WO2007053181A2 - Nanoparticules modifiables chimiquement élaborées par chimie de coordination métal-métalloligand - Google Patents

Nanoparticules modifiables chimiquement élaborées par chimie de coordination métal-métalloligand Download PDF

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WO2007053181A2
WO2007053181A2 PCT/US2006/020966 US2006020966W WO2007053181A2 WO 2007053181 A2 WO2007053181 A2 WO 2007053181A2 US 2006020966 W US2006020966 W US 2006020966W WO 2007053181 A2 WO2007053181 A2 WO 2007053181A2
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colloidal
particles
analyte
particle
bmsb
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PCT/US2006/020966
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WO2007053181A3 (fr
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Chad A. Mirkin
Moonhyun Oh
Byung-Keun Oh
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Northwestern University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/04—Nickel compounds
    • C07F15/045—Nickel compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages

Definitions

  • Micro- and nano-sized particles play important roles in many different areas, including catalysis, optics, biosensing, and data storage. Recent advances in this field have made it possible to control many of the chemical and physical properties of these solid-state materials through control over their size, shape, and composition. (Peng, et al. Nature 404:59 (2000); Horn et al., Angew. Chem. Int. Ed. 40:4331 (2001); and Chen et al. Angew. Ckem. Int. Ed. 44:2589 (2005)).
  • One important goal in this area is an ability to intentionally interconvert different particle compositions and structures through chemistry that occurs throughout the particle structure, in addition to chemistry on its surface.
  • colloidal particles comprising metal-organic coordination polymers.
  • the colloidal particles are assembled from a coordination of a metal salt and bis- metallo-tridentate Schiff base (BMSB) building blocks.
  • BMSB bis- metallo-tridentate Schiff base
  • the colloidal particles of the present invention have a formula (I) or (II):
  • R 1 is independently selected from the group consisting of H, hydroxyl, C 1-8 alkyl, OC 1-8 alkyl, Ci -8 heteroalkyl, OC 1-8 heteroalkyl, P(R 2 ) 2 , ary ⁇ , heteroaryl;
  • R 2 is the same or different and is selected from aryl or heteroaryl;
  • R 3 is independently selected from the group consisting of H, hydroxyl, C 1-8 alkyl, OCi -8 alkyl, C 1-8 heteroalkyl, OC 1-8 heteroalkyl, P(R 2 ) 2 , aryl, heteroaryl;
  • M and M' are independently selected from the group consisting of Zn, Cu, Mn, Pb, Ni, Cd, Co, and Cr;
  • L is null or a ligand selected from the group consisting of pyridine, methanol, acetate, dimethylsulfoxide, dimethylformamide, acetone, water, chloride, fluoride, iodide,
  • a method of synthesizing the colloidal particles wherein a metal salt solution and BMSB are admixed, then a nonpolar solvent is added to the admixture.
  • a nonpolar solvent are pentane, diethyl ether, hexane, benzene, xylenes, cyclohexane, and toluene.
  • the nonpolar solvent is added rapidly to the mixture of metal salt and BMSB, and the resulting colloidal particles have a diameter of about 100 to less than 1 ⁇ m.
  • the nonpolar solvent is added slowly, and the resulting colloidal particles have a diameter of about 1 ⁇ m to about 5 ⁇ m.
  • a sample containing or suspected of containing an analyte of interest is mixed with (1) a magnetic microparticle (MMP) which is modified with a tag. on its surface that is specific for the analyte and (2) a colloidal particle of the present invention which is modified with a tag on its surface that is specific for the analyte.
  • MMP magnetic microparticle
  • a sandwich structure of MMP-analyte-colloidal particle results, and is isolated, e.g., using a magnet.
  • the sandwich structure then is dissolved in pyridine, and a fluorescence is measured. The fluorescence is correlated to the presence or concentration of the analyte of interest.
  • the colloidal particles comprise Zn.
  • FIG. 1 shows a schematic of the preparation of colloidal particles of the invention from metal salts and bis-metallo-tridentate Schiff base (BMSB) building blocks;
  • FIG. 2 shows images, of colloidal particles prepared by the disclosed methods and analyzed by (a) optical microscopy, (b) and (c) fluorescence microscopy, and (d) scanning electron microscopy (SEM) where the inset in (d) is a high-resolution zoom-in image of the colloidal particles;
  • FIG. 4 shows emission spectra (excitation wavelength of 420 nm) of Zn-BMSB-Zn particles where the ancillary ligands have been systematically changed to dimethyl sulfoxide (DMSO), pyridine, dimethylformamide, acetone, methanol, or water;
  • DMSO dimethyl sulfoxide
  • pyridine dimethylformamide
  • acetone acetone
  • methanol or water
  • FIG. 5 shows a schematic of selective cation exchange of disclosed colloidal particles, where mixture of a colloidal particle and a metal salt (M") allows for the exchange of the M' ion of the colloidal particle to the M" ion, while the M ion remains unaffected;
  • M metal salt
  • FIG. 6 shows the chemical transformation of Zn-BMSB-Zn colloidal particles to Cu-BMSB-Zn particles via cation exchange, where (a) shows both the optical microscopy (OM, top) and fluorescence microscopy (FM, bottom) images of the mixture at time 0, (b) is at time 1 minute, (c) time 5 minutes, and (d) at time 60 minutes, (e) is a photograph of Zn- BMSB-Zn (right) and Cu-BMSB-Zn (left), and (f) is an emission spectra obtained by exciting at 420 nm;
  • FIG. 7 shows SEM images of (a) Zn-BMSB-Zn and (b) Cu-BMSB-Zn, where the scale bars indicate 5 ⁇ m;
  • FIG. 8 shows OM and FM (inset) images of (a) Zn-BMSB-Zn, (b) Cu-BMSB-Zn, (c) Mn-BMSB-Zn, and (d) Pb-BMSB-Zn, and (e) and (f) are photographs of, from left to right, Zn-BMSB-Zn, Cu-BMSB-Zn, Mn-BMSB-Zn, and Pb-BMSB-Zn, where (f) in with UV-irradation, indicating that only Zn-BMSB-Zn is fluorescent;
  • FIG. 9 shows a schematic of an analyte detection method using the colloidal- particles disclosed herein where a capture DNA-modified magnetic probe is mixed with a target DNA and a fluorescent colloidal particle further modified with a capture DNA to form a "sandwich" of the magnetic probe-target DNA-colloidal particle (step 1) and then isolated using a magnetic field (step 2), and dissolved with pyridine to create an amplified fluorescence signal (step 3); and
  • FIG. 10 shows (a) fluorescence spectroscopy of solution of colloidal particles dissolved in pyridine as a function of target DNA concentration in PBS buffer, and (b) shows fluorescence intensity of the particles quantified by integration of the area of the spectra from 580 to 615 nm for target DNA concentrations from 5 aM to 50 fM.
  • colloidal particles of polymerized metal-ligand networks made by coordination-chemistry-induced assembly of metal ions and carboxylate functionalized bis-metallo-tridentate Schiff base (BMSB) building blocks (FIG. 1).
  • the colloidal particles are formed by the polymerization of the BMSB and metal, ions, and the size of the colloidal particles can be controlled by the manner in which the BMSB and metal ions are mixed together.
  • Colloidal particles of the present invention have a formula (I) or (II):
  • R 1 is independently selected from the group consisting of H, hydroxy!, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 heteroalkyl, OC 1-8 heteroalkyl, P(R 2 ) 2 , aryl, heteroaryl;
  • R 2 is the same or different and is selected from aryl or heteroaryl;
  • R 3 is independently selected from the group consisting of H, hydroxyl, C 1-8 alkyl, OC 1-8 alkyl, C 1-8 heteroalkyl, OC 1-8 heteroalkyl, P(R 2 ) 2 , aryl, heteroaryl;
  • M and M' are independently selected from the group consisting of Zn, Cu, Mn, Pb, Ni, Cd, Co, and Cr;
  • L is null or a ligand selected from the group consisting of pyridine, methanol, acetate, dimethylsulfoxide, dimethylformamide, acetone, water, chloride, fluoride, iodide, bromid
  • alkyl includes straight chained and branched hydrocarbon groups containing the indicated number of carbon atoms, such as methyl, ethyl, and straight chain and branched propyl and butyl groups.
  • the hydrocarbon group can contain up to 8 carbon atoms.
  • alkyl also encompasses alkyl groups which are optionally substituted with, e.g., one or more halogen atoms, one or more hydroxyl groups, or one or more thiol groups. Also encompassed by the term “alkyl” are cycloalkyl groups.
  • Cycloalkyl is defined as a cyclic C 3 -C 8 hydrocarbon group, e.g., cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl.
  • Heteroalkyl and “heterocycloalkyl” are defined similar to alkyl and cycloalkyl, except at least one heteroatom is present in the structure. Suitable heteroatoms include N, S, and O.
  • halo or halogen is defined herein to include fluorine, bromine, chlorine, and iodine.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2-chlorophenyl, 3-chloropheny.l, 4-chlorophenyl, 2- methylphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 4-nitrophenyl, and the like.
  • arylC 1-3 alkyl and “heteroarylC 1-3 alkyl” are defined as an aryl or heteroaryl group having a C 1-3 alkyl substituent.
  • heteroaryl is defined herein as a monocyclic or bicyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, like halo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio, alkylsulfinyl, and alkylsulfonyl.
  • heteroaryl groups include thienyl, furyl, pyridyl, oxazolyl, quinolyl, isoquinolyl, indolyl, triazolyl, isothiazolyl, isoxazolyl, imidizolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
  • hydroxy is defined as -OH.
  • alkoxy is defined as -OR, wherein R is alkyl.
  • Colloidal particles of the present invention have a diameter of about 100 nm to about 5 ⁇ m, which is dependent upon the manner in which the colloidal particles are prepared.
  • a nonpolar solvent such as, e.g., diethyl ether or pentane
  • the result is smaller diameter colloidal particles, while the slow addition of the nonpolar solvent results in larger diameter colloidal particles.
  • BMSB molecules can be prepared through known chemical techniques. One such technique is outlined in the following scheme for the formation of a specific, nonlimiting BMSB.
  • BMSBs can be prepared by altering the starting di-aldehyde, aromatic amine, and/or metal salt.
  • the BMSB is then used to prepare the colloidal particles of the present invention.
  • the BMSB building blocks are important components of the strategy for making the colloidal particles disclosed herein. They are readily polymerizable through their carboxylate groups and allow manipulation of the chemical and physical properties of the resulting colloidal particles in a systematic manner through choice of BMSB ligand, type of metallation, and ancillary ligands.
  • the BMSB is mixed with a metal * salt (such as, e.g., M' (OAc) 2 ) in a pyridine solution.
  • the metal of the BMSB may be the same or different from the metal salt used.
  • the colloidal particles are prepared by the addition, either fast (to form smaller diameter colloidal particles) or slow (to form larger diameter colloidal particles), of a nonpolar solvent.
  • the nonpolar solvent typically pentane or diethyl ether, affects the solubility of the forming colloidal particle.
  • the fast addition of the nonpolar solvent causes the forming colloidal particle to precipitate out of solution more quickly, and the resulting colloidal particles are therefore smaller in diameter.
  • Slow addition of the nonpolar solvent allows for the colloidal particles to grow in solution for a longer period of time before precipitating out of solution, and, therefore, have larger diameters than those produced from the fast addition of the nonpolar solvent.
  • the nonpolar solvent used also effects the size of the resulting colloidal particles.
  • Diethyl ether typically provides smaller diameter colloidal particles, whereas pentane provides larger diameter colloidal particles under the same conditions.
  • the fast addition of diethyl ether results in colloidal particles having a diameter of about 190 ⁇ 60 rnn
  • fast addition of pentane results in colloidal particles having a diameter of about 780 ⁇ 230 nm.
  • Slow addition of diethyl ether results in colloidal particles having a diameter of about 1.60 ⁇ 0.47 ⁇ m
  • slow addition of pentane results in colloidal particles having a diameter of about 5 ⁇ m.
  • colloidal particle diameter can be controlled through the appropriate choice of nonpolar solvent and rate of addition of the nonpolar solvent to the mixture of BMSB and metal salt.
  • the polarity of the solvent affects the solubility of the resulting colloidal particles and, therefore, their average size.
  • FIG. 2 When pentane is used as an initiation solvent instead of diethyl ether, larger spherical microp articles (5 ⁇ 3 ⁇ m) are formed (FIG. 2).
  • the growth of the particles under this set of conditions can be observed by taking aliquots at various stages and characterizing the particles by SEM and OM.
  • This set of experiments also provides some mechanistic insight into the particle growth process.
  • clusters of smaller particles are observable (FIG. 2 A and 2D). These structures slowly anneal into single particles having smoother surfaces (FIG.
  • the proposed mechanism of the formation of the structures is via a two step cluster-fusion growth process (FIG. 2E).
  • the first step is aggregation of several small particles to form large cluster particles.
  • the second step is intraparticle fusion, resulting in large uniform spherical particles. This can occur because of the reversible nature of the metal coordination chemistry, which allows the system to anneal into a smooth particle.
  • the cluster fusion step can involve a plurality of particles or only a few, depending upon conditions, and the ultimate size of the large spherical particles depends upon the number of smaller particles involved in the fusion process.
  • the phrase "rapid addition,” or interchangeably “fast addition,” means herein that the nonpolar solvent is added to the mixture at a rate of at least 1 mL/sec, preferably at least 3 mL/sec, and most preferably at least 5 mL/sec.
  • the phrase “slow addition” means herein that the nonpolar solvent is added to the mixture at a rate of less than 1 mL/sec, preferably less than 1 mL/min, and most preferably, less than 1 mL/hour.
  • nonpolar solvent means a solvent which is immiscible or only slightly miscible in pyridine.
  • solubility parameter a solvent which is immiscible or only slightly miscible in pyridine.
  • Solvents with solubility parameters ( ⁇ ) of less than 19.0 can be used in the methods disclosed herein, more preferably less than 18.0, and most preferably less than 16.0.
  • Pentane has a solubility parameter of 14.4
  • diethyl ether has a solubility parameter of 15.4
  • toluene a solubility parameter of 18.3.
  • Solubility parameters can be found in any chemistry handbook, such as, e.g., Barton, Handbook of Solubility Parameters, CRC Press (1983).
  • Other examples of nonpolar solvents include benzene, xylenes, hexanes, cyclohexane, amyl acetate, and the like.
  • the physical properties of the colloidal particles can be affected both by the manner in which they are synthesized, as. discussed above, but also by the ancillary ligand, L, of the colloidal particle.
  • the ancillary ligand of the colloidal particles can be changed by mixing the colloidal particle with various solvents. For example, a red toluene suspension of colloidal particles 3a (FIG. 1), (M and M' are Zn, L is pyridine, and the BMSB is a compound of formula (I), where R 1 is null) turns yellow when methanol is added. This color change is attributable to the replacement of the pyridine ligand on the Zn metal centers with methanol.
  • the solvent can be removed from this complex and the resulting powder redispersed in toluene having 10% dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • the yellow solution turns red due to the formation of a zinc-DMSO adduct.
  • the emission spectra of colloidal particles having Zn metal centers and various ancillary ligands is shown in FIG. 4, where the ancillary ligand is DMSO, DMF, acetone, methanol, pyridine, or water.
  • the ancillary ligand can be easily altered by simple addition of the appropriate small molecule, and is completely reversible, with the exception of pyridine which dissolves the colloidal particle into its BMSB and metal salt components.
  • an initiation solvent such as diethyl ether or pentane results in the spontaneous formation of spherical inorganic polymer particles 3 (FIG. 1).
  • These particles form via coordination of the carboxylate groups on the BMSB precursor with the metal ions supplied by the acetate salt, and the polymerization process is completely reversible as evidenced by the formation of the starting materials upon addition of excess pyridine.
  • Spherical microscale colloidal particles are formed, instead of a macroscopic polymeric material of other reported organometallic polymerizations, due to the slow diffusion of a nonpolar solvent in the pyridine solution of the BMSB and metal salt at room temperature.
  • the addition of diethyl ether or pentane to the polar (e.g., pyridine) precursor solution results in precipitation due to the low solubility of the particles in nonpolar media.
  • the resulting particles are stable in organic solvents (toluene, methanol, DMF and dimethyl sulfoxide (DMSO)), water, and in the dried state.
  • Optical microscopy (OM, FIG. IA), fluorescence microscopy (FM, FIG. 1, B and C), and scanning electron microscopy (SEM, FIG. ID) images of example compositions show the spherical particles with an average diameter of 1.6 ⁇ 1.2 ⁇ m.
  • the chemical composition of the particles was determined by energy dispersive X-ray spectroscopy (EDX) and elemental analysis.
  • EDX energy dispersive X-ray spectroscopy
  • Control experiments with a BMSB which does not contain a free carboxylate group (2d in FIG. 1) show that the coordination polymer and therefore colloidal particles as disclosed herein will not form in the absence of the carboxylate groups.
  • Colloidal particles of the present invention can be prepared with a variety of different metals, including Zn, Cu ⁇ Ni, Pd, and Mn, by the choice of starting metal salt and starting BMSB.
  • Spherical nanoparticles of Cu-BMSB-Cu 3b (FIG. 1) synthesized by fast addition of pentane into a precursor solution having Cu-BMSB 2b and Cu(OAc) 2 -(H 2 O) Ib in pyridine have diameters similar to Zn-BMSB-Zn particles prepared via analogous procedures. Slow diffusion of pentane into a precursor solution containing 2b and Ib yields particles that are on average significantly larger than the particles formed from the fast addition method.
  • Ni-BMSB 2c and Ni(OAc) 2 -4(H2O) Ic gives spherical particles Ni-BMSB-Ni 3c.
  • particle compositions of 3b and 3c are not fluorescent because they are not made of fluorescent BMSB building blocks.
  • the synthetic methods disclosed herein provide dispersible micro- and nano-scale particles having highly tailorable physical and chemical properties, which can be controlled through choice of polymerizing metal ion, such as Zn(II), Cu(II), or Ni(II), BMSB, and ancillary ligands. Because certain BMSB building blocks can be prepared in enantiopure form (such as, e.g., those based upon a bi-naphthyl ring system) and are important compounds in homogeneous catalysis, this new class of material has great potential in asymmetric catalysis and chiral separations.
  • the approach utilizes two different types of ions, ones coordinated to the tridentate pockets of the BMSB ligands and ones that link the BMSB ligands thorough the carboxylate groups to form the polymers.
  • Zn(II) is used as the metal ion, it can be readily displaced from the BMSB tridentate pockets, but not from the carboxylate sites with a variety of metal ions (FIG. 5).
  • the cation exchange reaction rate is size dependent. Particles of about 200 nm undergo Cu(II) exchange reaction in a few minutes as compared to the hour required to effect it with the micron-scale particles. Again, FM and OM images clearly show the transformation with a minimal change in particle size; the average particle sizes measured before (212 nm) and after the cation exchange reaction (215 nm) by dynamic light scattering (DLS) are nearly identical (FIG. 8A vs. FIG. 8B).
  • metal salts can be used to exchange with the metal M of formulae (I) or (II).
  • Mn(II), Pb(II), Ni(II), Co(II) and Cu(II) are examples of such suitable metal ions, but metal salts of other metals, or of the same metals but alternative oxidation states (such as, e.g., Mn(IV)) are also contemplated.
  • the associated anion of the metal salt is preferably one which is not strongly coordinated to the metal center and can be replaced by alternate coordinating groups, such as, e.g., Schiff bases of the BMSB ligand moieties.
  • Such anions include acetate, trifluoroacetate, halide, nitrate, perchlorate, phosphate, sulfate, triflate, and the like.
  • the BMSB-metal moiety is a well-known catalytic center, and the colloidal particles can be used as catalysts in the same manner as a typical Schiff base-metal complex can be used. See, for instance, Desimoni et al, Chem. Rev., 103(8): 3119 (2003) and McManus, et al., Chem. i?ev.,104(9): 4151 (2004), each of which is incorporated herein in its entirety.
  • the colloidal particles disclosed herein can be used in biological and chemical detection of analytes. Because the colloidal particles are composed of hundred or thousands of fluorescent monomers (such as, e.g., colloidal particles of Zn-BMSB-Zn), minute quantities of an analyte of interest can be detected. The fluorescence of the colloidal particle is amplified by the dissolution of the colloidal particle into its monomelic components. Concentrations as low as about 50 aM (10 "18 M) of analyte are detectable using the colloidal particles disclosed herein. (FIG. 10)
  • colloidal particles disclosed herein can be used in "sandwich” type assays.
  • assays include, but are not limited to, ELISA, immunoassays using antibody-antigen- antibody interactions, magnetic microparticle (MMP) sandwich assays, and the like, wherein one component of the sandwich assay is modified to incorporate a colloidal particle as disclosed herein.
  • MMP magnetic microparticle
  • a probe can be attached to the colloidal particle.
  • exemplary probes are antibodies, antigens, polynucleotides, oligonucleotides, receptors, ligands, and the like.
  • polynucleotide is used broadly herein to mean a sequence of deoxyribonucleotides or ribonucleotides that are linked together by a phosphodiester bond.
  • oligonucleotide is used herein to refer to a polynucleotide that is used as a primer or a probe.
  • an oligonucleotide useful as a probe or primer that selectively hybridizes to a selected nucleotide sequence is at least about 10 nucleotides in length, usually at least about 15 nucleotides in length, and for example between about 15 and about 50 nucleotides in length.
  • Polynucleotide probes are particularly useful for detecting complementary polynucleotides in a biological sample.
  • a polynucleotide can be RNA or can be DNA, which can be a gene or a portion thereof, a cDNA, a synthetic polydeoxyribonucleic acid sequence, or the like, and can be single stranded or double stranded, as well as a DNA/RNA hybrid.
  • a polynucleotide, including an oligonucleotide e.g., a probe or a primer
  • nucleotides comprising a polynucleotide are naturally occurring deoxyribonucleotides, such as adenine, cytosine, guanine or thymine linked to T- deoxyribose, or ribonucleotides such as adenine, cytosine, guanine or uracil linked to ribose.
  • a polynucleotide or oligonucleotide also can contain nucleotide analogs, including non-naturally occurring synthetic nucleotides or modified naturally occurring nucleotides.
  • the covalent bond linking the nucleotides of a polynucleotide generally is a phosphodiester bond.
  • the covalent bond also can be any of numerous other bonds, including a thiodiester bond, a phosphorothioate bond, a peptide-like amide bond or any other bond known to those in the art as useful for linking nucleotides to produce synthetic polynucleotides.
  • nucleotide analogs or bonds linking the nucleotides or analogs can be particularly useful where the polynucleotide is to be exposed to an environment that can contain a nucleolytic activity, including, for example, a tissue culture medium or upon administration to a living subject, since the modified polynucleotides can be less susceptible to degradation.
  • selective hybridization or selectively hybridize refers to hybridization under moderately stringent or highly stringent conditions such that a nucleotide sequence preferentially associates with a selected nucleotide sequence over unrelated nucleotide sequences to a large enough extent to be useful in identifying the selected nucleotide sequence.
  • non-specific hybridization can occur, but is acceptable provided that hybridization to a target nucleotide sequence is sufficiently selective such that it can be distinguished over the non-specific cross- hybridization, for example, at least about 2-fold more selective, generally at least about 3.-fold more selective, usually at least about 5-fold more selective, and particularly at least about 10- fold more selective, as determined, for example, by an amount of labeled oligonucleotide that binds to target nucleic acid molecule as compared to a nucleic acid molecule other than the target molecule, particularly a substantially similar or homologous nucleic acid molecule other than the target nucleic acid molecule.
  • Conditions that allow for selective hybridization can be determined empirically, or can be estimated based, for example, on the relative GC: AT content of the hybridizing oligonucleotide and the sequence to which it is to hybridize, the length of the hybridizing oligonucleotide, and the number, if any, of mismatches between the oligonucleotide and sequence to which it is to hybridize.
  • An example of progressively higher stringency conditions is as follows: 2 x SSC / 0.1% SDS at about room temperature (hybridization conditions); 0.2 x SSC / 0.1% SDS at about room temperature (low stringency conditions); 0.2 x SSC / 0.1% SDS at about 42°C (moderate stringency conditions); and 0.1 x SSC at about 68°C. (high stringency conditions). Washing can be carried out using only one of these conditions, for example, high stringency conditions, or each of the conditions can be used, for example, for 10-15 minutes each, in the order listed above, repeating any or all of the steps listed. However, as mentioned above, optimal conditions will vary, depending on the particular hybridization reaction involved, and can be determined empirically.
  • the colloidal particles can include an antibody probe.
  • antibody is used in its broadest sense to include polyclonal and monoclonal antibodies, as well as antigen binding fragments of such antibodies.
  • An antibody useful in a method of the invention, or an antigen binding fragment thereof, is characterized, for example, by having specific binding activity for an epitope of an analyte.
  • an antibody can be detected using these antibody probe-modified colloidal particles.
  • the antibodies which can be detected include naturally occurring antibodies as well as non-naturally occurring antibodies, including, for example, single chain antibodies, chimeric, bifunctional and humanized antibodies, as well as antigen-binding fragments thereof.
  • non-naturally occurring antibodies can be constructed using solid phase peptide synthesis, can be produced recombinantly or can be obtained, for example, by screening combinatorial libraries consisting of variable heavy chains and variable light chains.
  • the term binds specifically or specific binding activity, when used in reference to an antibody means that an interaction of the antibody and a particular epitope has a dissociation constant of at least about 1 x 10 ⁇ 6 , generally at least about 1 x 1(J 7 , usually at least about 1 x 10 "8 , and particularly at least about 1 x 10 "9 or 1 x lO "10 or less.
  • Fab, F(ab')2, Fd and Fv fragments of an antibody that retain specific binding activity for an epitope of an antigen are included within the definition of an antibody.
  • the analyte detection methods disclosed herein can be performed, for example, by traditional sandwich assays known in the art. Such assays are described, for instance, in U.S. Patent 5,637,508; 5,639,626; 5,710,006; 6,096,563; 6,544,776; 6,686,208; and 6,670,115, each of which is incorporated herein by reference in its entirety.
  • the detection of the analyte in a sample can be performed by contacting a sample containing an analyte with a colloidal particle of the present invention which is modified to include a probe, wherein the probe binds to the analyte; and further contacting the sample with another probe which also binds to the analyte, wherein this second probe allows for the removal of the bound analyte from the sample, through, e.g., immobilization, magnetic separation, and the like.
  • the bound colloidal particle then, can be redissolved in pyridine and the fluorescence signal measured, wherein the fluorescence signal is indicative of the presence and/or concentration of the analyte in the sample. This amplification of fluorescence is such that very low levels of analyte can be detected.
  • analyte means any molecule or compound.
  • An analyte can be in the solid, liquid, gaseous or vapor phase.
  • gaseous or vapor phase analyte is meant a molecule or compound that is present, for example, in the headspace of a liquid, in ambient air, in a breath sample, in a gas, or as a contaminant in any of the foregoing. It will be recognized that the physical state of the gas or vapor phase can be changed by pressure, temperature as well as by affecting surface tension of a liquid by, for example, the presence of or addition of salts.
  • analyte detect binding of an analyte to a probe.
  • the analyte can be comprised of a member of a specific binding pair (sbp) and maybe a ligand, which is monovalent (monoepitopic) or polyvalent (polyepitopic), usually antigenic or haptenic, and is a single compound or plurality of compounds which share at least one common epitopic or determinant site.
  • the analyte can be a part of a cell such as bacteria or a cell bearing a blood group antigen such as A, B, D, etc., or an HLA antigen or a microorganism, e.g., bacterium, fungus, protozoan, or virus. In some cases, the analyte is charged.
  • a member of a specific binding pair is one of two different molecules, having an area on the surface or in a cavity which specifically binds to and is thereby defined as complementary with a particular spatial and polar organization of the other molecule.
  • the members of the specific binding pair are referred to as ligand and receptor (antiligand) or analyte and probe. Therefore, a probe is a molecule that specifically binds an analyte.
  • immunological pair such as antigen-antibody
  • specific binding pairs such as biotin-avidin, protein-lectin, hormones-hormone receptors, nucleic acid duplexes, IgG-protein A, polynucleotide pairs such as DNA-DNA, DNA-RNA, and the like are not immunological pairs but are included in the invention and the definition of sbp member.
  • Specific binding is the specific recognition of one of two different molecules for the other compared to substantially less recognition of other molecules.
  • the molecules have areas on their surfaces or in cavities giving rise to specific recognition between the two molecules.
  • Exemplary of specific binding are antibody-antigen interactions, enzyme- substrate interactions, polynucleotide hybridization interactions, and so forth.
  • Non-specific binding is non-covalent binding between molecules that is relatively independent of specific surface structures. Non-specific binding may result from several factors including hydrophobic interactions between molecules.
  • the colloidal particles of the present invention can be used to detect the presence of a particular target analyte, for example, a nucleic acid, oligonucleotide, protein, enzyme, antibody, or antigen.
  • the colloidal particles can also be used to screen bioactive agents, such as, for example, drug candidates, for binding, to a particular target or to detect agents like pollutants.
  • bioactive agents such as, for example, drug candidates, for binding, to a particular target or to detect agents like pollutants.
  • any analyte for which a probe moiety, such as a peptide, protein, oligonucleotide or aptamer, may be designed can be used in combination with the disclosed colloidal particles.
  • analytes include poly(amino acids), such as for example, polypeptides and proteins, polysaccharides, hormones, nucleic acids, and combinations thereof.
  • poly(amino acids) such as for example, polypeptides and proteins, polysaccharides, hormones, nucleic acids, and combinations thereof.
  • combinations include components of bacteria, viruses, prions, cells, chromosomes, genes, mitochondria, nuclei, cell membranes and the like.
  • Additional possible analytes include drugs, metabolites, pesticides, pollutants, and the like. Included among drugs of interest are the alkaloids.
  • alkaloids include morphine alkaloids, which includes morphine, codeine, heroin, dextromethorphan, their derivatives and metabolites; ***e alkaloids, which include ***e and benzyl ecgonine, their derivatives and metabolites; ergot alkaloids, which include the diethylamide of lysergic acid; steroid alkaloids; iminazoyl alkaloids; quinazoline alkaloids; isoquinoline alkaloids; quinoline alkaloids, which include quinine and quinidine; diterpene alkaloids, their derivatives and metabolites.
  • analyte further includes polynucleotide analytes such as those polynucleotides defined below. These include, for example, m-RNA, r-RNA, t-RNA, DNA, and DNA-RNA duplexes.
  • the term analyte also includes receptors that are polynucleotide binding agents, such as, for example, peptide nucleic acids (PNA), restriction enzymes, activators, repressors, nucleases, polymerases, histones, repair enzymes, chemotherapeutic agents, and the like.
  • PNA peptide nucleic acids
  • the analyte may be a molecule found directly in a sample such as a body fluid from a host.
  • the sample can be examined directly or may be pretreated to render the analyte more readily detectible.
  • the analyte of interest may be determined by detecting an agent probative of the analyte of interest such as a specific binding pair member complementary to the analyte of interest, whose presence will be detected only when the analyte of interest is present in a sample.
  • the agent probative of the analyte becomes the analyte that is detected in an assay.
  • the body fluid can be, for example, urine, blood, plasma, serum, saliva, semen, stool, sputum, cerebral spinal fluid, tears, mucus, and the like.
  • probes can be attached to colloidal particles through attachment via surface carboxylate moieties of the colloidal particle.
  • colloidal particles may be coupled with probes through biotin-avidin linkages.
  • avidin or streptavidin (or an analog thereof) can be covalently attached to the surface of the colloidal particles through one or more available carboxylate moieties a and a biotin-modified probe contacted with the avidin or streptavidin-niodified surface forming a biotin-avidin (or biotin- streptavidin) linkage.
  • avidin or streptavidin may be attached in combination with another protein, such as BSA, and optionally be crosslinked.
  • Probes having an amine, hydroxyl, or carboxylic acid functional group can be attached through water-soluble carbodiimide coupling reagents, such as EDC (l-ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide), or other coupling agents well known in the art, which couples carboxylic acid functional groups with amine groups, hydroxyl groups, and/or other carboxylic acid functional groups.
  • EDC l-ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide
  • Nucleotides attached to a variety of functional groups may be commercially obtained (for example, from Molecular Probes, Eugene, Oreg.; Quiagen (Operon), Valencia, Calif.; and IDT (Integrated DNA Technologies), Coralville, Iowa) and incorporated into oligonucleotides or polynucleotides.
  • Biotin-modified nucleotides are commercially available (for example, from Pierce Biotechnology, Rockford, 111., or Panomics, Inc. Redwood City, Calif.) and modified nucleotides can be incorporated into nucleic acids during conventional amplification techniques.
  • Oligonucleotides may be prepared using commercially available oligonucleotide synthesizers (for example, Applied Biosystems, Foster City, Calif). Additionally, modified nucleotides may be synthesized using known reactions, such as for example, those disclosed in, Nelson, P., Sherman-Gold, R, and Leon, R, "A New and Versatile Reagent for Incorporating Multiple Primary Aliphatic Amines into Synthetic Oligonucleotides," Nucleic Acids Res., 17:7179-7186 (1989) and Connolly, B., Rider, P.
  • nucleotide precursors may be purchased containing various reactive groups, - such as biotin, hydroxyl, sulfhydryl, amino, or carboxyl groups.
  • colloidal particles may be attached using standard chemistries.
  • Oligonucleotides of any desired sequence, with or without reactive groups for colloidal particle attachment may also be purchased from a wide variety of sources (for example, Midland Certified Reagents, Midland, Tex.).
  • Probes such as polysaccharides
  • colloidal particles for example, through methods disclosed in Aslam, M. and Dent, A., Bioconjugation: Protein Coupling Techniques for the Biomedical Sciences, Grove's Dictionaries, Inc., 229, 254 (1998). Such methods include, but are not limited to, periodate oxidation coupling reactions and bis-succinimide ester coupling reactions.
  • colloidal particle-labeled antibodies i.e., antibodies bound to a colloidal particle
  • colloidal particle-labeled antibodies are used to detect interaction of the colloidal particle-labeled antibodies with antigens.
  • immunoassays can be performed using known methods such as, for example, ELISA assays, Western blotting, or protein arrays, utilizing the colloidal particle-labeled antibody or colloidal particle-labeled secondary antibody, in place of a primary or secondary antibody labeled with an enzyme or a radioactive compound.
  • Another group of exemplary methods uses colloidal particle probes to detect a target nucleic acid. Such a method is useful, for example, for detection of infectious agents within a clinical sample, detection of an amplification product derived from genomic DNA or RNA or message RNA, or detection of a gene (cDNA) insert within a clone.
  • an oligonucleotide probe is synthesized using methods known in the art. The oligonucleotide probe then is used to functionalize a colloidal particle to produce a colloidal particle-labeled oligonucleotide probe.
  • the colloidal particle-labeled oligonucleotide probe is used in a hybridization reaction to detect specific binding of the colloidal particle-labeled oligonucleotide probe to a target polynucleotide.
  • the colloidal particle-labeled oligonucleotide probe can be used in a Northern blot or a Southern blot reaction.
  • the colloidal particle-labeled oligonucleotide probe can be applied to a reaction mixture that includes the target polynucleotide associated with a solid support, to capture the colloidal particle-labeled oligonucleotide probe.
  • the captured colloidal particle-labeled oligonucleotide probe can then be detected using fluorescence spectroscopy, with or without first being released from the solid-support. Detection of the captured colloidal particle-labeled oligonucleotide probe can be amplified by first dissolving the isolated hybridized entity, wherein the monomelic BMSB are released into solution. Because the fluorescence particles used in this method are composed of a huge number of fluorescence molecules (e.g., Zn-BMSB), the approach allows for detection of small amounts of target analyte, down to about 5 aM (10 "18 M).
  • a sample includes a wide variety of analytes that can be analyzed using the colloidal particles described herein.
  • a sample can be an environmental sample and includes atmospheric air, ambient air, water, sludge, soil, and the like.
  • a sample can be a biological sample, including, for example, a subject's breath, saliva, blood, urine, feces, various tissues, and the like.
  • colloidal particles described herein Commercial applications for the invention methods employing the colloidal particles described herein include environmental toxicology and remediation, biomedicine, materials quality control, monitoring of food and agricultural products for the presence of ⁇ pathogens, anesthetic detection, automobile oil or radiator fluid monitoring, breath alcohol analyzers, hazardous spill identification, explosives detection, fugitive emission identification, medical diagnostics, fish freshness, detection and classification of bacteria and microorganisms both in vitro and in vivo for biomedical uses and medical diagnostic uses, monitoring heavy industrial manufacturing, ambient air monitoring, worker protection, emissions control, product quality testing, leak detection and identification, oil/gas petrochemical applications, combustible gas detection, H 2 S monitoring, hazardous leak detection and identification, emergency response and law enforcement applications, illegal substance detection and identification, arson investigation, enclosed space surveillance, utility and power applications, emissions monitoring, transformer fault detection, food/beverage/agriculture applications, freshness detection, fruit ripening control, fermentation process monitoring and control applications, flavor composition and identification, product quality and identification, refrigerant and fumigant
  • Another application for the sensor-based fluid detection device in engine fluids is an oil/antifreeze monitor, engine diagnostics for air/fuel optimization, diesel fuel quality, volatile organic carbon measurement (VOC), fugitive gases in refineries,, food quality, halitosis, soil and water contaminants, air quality monitoring, fire safety, chemical weapons identification, use by hazardous material teams, explosive detection, breathalyzers, ethylene oxide or anesthetics detectors.
  • VOC volatile organic carbon measurement
  • Solvents and all other chemicals were obtained from commercial sources and used as received unless otherwise noted. AU deuterated solvents were purchased and used as received from Cambridge Isotopes Laboratories. 1 H and 13 C NMR spectra were obtained using a Varian Mercury 300 MHz or a Varian INOVA 400 MHz FT-NMR spectrometers. Infrared spectra of solid samples were obtained on a Thermo Nicolet Nexus 670 FT-IR spectrometer as KBr pellet. Diffuse reflectance spectra were obtained on a Varian Gary 5000 UV-Vis-NIR spectrophotometer.
  • Emission spectra were obtained on a Jobin Yvon SPEX Fluorolog fiuorometer using quartz cells (10 x 4 mm light path).
  • Electrospray ionization mass spectrometric (ESI-MS) spectra were obtained on a Micromass Quatro II Triple Quadrupole mass spectrometer, and all peaks are cosnsitent with a natural abundance isotopic distribution patterns. Elemental analyses were obtained from Quantitative Technologies Inc., Whitehouse, NJ.
  • Zn-BMSB 2a BSB SIa, synthesized as decribed above, (5 mg, 0.008 mmol) and Zn(OAc) 2 (3 mg, 0.016 mmol) were mixed in DMF (3 mL). The color of the solution changed immediately from yellow to red. Diethyl ether was added to precipitate the product as an orange powder (84% yield). The precipitate product was separated from supernatant and washed with diethyl ether (84% yield).
  • IR (KBr pellet, cm 4 ): 1659s, 1609s, 1588s, 1539w, 1506w, 1491m, 1425m, 1383s, 1339m, 1298m, 1223w, 1198w, 1173w, 1151w, 1121m, 1104m, 1061w, 1044w, 1024w, 958m, 898w, 843m, 788m, 748m, 663m, 478w.
  • Cu-BMSB 2b 2b was prepared using the same method as for 2a, except Cu(OAb) 2 (H 2 O) was used instead OfZn(OAc) 2 . A brown powder was obtained in 86% yield.
  • IR (KBr pellet, cm “1 ): 1653s, 1604s, 1585s, 1539w, 1522w, 1491m, 1427m, 1386s, 1369s, 1340m, 13Q6m, 126Ow, 1225w, 1194w, 1173w, 115Ow, 1123m, 1102m, 106 Iw, 1044w, 1023w, 956m, 898w, 846m, 784m, 748m, 666m, 506w, 481 w.
  • X-ray crystal structure determination of 2b A dark tabular crystal was mounted using oil on a glass fiber. Diffraction intensity data were collected with a Bruker SMART- 1000 CCD diffractometer equipped with a graphite-monochromated Mo Ka radiation source. The data collected were processed to produce conventional intensity data by the program SAINT-NT (Bruker). The intensity data were corrected for Lorentz and polarization effects. Absorption corrections were applied using the SADABS empirical method. The structures were solved by direct methods, completed by subsequent difference Fourier syntheses and refined by full matrix least-squares procedures, on F 2 . The disordered methanol was refined with a group anisotropic displacement parameter ⁇ and occupancies adding to fully occupied.
  • the remaining non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in idealized positions, except those on the disordered and partially occupied methanol, and the hydrogen atom on 05 (methanol), but not refined. The DMF was fixed to 1 A occupied. All software and sources of scattering factors are contained in the SHELXTL program package (version 5.10, G. Sheldrick, Bruker- AXS, Madison, WI).
  • Ni-BMSB 2c 2c was prepared using the same method as for 2a, except Ni(OAc) 2 -4(H 2 O) was used instead OfZn(OAc) 2 . A red powder was obtained in 82% yield.
  • ESI-MS m/z, pyridine/CH 2 Cl 2 ): calcd for [SIa - 4H + + 2Ni 2+ + 2 pyridine + H + J + , 883.1; found, 882.8.
  • IR (KBr pellet, cm “1 ): 1655s, 1608s, 1584s, 1545w, 1491m, 1419m, 1387s, 1339m, 1304m, 1263w, 1226w, 1193w, 1173w, 1151w, 1119m, 1104m, 1061w, 1048w, 1026w, 960m, 901 w, 841m, 786m, 749m, 668m, 517w, 479w.
  • 2d was. prepared using the same method as for 2a, except BSB SIb was used instead of BSB SIa. An orange powder was obtained in 81% yield.
  • the electrospray ionization mass spectra of 3b and 3c exhibit intense peaks associated with the metal-metalloligand repeat units, [2b - 2H + + Cu 2+ + (pyridine),, + H + J + and [2c - 2H + + Ni 2+ + (pyridine),, + H + ] + .
  • the NMR spectra of 3b and 3c were not informative because of the paramagnetic nature of these complexes, and the mass spectrum of 3a did not yield a monomer ion.
  • the measurement of Zeta potential of these particles reveals that particles are negatively charged (-12 mV), which is a result of the deprotonated carboxylate groups located on their surfaces.
  • Ancillary Iigands exchange reactions The 1 H NMR spectra of the methanol- ⁇ and OMSO-d ⁇ suspension of spherical particles 3a with ancillary Iigands L of pyridine and methanol respectively, show the peaks for free pyridine and methanol molecules, which are released from the metal upon replacement with methanol- ⁇ and OMSO-dg, respectively.
  • IR (KBr pellet, cm “1 ): 1605s, 1591sh, 1539m, 1506w, 1489w, 1465w, 1448m, 1425w, 1375s, 1341m, 1327m, 1299m, 1217m, 1194w, 1171w, 1148m, 1121m, 1069m, 1042m, 1015w, 955w, 894w, 842m, 787m, 749m, 698m, 663m, 636m, 478w, 419w.
  • Cu-BMSB-Cu 3b ESI-MS (m/z, pyridme/CH 2 Cl 2 ): calcd for [SIa - 6H + + 3Cu 2+ + 3 pyridine + H + J + , 1033.0; found, 1032.7, calcd for [SIa - 6H + + 3Cu 2+ + 2 pyridine + H + ] + , 954.0; found, 954.0.
  • IR (KBr pellet, cm “1 ): 1602s, 1589sh, 1539m, 1507w, 149Ow, 1466w, 1449m, 1425w, 1369s, 1342m, 1325m, 1262w, 1217m, 119Ow, 1172w, 1148m, 1124m, 1069m, 1043m, 1017w, 955w, 897w, 846m, 783m, 748m, 696m, 671m, 639m, 504w, 479w, 419w.
  • Ni-BMSB-Ni 3c ESI-MS (m/z, pyridine/CH 2 Cl 2 ): calcd for [SIa - 6H + + 3Ni 2+ + 4 pyridine + H + ] + , 1097.1; found, 1097.0.
  • IR (KBr pellet, cm '1 ): 1597s, 1589sh, 1542m, 1507w, 1497w, 1465w, 1448m, 1429w, 1385s, 1369m, 1343m, 1324m, 1269w, 1217m, 1192w, 1172w, 1149m, 1125m, 1070m, 1042m, 1017w, 951w, 897w, 856m, 786m, 757m, 693m, 639w, 516w, 494w, 419w.
  • FIG. 9 shows a schematic of the structures of both the MMP and the colloidal particles.
  • Fluorescence Amplification Based Bioassay for DNA The fluorescence amplification based bioassay method was tested with oligonucleotide associated with the anthrax lethal factor (5'-GGA TTA TTG TTA AAT ATT GAT AAG GAT-3') (SEQ. ID. NO: 3) in 0.3 M PBS buffer containing 0.025% Tween 20 as a target over a range of 5 aM (10 "18 ) to 50 fM (10 "15 M).
  • a sample solution (50 ⁇ L) with a set of target DNA concentration was added to a 50 ⁇ L of MMP probes functionalized with a single-strand DNA (SEQ.
  • SEQ. ID NO: 1 to capture the target DNA, and the solution was shaken on an orbital shaker at 50° C for 15 minutes and at 20°C for 45 minutes.
  • the fluorescence particles functionalized with a single-strand DNA (SEQ. ID NO: 2) to form a sandwich structure with the MMP probes that have captured the target DNA (e.g., SEQ. ID NO: 3) were then added to the solution. This solution was vigorously stirred at 20° C for 2 hours.
  • the magnetic separator was used to concentrate both unreacted magnetic particles and magenetic particles which captured the target DNA and fluorescence colloidal particles. These particles were vigorously washed six times with 0.3 M PBS buffer containing 0.025% Tween 20 to remove any unreacted fluorescence colloidal particles.

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Abstract

La présente invention concerne des particules colloïdales de polymères de coordination infinis. La présente invention concerne également des méthodes de synthèse des particules colloïdales et des méthodes de détection d'analytes biologiques et chimiques en utilisant lesdites particules colloïdales.
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WO2009133229A1 (fr) 2008-04-29 2009-11-05 Consejo Superior De Investigaciones Científicas Système organométallique d'encapsulation et de libération de composés d'intérêt, procédé d'obtention et ses applications
EP2287611A1 (fr) * 2009-07-31 2011-02-23 Fujifilm Corporation Procédé de détection et particule diélectrique contenant un matériau magnétique utilisé par le procédé de détection
US8456158B2 (en) 2009-07-31 2013-06-04 Fujifilm Corporation Detecting method and dielectric particles containing magnetic material employed in the detecting method
CN103323443A (zh) * 2013-07-11 2013-09-25 中国科学院化学研究所 一种具有可视化酒精度传感功能的无限配位聚合物的应用
CN103323443B (zh) * 2013-07-11 2015-11-11 中国科学院化学研究所 一种具有可视化酒精度传感功能的无限配位聚合物的应用
JP2015038052A (ja) * 2013-08-19 2015-02-26 国立大学法人 千葉大学 ビナフトール骨格を有するビスアミノイミン配位子及び触媒
US11452967B2 (en) 2017-07-17 2022-09-27 Zymergen Inc. Metal-organic framework materials
CN107602413A (zh) * 2017-09-13 2018-01-19 哈尔滨理工大学 Binol‑diform缩邻氨基苯酚类席夫碱及其合成方法与应用
CN107602413B (zh) * 2017-09-13 2019-08-20 哈尔滨理工大学 Binol-diform缩邻氨基苯酚类席夫碱及其合成方法与应用
CN110938232A (zh) * 2019-08-26 2020-03-31 兰州理工大学 具有希夫碱结构的金属离子阻燃络合物及制备方法
CN110938232B (zh) * 2019-08-26 2021-06-01 兰州理工大学 具有希夫碱结构的金属离子阻燃络合物及制备方法
WO2023008352A1 (fr) * 2021-07-29 2023-02-02 富士フイルム株式会社 Composition colorante, film, filtre optique, élément d'imagerie à l'état solide, dispositif d'affichage d'images, et multimère de pigment

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