitioned between brine (250 mL) and ethyl acetate (100 mL) .
  • Examples 1-3 were electropolymerized on Au, Pt and ITO electrodes using 10 mM of EDOT aqueous solution containing 0.1 M of lithium perchlorate (LiClO 4 ) as supporting electrolyte in the presence of 1 mM of hydrochloric acid (HCl) and 0.05 M of sodium dodecylsulphate (SDS) by applying cyclic potentials (-0.6 to 1.1 V vs. Ag/AgCl at a scan rate of 100 mV/s) or potentiostatic methods.
  • LiClO 4 lithium perchlorate
  • SDS sodium dodecylsulphate
  • PoIy(EDOT-OH) was electropolymerized on ITO substrate.
  • the phospholipid moieties were introduced similarly as in the synthesis of EDOT-PC.
  • the poly (EDOT-OH) - coated glass substrate was dipped into 2-chloro-2-oxo-l, 3, 2- dioxaphospholane (COP) solutions in anhydrous tetrahydrofuran (THF) at -20°C for 3 h.
  • the film was then washed with anhydrous THF, dried and dipped into anhydrous acetonitrile (CH 3 CN) in a pressure bottle.
  • Anhydrous trimethylamine was bubbled quickly to the solution mixture.
  • the pressure bottle was closed, and allowed to warm up to room temperature. After it was heated at 20°C for 16 h, the bottle was cooled.
  • the films were further washed with anhydrous CH 3 CN, and ready for measurements.
  • NIH3T3 cells and KB cells were cultured in DMEM and RPMI culture media, respectively, supplemented with fetal bovine serum (FBS) (10%), penicillin (200 units/mL) and streptomysin (200 ⁇ g/mL) (complete medium) .
  • FBS fetal bovine serum
  • penicillin 200 units/mL
  • streptomysin 200 ⁇ g/mL
  • the cultures were maintained at 37 0 C in a humidified atmosphere containing 5% of carbon dioxide (CO 2 ) .
  • CO 2 carbon dioxide
  • PEDOTs were electropolymerized onto clean ITO substrates from a solution containing 10 mM of EDOT monomers, 0.05 M of SDS, 0.1 M of LiClO 4 and 0.01 M of HCl at 1.1 V (vs. Ag/AgCl) with a cutoff charge density of 5 mC/cm 2 .
  • Multilayered PEDOT structures were made in a similar manner using layer-by-layer growth. The substrates were then cut into 10 mm * 8 mm pieces, and loaded into a 24-well plate. PEDOT/ITO substrate was pre- sterilized for 1 h in 70% ethanol. 500 ⁇ L of cell suspension was added into each " 24-well plate loaded with PEDOT/ITO substrate.
  • EDOT-OH and PEDOT-COOH films Coating of PEDOT-OH and PEDOT-COOH films. EDOT-OH and C2-EDOT-COOH monomers were dissolved in water by sonication in a water bath sonicator (Elma Transsonic 660/H, 35 kHz) for 30 min to prepare monomer solutions of 30 mM. For coating of PEDOT on nanoparticles, monomer solutions were added to aqueous solutions of colloidal silica and polystyrene (PS) beads. After the mixed solutions were stirred for 30 min, a solution containing 30 mM of APS and 10 mM of HCl was introduced. The chemical polymerization proceeded for 16 h at room temperature before it was quenched by methanol.
  • PS polystyrene
  • PEDOT coating on siliceous MCF 200 mg was placed in a round flask and degassed by using a mechanical pump. Monomer solutions were then injected into this flask, and the entire system is stirred under vacuum for 30 min. After that, vacuum was released and a solution containing APS and HCl was added under the atmospheric pressure to initiate the chemical polymerization.
  • the fibers were first immersed in the monomer solutions for 30 min. Then the solution containing APS and HCl was added to start the coating of PEDOT.
  • FESEM field emission scanning electron microscopy
  • AFM atomic force microscopy
  • FESEM was carried out with JEOL JSM-7400 at a vacuum of 10 "8 torr and an accelerating voltage of 10 kV.
  • Transmission electron microscopy (TEM) experiments were performed on a JEOL JEM- 3010 electron microscope with an acceleration voltage of 300 kV.
  • the nitrogen sorption isotherms were obtained with a

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Abstract

Polymère thiophène ponté poly(3, 4-alkylène) (PABT) fonctionnalisé de formule (I), dans laquelle Ai est une chaîne alkylène de pontage; Y1 et Y2 J sont, indépendamment, O, S ou N-R2, R2 représentant hydrogène, un groupe alkyle, un groupe alcényle, un groupe alkynyle, un cycloalkyle, un aryle ou un hétérocycle; R1 i est une chaîne fonctionnelle liée à la chaîne alkylène de pontage. L'invention porte également sur un procédé de préparation associé et sur un procédé pour déposer des polymères PABT fonctionnalisés sur une matrice ou une nanoparticule support non conductrice. Ces polymères servent dans la préparation d'interfaces bio-nano.
PCT/SG2008/000412 2007-10-25 2008-10-24 Thiophène ponté poly(3, 4-alkylène) (pabt) fonctionnalisé WO2009054814A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US7708908B2 (en) * 2007-02-28 2010-05-04 The Regents Of The University Of Michigan Carboxylic acid-modified EDOT for bioconjugation
CN102584850A (zh) * 2011-12-30 2012-07-18 南京工业大学 3，4-乙撑二氧噻吩的合成方法
US8784690B2 (en) 2010-08-20 2014-07-22 Rhodia Operations Polymer compositions, polymer films, polymer gels, polymer foams, and electronic devices containing such films, gels and foams
JP2022504918A (ja) * 2018-10-10 2022-01-13 フレックソリューション ドデシル硫酸塩がドープされたポリ（３，４－エチレンジオキシチオフェン）フィルム及びその製造方法

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7708908B2 (en) * 2007-02-28 2010-05-04 The Regents Of The University Of Michigan Carboxylic acid-modified EDOT for bioconjugation
US8784690B2 (en) 2010-08-20 2014-07-22 Rhodia Operations Polymer compositions, polymer films, polymer gels, polymer foams, and electronic devices containing such films, gels and foams
US9378859B2 (en) 2010-08-20 2016-06-28 Rhodia Operations Polymer compositions, polymer films, polymer gels, polymer foams, and electronic devices containing such films, gels and foams
CN102584850A (zh) * 2011-12-30 2012-07-18 南京工业大学 3，4-乙撑二氧噻吩的合成方法
JP2022504918A (ja) * 2018-10-10 2022-01-13 フレックソリューション ドデシル硫酸塩がドープされたポリ（３，４－エチレンジオキシチオフェン）フィルム及びその製造方法
JP7148719B2 (ja) 2018-10-10 2022-10-05 フレックソリューション ドデシル硫酸塩がドープされたポリ（３，４－エチレンジオキシチオフェン）フィルム及びその製造方法

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