CN101421623A - Nanostructured, its manufacture method and its using method of biological conjugation - Google Patents

Nanostructured, its manufacture method and its using method of biological conjugation Download PDF

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CN101421623A
CN101421623A CN 200480041964 CN200480041964A CN101421623A CN 101421623 A CN101421623 A CN 101421623A CN 200480041964 CN200480041964 CN 200480041964 CN 200480041964 A CN200480041964 A CN 200480041964A CN 101421623 A CN101421623 A CN 101421623A
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nanostructured
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amphipathic
styrene
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聂淑明
高晓虎
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Emory University
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Abstract

Disclose nanostructured, prepared the method for nanostructured, in the experimenter, detected the method for target and the method for treatment experimenter disease.An embodiment of nanostructured comprises a quantum dot and a hydrophobic protection structure.Hydrophobic protection structure comprises a kind of cap part and amphipathic multipolymer of adding, the sub-point of wherein hydrophobic protection structure package amount, and the present invention also has other embodiment certainly.

Description

Nanostructured, its manufacture method and its using method of biological conjugation
Mutual reference to related application
The application's statement is the right of priority of the U.S. Provisional Patent Application sequence number 60/532,028 of " nanostructured of biological conjugation, its manufacture method and its using method " to the exercise question of submitting on Dec 22nd, 2003, and it is incorporated herein by reference at this in full.
Invention field
The disclosure is usually directed to nanostructured, relates more specifically to the nanostructured of biological conjugation.
Background of invention
Recent progress shows, the semiconductive particles of nano-scale can the covalent bond biological identification molecule, such as peptide, antibody, nucleic acid or micromolecule part to use as fluorescence probe.Group compares with organic fluorescence.These quantum limit particulates or quantum dot (QD) show unique optics and electrical characteristics, such as the adjustable fluorescent emission of size and composition as seen to infrared wavelength, absorption coefficient and the very high-caliber brightness and the photostability of crossing over wide spectral range.Because their wide excitation spectrum and narrow/symmetrical emission spectrum, high-quality QD is also fine to be suitable for the light multipath transmission, wherein unites many colors and intensity with encoding gene, albumen and micromolecule storehouse.
Therefore, it is significances to many research fields that exploitation surpasses the organic dyestuff and the high sensitive of fluorescin inherent limitations and the probe of high specific, acquires molecular imaging and medical diagnosis from molecule and cell biological.
Brief summary of the invention
Say that briefly embodiment of the present disclosure comprises nanostructured, prepares the method for nanostructured, the method for target that detects the experimenter and the method for treatment experimenter disease, the present invention also has other embodiment certainly.A kind of embodiment of nanostructured comprises quantum dot and hydrophobic protection structure, and the present invention also has other embodiment certainly.Hydrophobic protection structure comprises a kind of cap part and amphipathic multipolymer of adding, the sub-point of wherein hydrophobic protection structure package amount.
Another embodiment of nanostructured comprises at least a nano-substance and hydrophobic protection structure.Hydrophobic protection structure comprises at least a compound, and this compound is selected from and adds cap part, amphipathic multipolymer and its combination, and wherein hydrophobic protection structure bag is by nano-substance.
A kind of embodiment for preparing a kind of method of nanostructured comprises: a kind of nano-substance is provided; Form the hydrophobic protection structure around nano-substance, it comprises and is selected from least a compound that adds cap part, amphipathic multipolymer and its combination that the present invention also has other embodiment certainly.
A kind of embodiment of the method for detection experimenter's target comprises: above-mentioned a kind of nanostructured is provided, it has a kind of biocompatible compound of general alignment at hydrophobic protection body structure surface, with at least a probe of general alignment at hydrophobic protection body structure surface, wherein first probe has the affinity to target; Guide nanostructured into experimenter; And determine by detecting nano-substance among the experimenter that the present invention also has other embodiment certainly corresponding to the existence of the target of probe.
A kind of embodiment of the method for a kind of disease of treatment experimenter comprises a kind of nanostructured that provides above-mentioned, it has a kind of biocompatible compound of general alignment at hydrophobic protection body structure surface, with at least a probe of general alignment at hydrophobic protection body structure surface, wherein first probe has the affinity to target; Guide nanostructured into need this disease of treatment experimenter, the present invention also has other embodiment certainly.
Description of drawings
Further aspect of the present disclosure is easier to understand in the time of will combining by its each following embodiment of description and with accompanying drawing.
Fig. 1 represents model's embodiment of nanostructured.
Fig. 2 A to 2D represents to form model's method of nanostructured shown in Figure 1.
Fig. 3 A represents to be used for the signal of the quantum dot of the biological conjugation of cancer target and imaging in the body.
Fig. 3 B represents to have the chemical modification of the triblock copolymer of 8-carbon side chain.
Fig. 3 C represents to be permeated and retained the QD probe by seepage tumor vascular system (passive target), and the QD-antibodies of high-affinity combination is in tumour antigen (initiatively target).
Fig. 4 is illustrated in the prostate gland cancer cell of cultivation immunocytochemical study QD-PSMA antibody (Ab) in conjunction with active.The plate on top is represented bright-field and fluorescence imaging that the C4-2 cell of the PSMA-positive is obtained, as by existing the QD-PSMA-Ab compound to be disclosed on the cell surface.Middle plate is illustrated in the negative staining of the C4-2 cell detection that is exposed to QD-PEG and does not have PSMA-Ab.The plate of bottom is illustrated in observed negative staining in the PC-3 cell that lacks the PSMA expression.
Fig. 5 A and 5B represent the QD picked-up in the 6 kinds of different normal host organs (Fig. 5 A) and C4-2 tumour (Fig. 5 B) heterograft in the athymic nude mouse of histological examination, retain and distribute.QD picked-up and retain by use a left side, in and three kinds of finishinges of right row indication and estimating.At left column, QD is by surperficial hydroxy-acid group bag quilt (6.0nmol and 6hrs circulation).At middle row, QD is by PEG group pan coating (6.0nmol and 24hrs circulation).At right side row, QD is by PEG finishing and biological conjugation PSMA antibody (0.4nmol and 2hrs circulation).Left column is the same with middle row, except the amount of QD injection all is reduced to 0.4nmol and circulation is reduced to 2 hours.All images is all from the 5-10 μ m thin tissue section on the incident fluorescence microscope.All tumours have similar size, are measured as along the about 0.5-1cm of major axis.QD by its distinctive red-fluorescent orange detects, all other signals all are because the background autofluorescence.
Fig. 6 A to 6D represents to include the light spectrum image-forming of QD-PSMA Ab bond in the heteroplastic live animal of C4-2 tumour.Orange-red fluorescence signal indication tumor of prostate (Fig. 6 B and 6D) of in the mouse that lives, growing.Use the comparative study of healthy mice (no tumour) and same amount QD injection to represent there is not local fluorescence signal (Fig. 6 A and 6C).Fig. 6 A is an original image; Fig. 6 B is the autofluorescence image of non-mixing; Fig. 6 C is the QD image of non-mixing; Fig. 6 D is the image of stack.In vivo after the imaging, histology and immunocytochemistry inspection confirm that the QD signal is from below tumour.
Fig. 7 represents to use fluoroscopic image in the body of the mouse that has tumour that has the QD probe that three kinds of different surfaces modify: hydroxy-acid group (left side), PEG group (in) and PEG-PSMA Ab bond (right side).For every kind of finishing, the mouse alive of the C4-2 human benign prostatic tumour of onesize from having (diameter 0.5-1.0cm) obtains coloured image (top), from QD and zoodermic two kinds of fluorescence spectrums (middle part) and spectrally resolved image (bottom).Amount and the round-robin length of injection QD were: to COOH probe 6nmol and 6 hours; To PEG probe 6nmol and 24 hours; To PSMA probe 0.4nmol and 2 hours (with identical among Fig. 4).The site of observing the QD injection on mousetail is red point.In the about spectral signature (QD curve, intermediate plate) of 700nm is the artefact that the mathematics match by original QD spectrum causes, and it is to removing background and have very little or not having effect.
Fig. 8 A represents to the susceptibility of the QD-mark and GFP-transfected cancer cell and spectrum relatively, in-vivo imaging when Fig. 8 B represents the microballon of polychrome QD-coding.The cancer cell of the right hand graphical representation QD-mark of Fig. 8 A and 8B (on) and the cell (descending) of GFP-mark.
Fig. 9 A and 9B represent relatively to be used for the redness-emission QD and the red organic dyestuff of optical imagery in the body.Fig. 9 A represents an image, and its blue excitation light in the long-channel emission (long-passemission) of 470nm and 515nm obtains, image of Fig. 9 B, and its yellow exciting light at the long-channel of 570nm and 600nm obtains.Cancer cell in the cell culture (MDA-MB-231) (embeds the 250-NM particulate of organic dyestuff, λ with Tat-QD or Tat-nanometer pearl Ex=575, λ Em=615nm, Sigma-Aldrich, St Louis, MO) mark.When using incident fluorescence microexamination before injection, the cell of QD-and dye marker is similar light.Two adjacent sites that about 1000 cells are subcutaneously injected into mouse alive are used for in-vivo imaging.
Figure 10 A represents to describe the figure of nude mouse skin samples at the autofluorescence spectrum of four kinds of excitation wavelengths (λ=350,480,535 and 560nm).Notice that existence is up to the remarkable autofluorescence of 800-850nm with at the background peak value of about 670nm.Figure 10 B represents comparison mouse skin and the QD emission spectrum that obtains under same shooting conditions, prove that the QD signal can transfer to the spectral region of minimizing autofluorescence.
Detailed Description Of The Invention
According to purpose of the present disclosure, as comprise and describe widely herein, embodiment of the present disclosure relate in one aspect biological conjugation nanostructured (after this being nanostructured), make the method for these nanostructureds and use the method for these nanostructureds. Nanostructured is cognizable and can detects individually. In this, thus can decorated nanometer structure nanostructured and some target molecule interact, this allows to detect target molecule (for example in body) thereby determines for example zone at target molecule place.
Nanostructured can be used for a lot of fields, such as, but not limited to, biomolecule arrays system, biological sensing (biosensing), biomarker, gene expression research, albumen research, medical diagnosis, diagnostics library, micro-fluidic (microfluidic) system, transport agent, cosmetics, detergent and nanoparticle-polymer array (as, self-assembly, lithographic printing and pattern form). Especially, nanostructured can be used for in-vivo diagnostic and/or treatment application, such as, but be not limited to, target and/or imaging disease and/or state (for example, disease type in the identification activity thing, the approximated position of location disease, and the transportation medicine is to sick cell (as cancer cell)), as describing in detail in embodiment 1. Nanostructured is combined with light spectrum image-forming and can is used for multi-channel image and at single living cell, detects gene, albumen and analog.
The embodiment of nanostructured includes but not limited to, the hydrophobic protection structure of a kind of nano-substance (as quantum dot, metal particle and metal oxide microparticle) and a kind of coated nano-substance. In addition, nanostructured can include but not limited to, ((MW approximately 500 to 50 as polyethylene glycol for a kind of compound of biocompatibility, 000 and 1000 to 10,000), glucan and derivative are such as GAG and carboxyl glucan and polysaccharide) and a kind of probe (as polynucleotides, polypeptide, a kind of therapeutic agent and/or a kind of medicine). The compound of biocompatibility and/or probe general alignment (as be connected to hydrophobic protection body structure surface and/or be connected in hydrophobic protection structure) are on hydrophobic protection structure. Hydrophobic protection structure comprises a kind of cap part and/or amphipathic copolymer (as amphipathic nature block polymer, amphipathic random copolymer, amphipathic alternate copolymer, amphipathic periodic copolymer and its combination) of adding.
At another embodiment, nanostructured can comprise two or more nano-substances or two or more type nano-substances. In addition, nanostructured can comprise have two or more copolymers hydrophobic protection structure of (as two or more block copolymers). And nanostructured can comprise multiple nano-substance and multiple copolymer (as block copolymer). In addition, nanostructured can comprise the probe with difference in functionality (funciton) that two or more are dissimilar. And nano-substance and copolymer (as block copolymer) can be assembled in micro-structural and macrostructure.
At another embodiment, nanostructured can be included in porous material, porous material is such as, but not limited to, mesopore material (as aperture, being about 1 to 100 nanometer (nm)), large pore material (as aperture greater than about 100nm) and mix mesopore/large pore material. Porous material can be made by a kind of material, this material such as, but not limited to, polymer, copolymer, metal, silicon materials, cellulose, pottery, zeolite and its combination. Preferred porous material is silicon materials and polystyrene and polystyrene copolymer (as divinylbenzene, methacrylic acid (methacylic acid), maleic acid). The shape of porous material can be but be not limited to, spherical, cube, solely stone (monolith) (being bulk material), two and three dimensions array. The preferable shape of porous material is spherical (as silica bead and polymer beads (as the chromatogram pearl), pottery and molecular sieve).
Fig. 1 represents model's embodiment 100 of nanostructured.Nanostructured includes but not limited to have the nano-substance 102 of hydrophobic protection structure 104, and hydrophobic protection structure bag is by nano-substance 102.In addition, nanostructured 100 can include but not limited to, a kind of biocompatible compound 112 and a kind of probe 114.Hydrophobic protection structure 104 comprises a kind of cap ligand layer 106 and/or copolymer layer 108 (as amphipathic nature block polymer) of adding.Following one exemplary embodiment will be used amphipathic nature block polymer, but other multipolymer can be used in combination with segmented copolymer and use separately or use with combination in any, other multipolymer such as, but not limited to, amphipathic random copolymers, amphipathic alternating copolymer, amphipathic periodic copolymer and its combination.In addition, term " amphipathic nature block polymer " after this will be called " segmented copolymer ".
Usually, the mode can Fig. 2 A to 2D described of nanostructured 100 forms.Fig. 2 A illustrates nano-substance 102, and Fig. 2 B illustrates to be arranged in and adds cap ligand 1 06 on the nano-substance 102.Fig. 2 C illustrates to be arranged in and adds on the cap ligand 1 06 to form the segmented copolymer of hydrophobic protection structure 104.Fig. 2 D illustrates biocompatible compound 112 and probe 114 is added on the hydrophobic protection structure 104.
As mentioned above, nanostructured can comprise the nano-substance of many types, such as, but not limited to, semiconductor, metal and metal oxide nanoparticles are (as gold, silver, copper, titanium, nickel, platinum, palladium, its oxide (as Cr 2O 3, Co 3O 4, NiO, MnO, CoFe 2O 4, and MnFeO 4) and its alloy), metalloid and quasi-metal oxides nanoparticle, lanthanide series metal nanoparticle and combination thereof.Especially, semiconductor-quantum-point as described below and United States Patent (USP) 6,468,808 and International Patent Application WO 03/003015, it is incorporated herein by reference.And magnetic nanometer particles (as having magnetic and paramagnetic) can include but not limited to that iron nanoparticle and iron composite nano particle are (as Fe 2O 3, Fe 3O 4, FePt, FeCo, FeAl, FeCoAl, CoFe 2O 4, and MnFeO 4).
As mentioned above, nanostructured can comprise quantum dot, such as, but not limited to, the emitting semiconductor quantum dot.Usually, quantum dot comprises a nuclear and a cap, yet also can use the quantum dot that does not add cap." nuclear " is the semiconductor of nanometer size.Endorse being used in the theme of the present disclosure although any IIA-VIA, IIIA-VA or IVA-IVA, IVA-VIA be semi-conductive, nuclear must be the sort ofly to obtain luminescent quantum dot after in conjunction with a cap.The IIA-VIA semiconductor is a kind of compound, at least a IIB family's element in its containing element periodic table and at least a VIA family element, or the like.Endorse to comprise two or more elements.At an embodiment, nuclear is IIA-VIA, IIIA-VA or IVA-IVA semiconductor, and size is from about 1nm to about 20nm.At another embodiment, nuclear is preferred IIA-VIA semiconductor, and size is from about 2nm to about 10nm.For example, endorse to be CdS, CdSe, CdTe, ZnSe, ZnS, PbS, PbSe or a kind of alloy.
" cap " is a kind of semiconductor, and it is different from the semiconductor of nuclear and is incorporated into nuclear, thereby forms the top layer on the nuclear.Cap can be the sort of in conjunction with one obtain luminescent quantum dot after giving semiconductor core.Cap should make the nuclear passivation, by having the band gap higher than nuclear.For example, cap can be ZnS or CdS.Nuclear can include but not limited to that with the combination of cap cap is ZnS when nuclear is CdSe or CdS, and cap is CdS when nuclear is CdSe.Other example quantum dot includes but not limited to CdS, ZnSe, CdSe, CdTe, CdSe xTe 1-x, InAs, InP, PbTe, PbSe, PbS, HgS, HgSe, HgTe, CdHgTe and GaAs.
The wavelength of quantum dot emission (being color) can be selected according to the physical characteristics of quantum dot, such as the size and the material of nanocrystal.The light (as UV, nearly IR and IR) of known quantum dot emission from about 300 nanometers (nm) to 1700nm.The color of quantum dot includes but not limited to, red, blue, green and its combination.Color or fluorescent emission wavelength can be regulated continuously.The light wavelength band of quantum dot emission depends on the material of making nuclear and cap by the size of nuclear or the size decision of nuclear and cap.The emission wavelength band can center on nuclear one or more caps of adding by the composition of change QD and regulate with size and/or when forming concentric shells.
Can control the color intensity of quantum dot.To every kind of color, use 10 strength levels (0,1,2 ... 9) provide 9 separately codings (10 1-1), can not be distinguished from background owing to level " 0 ".The numeral of coding increases employed every kind of intensity and every kind of color index ground.For example, the scheme of three kinds of colors and 10 kinds of intensity produces 999 (10 3-1) coding, and the scheme of six kinds of colors and 10 kinds of intensity to have theoretical code capacity be about 100 ten thousand (10 6-1).Usually, n kind strength level and m kind color produce (n m-1) unique code.Use the intensity of quantum dot to be applied to comprise a plurality of dissimilar nanostructureds, also be applied to comprise a plurality ofly dissimilarly have the quantum dot of varying strength level and be included in nanostructured in the porosint with quantum dot of varying strength level.Quantum dot can absorb energy from for example electromagnetic radiation source (bandwidth is wide or narrow), and can be transmitted in the detected electromagnetic radiation of narrow wavelength when being excited.Quantum dot can be launched about 40nm or the littler interior radiation of narrow wavelength band (FWHM, full width at half maximum), thereby allows to use simultaneously having of a plurality of different colours quantum dot few or that do not have spectrum to overlap.
Quantum dot synthetic is well-known and is described in US Patent No 5,906,670,5,888,885,5,229,320,5,482,890,6,468,808,6,306,736,6,225,198 or the like, International Patent Application WO 03/003015, (all these is incorporated herein by reference) and in many research articles.The wavelength of quantum dot emission and other physics and chemical feature have been described in United States Patent (USP) 6,468, and 808 and International Patent Application WO 03/003015, and do not describe in further detail.In addition, the method for preparing quantum dot is described in United States Patent (USP) 6,468, and 808 and International Patent Application WO 03/003015 and not describing in further detail.
As mentioned above, hydrophobic protection structure comprises and adds cap part and/or segmented copolymer.Especially, when nano-substance was quantum dot, hydrophobic protection structural sheet comprised and adds cap part and segmented copolymer, wherein adds cap part and segmented copolymer and interacts to form hydrophobic protection structure.Similarly, select to add cap part and segmented copolymer to form suitable hydrophobic protection structure.For example, segmented copolymer and nano-substance can be interacted by interaction, such as, but not limited to, hydrophobic interaction, aqueous favoring interaction, π-stack (pi-stacking) or the like depend on the pan coating of nano-substance and the molecular structure of polymkeric substance.Be provided in following embodiment 1 about other details that adds cap part and segmented copolymer.
Add the cap part nano-substance (as quantum dot) is added cap and form one deck on nano-substance, it is connected with segmented copolymer subsequently to form hydrophobic protection structure.Add the cap part and can comprise compound, such as, but not limited to, a kind of O=PR 3Compound, a kind of O=PHR 2Compound, a kind of O=PHR 1Compound, a kind of H 2NR compound, a kind of HNR 2Compound, a kind of NR 3Compound, a kind of HSR compound, a kind of SR 2Compound and its combination." R " can be C 1To C 18Hydrocarbon, such as, but not limited to, straight chain hydrocarbon, branched-chain hydrocarbon, cyclic hydrocarbon, replacement hydrocarbon (as halo), stable hydrocarbon, unsaturated hydrocarbon and its combination.Preferably, hydrocarbon is a kind of saturated straight chain C 4To C 18Hydrocarbon, a kind of saturated straight chain C 6To C 18Hydrocarbon and a kind of saturated straight chain C 18Hydrocarbon.The combination of R group can connect P, N or S.Especially, chemicals can be selected from three-octyl group phosphine oxide, stearic acid and octyl group decyl amine (octyldecyl amine).
As mentioned above, multipolymer includes but not limited to: amphipathic nature block polymer, amphipathic random copolymers, amphipathic alternating copolymer, amphipathic periodic copolymer and its combination.Amphipathic random copolymers can include but not limited to: random copolymers gathers (methyl acrylate-co-acrylic acid); Random copolymers gathers (methylmethacrylate-co-n-butyl acrylate); Random copolymers gathers (methylmethacrylate-co-hydroxypropyl acrylate); Random copolymers gathers (styrene-co-is to the chlorovinyl benzoic acid); Random copolymers gathers (styrene-co-4-hydroxy styrenes); Random copolymers gathers (styrene-co-4-vinyl benzoic acid); Random copolymers gathers (styrene-co-4-vinylpyridine); With its combination.Amphipathic alternating copolymer can include but not limited to: poly-(maleic anhydride-alt-1-octadecylene), poly-(maleic anhydride-alt-1-tetradecene), alternating copolymer poly-(tertbutyloxycarbonyl (carbo tert.butoxy)-α-Jia Jibenyixi-alt-maleic anhydride) and alternating copolymer poly-(tertbutyloxycarbonyl norborene-alt-maleic anhydride) and its combination.
Segmented copolymer comprises amphipathic two or triblock copolymer.In addition, this multipolymer can comprise the hydrocarbon side chain, such as, but not limited to, 1-18-carbocyclic aliphatic family side chain, 1-18-carbon alkyl branches and its combination.And this pair or triblock copolymer have at least one hydrophobic block and at least one hydrophilic block.
Below be model's tabulation of amphipathic random copolymers and alternating copolymer: random copolymers gathers (dimethyl siloxane-co-diphenyl siloxane); Random copolymers gathers (methyl acrylate-co-acrylic acid); Random copolymers gathers (methylmethacrylate-co-n-butyl acrylate); Random copolymers gathers (methylmethacrylate-co-tert-butyl acrylate); Random copolymers gathers (methylmethacrylate-co-hydroxypropyl acrylate); Random copolymers gathers (methacrylate tetrahydrofuran ester-co-ethyl methacrylate); Random copolymers gathers (styrene-co-4-bromstyrol); Random copolymers gathers (styrene-co-butadiene); Random copolymers gathers (styrene-co-diphenylethlene); Random copolymers gathers (styrene-co-methacrylate tert-butyl ester); Random copolymers gathers (styrene-co-4-vinyl benzoic acid tert-butyl ester); Random copolymers gathers (styrene-co-is to the carboxyl chlorostyrene); Random copolymers gathers (styrene-co-p-chloromethyl styrene); Random copolymers gathers (styrene-co-methylmethacrylate); Random copolymers gathers (styrene-co-4-hydroxy styrenes); Random copolymers gathers (styrene-co-4-vinyl benzoic acid); Random copolymers gathers (styrene-co-4-vinylpyridine); Alternating copolymer gathers (tertbutyloxycarbonyl α-Jia Jibenyixi-alt-maleic anhydride); Alternating copolymer gathers (tertbutyloxycarbonyl norborene-alt-maleic anhydride); Alternating copolymer gathers (α-Jia Jibenyixi-alt-methylmethacrylate); Alternating copolymer gathers (styrene-alt-methylmethacrylate).
Below be the example tabulation of amphipathic multipolymer: based on the multipolymer (as: poly-(acrylic acid-b (block)-methylmethacrylate) of poly-((methyl) acrylic acid); Poly-(methylmethacrylate-b-acrylic acid); Poly-(methylmethacrylate-b-PAA); Poly-(PAA-b-methylmethacrylate); Poly-(methacrylate-b-methacrylate peopentyl ester); Poly-(methacrylate peopentyl ester-b-methacrylate); Poly-(the methacrylate tert-butyl ester-b-oxirane); Poly-(methylmethacrylate-b-SODIUM METHACRYLATE); With poly-(methylmethacrylate-b-N, N-DMAA)), based on the multipolymer (as: poly-(butadiene (1, the 2-addition)-b-methacrylic acid) of polydiene and hydrogenation polydiene; Poly-(butadiene (1, the 4-addition)-b-acrylic acid); Poly-(butadiene (1, the 4-addition)-b-PAA); Poly-(butadiene (1, the 4-addition)-b-oxirane); Poly-(butadiene (1, the 2-addition)-b-oxirane); Poly-(butadiene (1, the 2-addition)-b-oxirane)-hydroxybenzoic acid ester terminal; Poly-(butadiene-b-oxirane) diblock copolymer of 4-methoxy benzoic acid ester (benzoylester) end-blocking; Poly-(butadiene-b-N-methyl-4-vinylpridine drone iodide (pyridinium iodide)); Poly-(isoprene-b-N-methyl-2-vinylpyridine drone iodide); Poly-(isoprene-b-oxirane) (1, the 4-addition); Poly-(isoprene-b-oxirane) (1,2-and 3,4-addition); Poly-(propylene-ethylene-b-oxirane); With hydrogenation poly-(isoprene-b-oxirane) (1,2 addition)), based on the multipolymer (as: poly-(ethene-b-oxirane) and poly-(isoprene-b-oxirane)) of hydrogenated diene hydrocarbon, (as: gather (oxirane-b-acrylic acid) based on the multipolymer of poly-(oxirane); Poly-(oxirane-b-6-caprolactone); Poly-(oxirane-b-6-(4 '-cyanobiphenyl-4-oxygen base) own ester of methacrylate); Poly-(oxirane-b-lactide); Poly-(oxirane-b-methacrylate-2-hydroxyl ethyl ester); Poly-(oxirane-b-methylmethacrylate); Poly-(methylmethacrylate-b-oxirane); Poly-(oxirane-b-methacrylate); Poly-(oxirane-b-2-Jia oxazolin); Poly-(oxirane-b-propylene oxide); Poly-(oxirane-b-tert-butyl acrylate); Poly-(oxirane-b-methacrylate tetrahydrofuran ester); With poly-(oxirane-b-N, N-methacrylate dimethyl ethyl ester)), based on the multipolymer (as: poly-(isobutylene-b-oxirane)) of polyisobutylene, based on the multipolymer (as: poly-(styrene-b-acrylic acid) of polystyrene; Poly-(styrene-b-PAA); Poly-(styrene-b-acrylamide); Poly-(p-chloromethyl styrene-b-acrylamide); Poly-(styrene-co-p-chloromethyl styrene-b-acrylamide); Poly-(styrene-co-p-chloromethyl styrene-b-acrylic acid); Poly-(styrene-b-acrylic acid caesium); Poly-(styrene-b-oxirane); Poly-(4-styrene sulfonic acid-b-oxirane); Poly-(styrene-b-methacrylate); Poly-(styrene-b-SODIUM METHACRYLATE); Poly-(styrene-b-N-methyl-2-vinylpyridine drone iodide); With poly-(styrene-b-N-methyl-4-vinylpyridine drone iodide)), based on the multipolymer (as: poly-(dimethyl siloxane-b-acrylic acid)) of polysiloxane, based on the multipolymer (as: poly-(2-vinyl naphthalene-b-acrylic acid)) of poly-(2-vinyl naphthalene), based on the multipolymer (as: poly-(2-vinylpyridine-b-oxirane) of poly-(vinylpyridine and N-methyl ethylene pyridinium iodide); Poly-(N-methyl-2-vinylpyridine drone iodide-b-oxirane); With poly-(N-methyl-4-vinylpridine drone iodide-b-methylmethacrylate)).
Below be the example tabulation of amphiphilic diblock copolymer: based on the multipolymer (as: poly-(n-butyl acrylate-b-methylmethacrylate) of poly-((methyl) acrylic acid); Poly-(n-butyl acrylate-b-dimethyl siloxane-co-diphenyl siloxane); Poly-(tert-butyl acrylate-b-methylmethacrylate); Poly-(tert-butyl acrylate-b-4-vinylpyridine); Poly-(acrylic acid-2-ethyl hexyl ester-b-4-vinylpyridine); Poly-(the methacrylate tert-butyl ester-b-2-vinylpyridine); Poly-(acrylic acid-2-hydroxyl ethyl ester-b-acrylic acid peopentyl ester); Poly-(methacrylate-2-hydroxyl ethyl ester-b-methacrylate peopentyl ester); Poly-(methacrylate-2-hydroxyl ethyl ester-positive butyl ester of b-methacrylate); Poly-(methacrylate-2-hydroxyl ethyl ester-b-methacrylate tert-butyl ester); Poly-(methylmethacrylate-b-vinyl cyanide); Poly-(methylmethacrylate-b-methacrylate tert-butyl ester); Poly-(isotaxy methylmethacrylate-b-syndiotaxy methylmethacrylate); Poly-(methylmethacrylate-b-tert-butyl acrylate); Poly-(methylmethacrylate-b-methacrylate trifluoro ethyl ester); Poly-(methylmethacrylate-b-methacrylate-2-hydroxyl ethyl ester and cholesteryl chloro-carbonate); Poly-(methylmethacrylate-b-Red-1 200 acrylate); Poly-(methylmethacrylate-b-methacrylate-2-hydroxyl ethyl ester); Poly-(methylmethacrylate-b-acrylic acid peopentyl ester); With poly-(methacrylate-b-methacrylate-2-pyran oxygen ethyl ester (2-pyranoxy ethylmethacrylate))), based on the multipolymer (as: poly-(butadiene (1, the 2-addition)-b-methacrylate isobutyl ester) of polydiene; Poly-(butadiene (1, the 2-addition)-b-s-butyl isocrotonate); Poly-(butadiene (1, the 4-addition)-b-tert-butyl acrylate); Poly-(butadiene (1, the 2-addition)-b-tert-butyl acrylate); Poly-(butadiene (1, the 2-the addition)-b-methacrylate tert-butyl ester); Poly-(butadiene (1, the 4-addition)-b-6-caprolactone); Poly-(butadiene (1, the 4-addition)-b-dimethyl siloxane); Poly-(butadiene (1, the 4-addition)-b-methylmethacrylate) (syndiotaxy); Poly-(butadiene (1, the 2-addition)-b-methylmethacrylate); Poly-(butadiene (1, the 4-addition)-b-4-vinylpyridine); Poly-(isoprene (1, the 4-addition)-b-methylmethacrylate (syndiotaxy)); Poly-(isoprene (1, the 4-addition)-b-2-vinylpyridine); Poly-(isoprene (1, the 2-addition)-b-4-vinylpyridine); With poly-(isoprene (1, the 4-addition)-b-4-vinylpyridine)), based on the multipolymer (as: poly-(isobutylene-b-methacrylate tert-butyl ester) of polyisobutylene; Poly-(isobutylene-b-6-caprolactone); Poly-(isobutylene-b-dimethyl siloxane); Poly-(isobutylene-b-methylmethacrylate); Poly-(isobutylene-b-4-vinylpyridine)), based on the multipolymer (as: poly-(styrene-b-n-butyl acrylate) of polystyrene; Poly-(styrene-b-tert-butyl acrylate); Poly-(styrene-b-tert-butyl acrylate), wide distribution (broad distribution); Poly-(styrene-b-Red-1 200 acrylate); Poly-(p-chloromethyl styrene-b-tert-butyl acrylate); Poly-(styrene-b-N-N-isopropylacrylamide); Poly-(styrene-positive butyl ester of b-methacrylate); Poly-(styrene-b-methacrylate tert-butyl ester); Poly-(styrene-b-methacrylate cyclohexyl); Poly-(styrene-b-methacrylate cholesteryl oxygen ketonic oxygen (cholesteryloxycarbonyloxy) ethyl ester); Poly-(styrene-b-N, N-methacrylate dimethylamino ethyl ester); Poly-(styrene-b-ethyl methacrylate); Poly-(styrene-b-methacrylate-2-hydroxyl ethyl ester); Poly-(styrene-b-methacrylate-2-hydroxypropyl acrylate); Poly-(styrene-b-methylmethacrylate); Poly-(styrene-b-methylmethacrylate); Poly-(styrene-b-methacrylate n-propyl); Poly-(styrene-b-butadiene (1, the 4-addition)); Poly-(styrene-b-butadiene (1, the 2-addition)); Poly-(styrene-b-isoprene (1, the 4-addition)); Poly-(styrene-b-isoprene (1,2-addition or 3,4-addition)); Poly-(styrene-b-isoprene (1, the 4-addition)), hydrogenation; Tapered block copolymer gathers (styrene-b-butadiene); Tapered block copolymer gathers (styrene-b-ethene); Poly-(styrene-b-6-caprolactone); Poly-(styrene-b-1-lactide); Poly-(styrene-b-dimethyl siloxane), the trimethyl silane end group; Poly-(styrene-b-dimethyl siloxane), the silanol end group; Poly-(styrene-b-methyl phenyl siloxane); Poly-(styrene-b-ferrocenyl dimethylsilane); Poly-(styrene-b-t-butyl styrene); Poly-(styrene-b-tert-butoxy styrene); Poly-(styrene-b-4-hydroxy styrenes); Poly-(4-ammonia benzyl (amino benzyl)-b-styrene); Poly-(styrene-b-2-vinylpyridine); Poly-(styrene-b-4-vinylpyridine); With poly-(α-Jia Jibenyixi-b-4-vinylpyridine)), based on the multipolymer (as: poly-(2-vinyl naphthalene-b-n-butyl acrylate) of poly-(vinyl naphthalene); Poly-(2-vinyl naphthalene-b-tert-butyl acrylate); Poly-(2-vinyl naphthalene-b-methylmethacrylate); With poly-(2-vinyl naphthalene-b-dimethyl siloxane)), based on the multipolymer (as: poly-(2-vinylpyridine-b-6-caprolactone) of poly-(vinylpyridine); Poly-(2-vinylpyridine-b-methylmethacrylate); With poly-(4-vinylpridine-b-methylmethacrylate)), poly-(propylene oxide-b-6-caprolactone) (as: poly-(propylene oxide-b-6-caprolactone)), based on the multipolymer (as: poly-(dimethyl siloxane-b-n-butyl acrylate) of polysiloxane; Poly-(dimethyl siloxane-b-tert-butyl acrylate); Poly-(dimethyl siloxane-b-methacrylate tert-butyl ester); Poly-(dimethyl siloxane-b-6-caprolactone); Poly-(dimethyl siloxane-b-6-(4 '-cyanobiphenyl-4-oxygen base) own ester of methacrylate); Poly-(dimethyl siloxane-b-1-methacrylate ethoxy ethyl ester); Poly-(dimethyl siloxane-b-hydroxy-ethyl acrylate); With poly-(dimethyl siloxane-b-methylmethacrylate)), based on the multipolymer (as: poly-(oxirane-b-adipic anhydride) of adipic anhydride; Poly-(propylene oxide-b-adipic anhydride); Poly-(dimethyl siloxane-b-adipic anhydride); Poly-(methylmethacrylate-b-adipic anhydride); With poly-(2-vinylpyridine-b-adipic anhydride)).
Below be the example tabulation of amphipathic a-b-a triblock copolymer: based on the triblock copolymer (as: poly-(n-butyl acrylate-b-9,9-di-n-hexyl-2,7-fluorenes-b-n-butyl acrylate) of poly-((methyl) acrylic acid); Poly-(tert-butyl acrylate-b-9,9-pair-n-hexyl-2,7-fluorenes-b-tert-butyl acrylate); Poly-(acrylic acid-b-9,9-di-n-hexyl-2,7-fluorenes-b-acrylic acid); Poly-(tert-butyl acrylate-b-methylmethacrylate-b-tert-butyl acrylate); Poly-(tert-butyl acrylate-b-styrene-b-tert-butyl acrylate); Poly-(methylmethacrylate-b-butadiene (1, the 4-addition)-b-methylmethacrylate); Poly-(methylmethacrylate-b-n-butyl acrylate-b-methylmethacrylate); Poly-(methylmethacrylate-b-methacrylate tert-butyl ester-b-methylmethacrylate); Poly-(methylmethacrylate-b-methacrylate tert-butyl ester-b-methylmethacrylate); Poly-(methylmethacrylate-b-methacrylate-b-methylmethacrylate); Poly-(methylmethacrylate-b-dimethyl siloxane-b-methylmethacrylate); Poly-(methylmethacrylate-b-9,9-di-n-hexyl-2,7-fluorenes-b-methylmethacrylate); Poly-(methylmethacrylate-b-styrene-b-methylmethacrylate); Poly-(ethyl methacrylate iodate trimethyl ammonium-b-9,9-di-n-hexyl-2,7-fluorenes-b-ethyl methacrylate iodate trimethyl ammonium); Poly-(N, N-dimethylaminoethyl methacrylate-b-9,9-di-n-hexyl-2,7-fluorenes-b-N, N-dimethylaminoethyl methacrylate); With poly-(N, N-dimethylaminoethyl methacrylate-b-propylene oxide-b-N, N-dimethylaminoethyl methacrylate)), the triblock copolymer based on polybutadiene (as: gathers (butadiene (1, the 4-addition)-b-styrene-b-butadiene (1, the 4-addition))), the triblock copolymer based on poly-(oxirane) (as: gathers (oxirane-b-9,9-di-n-hexyl-2,7-fluorenes-b-oxirane); Poly-(oxirane-b-propylene oxide-b-oxirane); Poly-(oxirane-b-styrene-b-oxirane); With poly-(propylene oxide-b-dimethyl siloxane-b-propylene oxide)), polylactone and polylactide diblock copolymer (as: poly-(lactide-b-oxirane-b-lactide); Poly-(caprolactone-b-oxirane-b-caprolactone); And α, poly-(lactide-b-oxirane-b-lactide) of ω-two acryloyl (diacrylonyl) end-blocking), based on the triblock copolymer (as: poly-(2-first oxazolin-b-dimethyl siloxane-b-2-first oxazolin)) of poly-oxazoline, based on the triblock copolymer (as: poly-(styrene-b-acrylic acid-b-styrene) of polystyrene; Poly-(styrene-b-butadiene (1, the 4-addition)-b-styrene); Poly-(styrene-b-butadiene (1, the 2-addition)-b-styrene); Poly-(styrene-b-butylene-b-styrene); Poly-(styrene-b-n-butyl acrylate-b-styrene); Poly-(styrene-b-tert-butyl acrylate-b-styrene); Poly-(styrene-b-9,9-di-n-hexyl-2,7-fluorenes-b-styrene); Poly-(styrene-b-ethyl acrylate-b-styrene); Poly-(styrene-b-isoprene-b-styrene); Poly-(styrene-b-oxirane-b-styrene); Poly-(styrene-b-4-vinylpyridine-b-styrene); With poly-(styrene-b-dimethyl siloxane-b-styrene)), based on the triblock copolymer (as: poly-(2-vinylpyridine-b-butadiene (1, the 2-addition)-b-2-vinylpyridine) of poly-(vinylpyridine); Poly-(2-vinylpyridine-b-styrene-b-2-vinylpyridine); With poly-(4-vinylpridine-b-styrene-b-4-vinylpyridine)).
Below be the example tabulation of amphipathic a-b-c triblock copolymer: poly-(styrene-b-butadiene-b-methylmethacrylate) (as: poly-(styrene-b-butadiene-b-methylmethacrylate)), poly-(styrene-b-butadiene-b-2-vinylpyridine) (as: poly-(styrene-b-butadiene-b-2-vinylpyridine)), poly-(styrene-b-tert-butyl acrylate-b-methylmethacrylate) (as: poly-(styrene-b-tert-butyl acrylate-b-methylmethacrylate)), poly-(styrene-b-isoprene-b-methacrylic acid glycidyl ester) (as: poly-(styrene-b-isoprene-b-methacrylic acid glycidyl ester)), poly-(styrene-b-2-vinylpyridine-b-oxirane) (as: poly-(styrene-b-2-vinylpyridine-b-oxirane)), poly-(styrene-b-anthracene methyl methacrylate-b-methylmethacrylate) (as: poly-(styrene-b-anthracene methyl methacrylate-b-methylmethacrylate)), poly-(styrene-b-tert-butyl acrylate-b-2-vinylpyridine) (as: poly-(styrene-b-tert-butyl acrylate-b-2-vinylpyridine)), with poly-(styrene-b-methacrylate tert-butyl ester-b-2-vinylpyridine) (as: poly-(styrene-b-methacrylate tert-butyl ester-b-2-vinylpyridine)).
Below be the amphipathic functionalized diblock and the example tabulation of triblock copolymer: amino-terminated poly-(dimethyl siloxane-b-diphenyl siloxane); Amino-terminated poly-(styrene-b-isoprene); Amino-terminated poly-(oxirane-b-lactone); Hydroxy-end capped poly-(styrene-b-2-vinylpyridine); Hydroxy-end capped polystyrene-b-gathers (methylmethacrylate); Poly-(styrene-b-butadiene (1, the 2-addition)) of Alpha-hydroxy end-blocking; Poly-(butadiene-b-oxirane) diblock copolymer of 4-methoxy benzoic acid ester (benzyolester) end-blocking; Poly-(butadiene-b-oxirane) diblock copolymer of succinic acid end-blocking; α, poly-(oxirane-propylene oxide-oxirane) of ω-two succinimido succinate end-blocking; Methyl alcohol (cabinol) links (junction) poly-(styrene-b-isoprene (1, the 4-addition)); Link poly-(styrene-b-2-vinylpyridine) with silane.
In addition, be below the example list of amphipathic nature block polymer: poly-(1-vinyl pyrrolidone-co-vinylacetate); Poly-(ethene-co-propylene-co-5-methylene-2-ENB); Poly-(styrene-co-acrylonitrile); Poly-(2-vinylpyridine-co-styrene); Poly-(ethene-co-methacrylate) sodium salt; Poly-(acrylonitrile-co-butadiene-co-styrene); Poly-(vinyl chloride-co-vinylacetate-co-maleic acid); Poly-(ethene-co-vinylacetate); Poly-(ethene-co-ethyl acrylate); Poly-(4-vinylpridine-co-styrene); Poly-(ethene butyral-co-vinyl alcohol-co-vinylacetate); Poly-(methylmethacrylate-co-methacrylate); Poly--(vinyl chloride-co-vinylacetate-co-hydroxypropyl acrylate);
Figure A200480041964D0022152526QIETU
HM 552; Poly-(vinyl chloride-co-vinylacetate-co-vinyl alcohol); Poly-(styrene-co-divinylbenzene); Poly-(DL-lactide-co-glycolide); Poly-(acrylonitrile-co-methyl acrylate); Poly-[vinyl chloride-co-(1-methyl-4-ethene piperazine)]; Poly-(2-isopropenyl-2-oxazoline-co-methylmethacrylate); Poly-(fetrafluoroethylene oxide-co-difluoro methylene oxide (difluoromethylene oxide)), α, omega-diol, ethoxyquin; Poly-[dimethyl siloxane-co-methyl (3-hydroxypropyl) siloxanes]-graft (grafting)-PEG methyl ether; Poly-(acrylonitrile-co-methacrylonitrile); Poly-(ethene-co-1-butylene); Poly-(vinylidene fluoride-co-hexafluoropropene); Poly-(ethene-co-1-octene); Poly-(ethene-co-methyl acrylate); Poly-(acrylonitrile-co-butadiene), the amine end-blocking; Poly-(perfluoropropene oxide-co-perfluor formaldehyde); Poly-(butyl isocrotonate-co-methacrylate isobutyl ester); Poly-(styrene-co-maleic anhydride), part isooctyl acrylate, the cumene end-blocking; Poly-(acrylonitrile-co-butadiene-co-acrylic acid), the dicarboxyl end-blocking; Poly-(vinyl alcohol-co-ethene); Poly-(dimethyl siloxane-co-methyl phenyl siloxane); Poly-(styrene-co-maleic anhydride); Poly-(bisphenol-A-co-3-chloro-1,2-expoxy propane); Poly-(styrene-co-butadiene); Poly-[(R)-3-hydroxybutyrate-co-(R)-3-hydroxypentanoic acid]; Poly-(vinyl alcohol-co-vinylacetate-co-methylene-succinic acid); Poly-(methyl styrene-co-indenes), hydrogenation; Poly-(4-Vinyl phenol-co-2-methacrylate hydroxyl ethyl ester); Poly-(styrene-co-maleic anhydride), the cumene end-blocking; Poly-(methylmethacrylate-co-ethylene glycol dimethacrylate); Poly-(ethene-co-propylene); Poly-(styrene-co-maleic acid), part isobutyl group/methyl mixed ester; Poly-(bisphenol-A-co-3-chloro-1,2-expoxy propane), the glycidyl end-blocking; Poly-(methylmethacrylate-co-methacrylate); Poly-(2-acrylamido-2-methyl isophthalic acid-propane sulfonic acid-co-acrylonitrile); Poly-(propylene-co-tetrafluoroethene); Poly-(butyl isocrotonate-co-methylmethacrylate); Poly-(dimethyl siloxane-co-alkyl methyl siloxanes); Poly-(acrylic-co-acrylamide) sylvite; Poly-(formaldehyde-co-1,3-cyclic heptane dioxide (dioxepane)); Poly-(CTFE-co-vinylidene fluoride); Poly-(melamine-co-formaldehyde), the propylene souring soln; Poly-(pentafluorostyrene-co-methacrylic acid glycidyl ester); Poly-(1,1,1,3,3,3-hexafluoro isopropyl butenoate-co-methacrylic acid glycidyl ester); Poly-(2,2,3,4,4,4-hexafluoro butyl methacrylate-co-methacrylic acid glycidyl ester); Poly-(2,2,3,3,3-, five fluoropropyl methacrylate-co-methacrylic acid glycidyl esters); Poly-[(propyl group methacrylyl-seven isobutyl group-PSS)-co-(the positive butyl ester of methacrylate)]; Poly-(PMDA-co-4,4 '-diaminodiphenyl ether (4,4 '-oxydianiline)), amic acid solution; Poly-(the methacrylate tert-butyl ester-co-methacrylic acid glycidyl ester); Poly-[(propyl group methacrylyl-seven isobutyl group-PSS)-co-(methacrylate hydroxyl ethyl ester)]; Poly-[(metaphenylene ethenylidene)-co-(2,5-dioctyl (dioctoxy)-to phenylene vinylidene)]; Poly-[(methylmethacrylate)-co-(9-anthracene methyl methacrylate)]; Poly-[(methylmethacrylate)-co-(2-naphthyl acrylic acid)]; Poly-[(methylmethacrylate)-co-(7-(4-trifluoromethyl) cumarin MAAm)]; Poly-[(methylmethacrylate)-co-(9-anthracene methacrylate)]; Poly-[(methylmethacrylate)-co-(9H-carbazole-9-ethyl methacrylate)]; Poly-[(propyl group methacrylyl-seven isobutyl group-PSS)-co-(methylmethacrylate)]; Poly-[(isobutene-alt-maleic acid, ammonium salt)-co-(isobutene-alt-maleic anhydride)]; Poly-(1,2-ethylidene carbonyl-co-1,2-propylidene carbonyl); Poly-[4,5-, two fluoro-2,2-two (trifluoromethyl)-1,3-dioxole-co-tetrafluoroethene]; Poly-(dimethyl siloxane-co-diphenyl siloxane), trimethylsilyl endblocked; Poly-(dimethyl siloxane-co-methyl hydrogen radical siloxane), trimethylsilyl endblocked; Poly-(dimethyl siloxane-co-diphenyl siloxane), the divinyl end-blocking; Poly-(styrene-co-methylmethacrylate); Poly-(styrene-co-AMS); Poly-(terephthalic acids-Isosorbide-5-Nitrae-cyclohexane two methylene esters-co-terephthalic acids ethyl); AmberjetTM4200; Poly-[dimethyl siloxane-co-methyl (3-hydroxypropyl) siloxanes]-graft (grafting)-PEG [3-(trimethyl ammonium) propyl chloride (3-(trimethylammonio) propyl chloride)] ethereal solution; Poly-[dimethyl siloxane-co-methyl (3-hydroxypropyl) siloxanes]-graft (grafting)-poly-(ethylene/propylene enol); Poly-(ethene-co-butyl acrylate); Poly-(ethene-co-ethyl acrylate-co-maleic anhydride); Poly-(ethyl methacrylate-co-methyl acrylate); Poly-(ethene-co-1-butylene-co-1-hexene); Poly-(melamine-co-formaldehyde), the solution of isobutyl; Poly-[bisphenol a carbonate-co-4,4 '-(3,3,5-trimethyl cyclohexylene) xenol carbonic ester]; Poly-(acrylamide-co-acrylic acid); Poly-(styrene-co-maleic acid), part sec-butyl/methyl mixed ester; Poly-(4-HBA-co-6-hydroxy-2-naphthoic acid); Poly-[terephthalic acids butylidene ester-co-gathers (alkylene glycol) terephthalate]; Poly-(ethene-co-vinylacetate-co-methacrylate); Poly-(melamine-co-formaldehyde), methylate; Poly-(acrylonitrile-co-butadiene), the dicarboxyl end-blocking; Poly-(vinyl chloride-co-vinylacetate-co-2-hydroxypropyl acrylate); Poly-(fetrafluoroethylene oxide-co-difluoro methylene oxide) α, omega-diol; Poly-(melamine-co-formaldehyde), butylation solution; Poly-[(phenyl glycidyl ether)-co-formaldehyde]; Poly-(acrylamide-co-diallyldimethylammonium chloride) solution; Poly-(tetrafluoroethene-co-perfluor (propyl vinyl ether)); Poly-(4-vinylpridine-co-butyl isocrotonate); Poly-(dimeric dibasic acid-co-alkyl polyamine); Poly-(1-vinyl pyrrolidone-co-2-methacrylate dimethylaminoethyl), quaternised solution; Poly-(methylmethacrylate-co-ethyl acrylate);
Figure A200480041964D0024152611QIETU
FC550; poly (ethylene Vinyltoluene-co-α-methyl styrene); poly (3 - chloro-1 ,2 - ethylene oxide-co-ethylene oxide-co-alkyl Glycidyl ether); poly (dimethylsiloxane-co-methyl-hydrogen-siloxane); polybutadiene -Graft (graft) - poly (methyl acrylate-co-acrylonitrile); poly (styrene-co-maleic anhydride), section Stars 2 - butoxyethyl, cumene end-capped; poly (dimethylamine-co-3-chloro-1 ,2 - propylene oxide) was dissolved Liquid; poly (ethylene-co-acrylic acid); poly (acrylamide-co-acrylic acid) partial sodium salt; poly (Sat Fluoride-co-propylene oxide difluoro methylene oxide) monoalkyl amide; poly (1 - vinyl pyrrolidone -Co-2-dimethylaminoethyl methacrylate methacrylic acid) solution; poly (acrylic acid-co-maleic acid) sodium salt; poly (ethylene Ene-co-acrylic acid, zinc salt); poly (ethylene-co-tetrafluoroethylene); poly (2,2,2 - trifluoroethyl iso Crotonate-co-glycidyl methacrylate); poly (pentabromophenyl acrylate-co-methacrylic ester Glycidyl); poly (2,2,3,3,4,4,4 - Heptabromodiphenyl methacrylate-co-butyl methacrylate shrink Glycerol); poly [methyl methacrylate-co-(Disperse Yellow 7 methacrylates)]; poly (2,2,3,3 - Tetrafluoro-propyl methacrylate-co-glycidyl methacrylate); poly (methacrylic acid pentabromophenyl Acrylate-co-glycidyl methacrylate); poly [methyl methacrylate-co-(methacrylic acid Disperse Orange 3 Amine)]; poly [((S) -1 - (4 - nitrophenyl) -2 - methyl-pyrrolidine) acrylate-co-methacrylic Methyl]; poly [(methyl methacrylate)-co-(Disperse Red 13 methacrylates)]; poly [(iso Butenoic acid methyl ester)-co-(Disperse Red 13 acrylate)]; poly [methyl methacrylate-co-(N-(1 - Naphthyl)-N-phenyl-acrylamide)]; poly [(propyl-methacryloyl - Seven isobutyl-PSS)-co- Styrene]; poly (pyromellitic dianhydride-co-thionine); poly (ethylene glycol)-co-4-benzyloxy benzyl alcohol, Crosslinked polymer (polymer bound); poly [(isobutylene-alt-maleimide)-co-(isobutyl Ene-alt-maleic anhydride)]; poly [dimethyl siloxane-co-(3 ​​- aminopropyl) methyl siloxane]; poly [bis Dimethylsiloxane-co-[3 - (2 - (2 - hydroxyethoxy) ethoxy) propyl) methylsiloxane]]; poly (1,1 - Vinylidene chloride-co-acrylonitrile-co-methyl methacrylate); poly (ethylene-co-1, 2 - butylene) diol; Poly (DL-lactide-co-caprolactone) (40:60); poly (methyl methacrylate-co-methacrylic acid Butyl); poly (ethylene oxide-co-tetrafluoroethylene difluoromethylidene oxide) α, ω-diol bis (2,3 - dihydroxy- Propyl ether); poly [dimethyl siloxane-co-(2 - (3,4 - epoxycyclohexyl) ethyl)-methyl-silicone Alkyl]; poly (vinyl chloride-co-isobutyl vinyl ether); poly (benzofuran-co-indene); poly (styrene Ene-co-4-bromo-styrene-co-divinylbenzene); poly (ethylene-co-butyl acrylate-co-monoxide Carbon); poly (vinyl acetate-co-butyl maleate-co-isobornyl acrylate) solution; poly (3,3 ', 4,4' - benzophenone tetracarboxylic dianhydride-co-4, 4'-diaminodiphenyl ether (oxydianiline) / 1,3 - Phenylenediamine), amic acid (solution); poly (tetrafluoroethylene-co-vinylidene fluoride-co-propylene); Poly (ethylene-co-methacrylic acid), a lithium salt; poly (styrene-co-butadiene-co-methyl methacrylate); Poly (1,1 - chloride-co-vinyl chloride); poly (styrene-co-maleic acid), part of the isobutyl ester; Poly [4,4 '- methylenebis (phenyl isocyanate)-alt-1, 4 - butanediol / poly (ethylene-co-propylene glycol) / Polycaprolactone]; poly (ethylene-co-methacrylic acid); poly (isobutylene-co-maleic acid) sodium salt; poly (Ethylene-co-methacrylic acid) zinc; poly (4 - styrenesulfonate-co-maleic acid) sodium salt; poly (C Ene-nitrile-co-butadiene-co-acrylic acid), glycidyl methacrylate diester (glycidyl methacrylate diester); poly (urea-co-formaldehyde), butylated solution; poly (ethylene-co-isobutyl methacrylate-co- Crotonic acid glycidyl esters); poly [(phenyl glycidyl ether)-co-dicyclopentadiene]; poly [(N- O-tolyl glycidyl ether)-co-formaldehyde]; poly (urea-co-formaldehyde), methylated; poly (propylene Acid-co-maleic acid) solution; poly (3 - hydroxybutyrate-co-3-hydroxyvalerate); poly (p-toluenesulfonyl Amine-co-formaldehyde); poly (styrene-co-allyl alcohol); poly (2 - acrylamido-2 - methyl-1 - C Alkyl sulfonic acid-co-styrene); poly (acrylonitrile-co-butadiene); poly (4 - vinyl phenol-co-isobutyl Butenoate); poly [dimethyl siloxane-co-methyl (3 - hydroxypropyl) siloxane]-graft-poly (ethylene Ene-ran (random) - propylene glycol) methyl ether; poly (hexafluoropropylene oxide-co-propylene difluoro methylene oxide) Single aminosilane; poly (dimethylamine-co-3-chloro-1 ,2 - ethylene oxide-co-1, 2 - ethylenediamine) solution; Poly (ethylene-co-butyl acrylate-co-maleic anhydride); poly (trimellitic anhydride chloride-co-4, 4'-methylene Diphenylamine); poly [methyl methacrylate-co-(acrylamide Disperse Orange 3)]; poly [((S) -1 - (4 - nitrophenyl) -2 - methyl-pyrrolidine) methacrylate-co-methyl methacrylate]; poly [(C Methacryloyl group - Seven isobutyl-PSS)-co-(tert-butyl methacrylate)]; poly [(methacrylic acid Methyl)-co-(2 - naphthyl methacrylate)]; poly [methyl methacrylate-co-(fluorescein O-propylene Ester (fluoresceinO-acrylate))]; poly [methyl methacrylate-co-(O-methacrylic acid fluorescent yellow Ester)]; poly {[2 - [2 ', 5'-bis (2' - ethyl-hexyloxy) phenyl] -1,4 - phenylenevinylene]-co-[2 - Methoxy-5 - (2'-ethyl-hexyloxy) -1,4 - phenylenevinylene]}; poly [(methyl methacrylate) -Co-(Disperse Red 1 acrylate)]; poly (4 - hydroxybenzoic acid terephthalic acid-co-vinyl acetate); Poly (1,1 - chloride-co-acrylonitrile); poly (dimethylsiloxane-co-diphenylsiloxane), Dihydroxy-terminated; poly (1,4 - butylene adipate-co-1, 4 - butylene succinate ester) to 1,6 - Isocyanurate groups hexane extended (extended); poly (dicyclopentadiene-co-p-cresol); poly [acrylic acid Acrylate-co-methacrylic acid-co-3-(1 - isocyanato-in-1 - methylethyl)-α-methyl styrene], and Nonylphenol ethoxylated adduct solution; poly (3 - chloro-1 ,2 - ethylene oxide-co-ethylene oxide); Poly (bisphenol A-co-4-nitro-phthalic anhydride-co-1, 3 - phenylene diamine); poly (ethylene-co-methyl methacrylate-co- Acrylic acid); poly (propylene-co-1-butene); Nylon6/66; poly (ethylene-co-acrylic acid) sodium Salts; poly (ethylene-co-vinyl acetate-co-carbon monoxide); poly (melamine-co-formaldehyde), Methylated / butylated (55/45); poly (maleic acid-co-olefin) sodium salt solution; Poly ( Fluoro ethylene oxide-co-difluoromethylene oxide) α, ω-diisocyanate; poly (lauryl methacrylate Two ester-co-methacrylic acid glycol ester); poly [(phenyl isocyanate)-co-formaldehyde]; poly [2,6 - bis (Hydroxymethyl)-4 - methyl phenol-co-4-hydroxybenzoic acid]; poly (ethylene oxide-co-tetrafluoroethylene difluoroparaxylylene Methyl oxide) α, ω-dicarboxylic acid; poly [methyl methacrylate-co-(Disperse Yellow 7 acrylate)]; Poly [(methyl methacrylate)-co-(9H-carbazol - ethyl acrylate)]; poly [(methyl methacrylate Ester)-co-(N-(1 - naphthyl)-N-phenyl methacrylamide)]; poly [(methyl methacrylate)-co- (Disperse Red 1 methacrylates)]; poly (L-lactide-co-caprolactone-co-glycolide); poly [iso Butenoic acid methyl ester-co-(7 - (4 - trifluoromethyl) coumarin acrylamide)]; poly [dimethyl siloxane -Co-methyl-(3,3,3 - trifluoropropyl) siloxane]; poly [dimethyl siloxane-co-methyl-(stearoyl Alkoxy) siloxane]; poly (hexafluoropropylene oxide-co-propylene difluoromethylidene oxide) alcohols, ethoxylated Of phosphate; poly (ethylene-co-1, 2 - butene) monohydric alcohol (mono-ol); poly [dimethyl siloxane -Co-methyl (3 - hydroxypropyl) siloxane]-graft (graft) - tetrakis (1,2 - butanediol); poly (1,4 - hexyl Acid-co-butylene polycaprolactam); poly (vinyl acetate-co-crotonic acid); poly (propylene T-butyl acrylate-co-acrylate-co-methacrylic acid); poly (1 - vinyl pyrrolidone-co-styrene Ene); poly (ethylene oxide-co-tetrafluoroethylene difluoromethylidene oxide)-α, ω-bis (carboxylate); Poly (1,1 - chloride-co-methyl acrylate); poly (acrylonitrile-co-1, 1 - vinylidene chloride-co-isobutyl Methyl ester); poly (styrene-co-maleic anhydride), and some cyclohexyl / isopropyl ester, cumene end-capped The; poly (4 - ethyl styrene-co-divinylbenzene); poly (dimethylsiloxane-co-dimer acid), Bis (perfluoro-dodecyl) capped; poly (styrene-co-maleic anhydride), partial propyl ester, dry Alkenyl-terminated; poly (dimer acid-co-ethylene glycol), hydrogenated; poly (ethylene-co-methacrylic acid condensation Water, glycerol); poly [dimethyl siloxane-co-methyl (3 - hydroxypropyl) siloxane]-graft (graft) - Poly (ethylene glycol) of 3 - amino propyl ether; poly (dimer acid-co-1, 6 - hexanediol-co-adipate), hydrogenated The; poly (3,3 ', 4,4' - biphenyl tetracarboxylic dianhydride-co-1, 4 - phenylene diamine), and the amic acid solution; and poly [N, N'-bis (2,2,6,6 - tetramethyl-4 - piperidyl (piperidinyl)) -1,6 - hexanediamine-co-2, 4 - dichloro-6 - Morpholino-1, 3,5 - triazine]. ...
Especially, segmented copolymer can comprise a kind of ABC three block structures, and it has for example a butyl polyacrylate section, a polyethyl acrylate section and polyisobutylene acid section.This segmented copolymer can comprise a kind of diblock and/or triblock copolymer, and it has two or more different poly--aliphatics-acrylate sections.In addition, segmented copolymer can comprise a kind of diblock and/or triblock copolymer, and it has two or more gathering-alkyl-acrylate section.
In addition, segmented copolymer can use with a kind of washing agent and/or a kind of lipid, or is replaced by them in some embodiments.For example, washing agent can include but not limited to: AOT, brij family, lgepal family, triton family, SDS, and every kind derivant.Especially, washing agent can comprise dioctyl sodium sulphosuccinate salt, polyglycol lauryl ether, octylphenoxy polyethoxy ethanol, octyl phenyl polyglycol, uncle's octylphenoxy polyethoxy ethanol, polyglycol uncle octyl phenyl ether, 4-(1,1,3,3-tetramethyl butyl) phenyl-polyglycol, lauryl sodium sulfate salt and glycollic acid ethoxyquin Octyl Ether.And this segmented copolymer can comprise lipid, such as, but not limited to the derivant of: lipid-PEG, natural lipid, synthetic lipid, sphingolipid and every kind.
Nanostructured can be connected to a kind of probe molecule.Probe molecule can be any molecule that can directly or indirectly be connected to nanostructured by a kind of connector.Probe molecule can be connected to nanostructured by any firm physics or chemical association (association) directly or indirectly by any suitable method.
At a kind of embodiment, probe molecule has a kind of affinity to one or more target molecules (as cancer cell), to its detection (as determine to exist and/or in the close position of blood vessel (health) lining) expect.For example, if target molecule is a nucleotide sequence, thereby should select probe molecule roughly with the complementation of target molecule sequence, the hybridization of target and probe so takes place.Term " roughly complementary " is meant that probe molecule is sufficiently to be complementary to target sequence to hybridize under the reflection condition of selecting.
Probe molecule and target molecule can include but not limited to, polypeptide (as albumen such as, but not limited to a kind of antibody (monoclonal or polyclone)), nucleic acid (monomer and oligomerization), polysaccharide, sugar, fatty acid, steroids, purine, pyrimidine, medicine (as little compound medicine), part or its combination.
Use phrase " polypeptide " or " albumen " to be meant and comprise a kind of protein, a kind of glycoprotein, a peptide species, a kind of peptide and analog, or natural separation from virus, bacterium, plant or animal (as mammal, people for example) source or synthetic and its fragment.A kind of preferred albumen or its fragment include but not limited to: a kind of antigen reactivity fragment of a kind of epi-position of a kind of antigen, a kind of antigen, a kind of antibody or a kind of antibody.
Use phrase " nucleic acid " to be meant and comprise DNA and RNA, or natural separation from virus, bacterium, plant or animal (as mammal, people for example) source or synthetic, strand, double-stranded, comprise natural or the nucleotide that non-natural produces or the nucleotide of chemical modification.
In addition, probe also can include but not limited to, medicine, therapeutic agent, radiology agent, small-molecule drug and its combination, and it can be used for the treatment of target molecule and/or interested relevant disease or state.Medicine, therapeutic agent and radiology agent can be selected based on the treatment of plan and state to be treated and/or disease.At a kind of embodiment, nanostructured can comprise that two or more are used for the treatment of the probe of state and/or disease.
Below be the non-limiting example tabulation of operable probe: Proleukin TM, Campath TM, Panretin TM, Zyloprim TM, Hexalen TM, Ethyol TM, Arimidex TM, Trisenox TM, Elspar TM, TICE BCG TM, Targretin TM, Blenoxane TM, Bulsulfex TM, Myleran TM, Methosarb TM, Xeloda TM, Paraplatin TM, BCNU, BiCNU TM, Gliadel Wafer TM, Celebrex TM, Leukeran TM, Platinol TM, Leustatin ,-2-CdA TM(leustatin), Cytoxan (endoxan), Neosar TM, Cytoxan Injection TM, CytoxanTablet TM, Cytosar-U TM(Cytosar), DepoCyt TM, DTIC-Dome TM, Cosmegen TM, Aranesp TM, DanuoXome TM, Daunorubicin TM, Cerubidine TM, Ontak TM, Zinecard TM, Taxotere TM, Adriamycin (adriamycin), Rubex TM, Adriamycin PFSInjectionintravenous (intravenous injection) Injection TM, Doxil TM, Dromostanolone TM, Masterone TM, Elliott ' s B Solution TM, Ellence TM, epogen TM, Emcyt TM, Etopophos TM, Vepesid TM, Aromasin TM, Neupogen TM, FUDR TM, Fludara TM, Adrucil TM, Faslodex TM, Gemzar TM, Mylotarg TM, Zoladex Implant TM, Zoladrex TM, Hydrea TM, Zevalin TM, Idamycin TM, IFEX TM, Gleevec TM, Roferon-A TM, Intron A TM, Camptosar TM, Femara TM, Wellcovorin (calcium leucovorin preparation), Leucovorin TM, Leucovorin TM, Ergamisol TM, CeeBU TM, Mustargen TM, Megace TM, Alkeran TM, Purinethol TM, Mesnex TM, Methotrexate TM, Uvadex TM, Mutamycin TM, Mitozytrex TM, Lysodren TM, Novatrone TM, Durabolin-50 TM, Verluma TM, Neumega TM, Eloxatin TM, Paxene TM, Taxol TM, Aredia TM, Adagen (adenosine deaminase) TM, Oncaspar TM, Neulasta TM, Nipent TM, Vercyte TM, Mithracin TM, Photofrin TM, Matulane TM, Atabrine TM, Elitek TM, Rituxan TM, Prokine TM, Zanosar TM, Sclerosol TM, Nolvadex TM, Temodar TM, Vumon TM, Teslac TM, Thioguanine TM, Thioplex TM, Hycamtin TM, Fareston TM, Bexxar TM, Herceptin TM, Vesanoid TM, Uracil Mustard Capsules TM, Valstar TM, Velban TM, Oncovin TM, Navelbine TM, and Zometa TM
At a kind of embodiment, nanostructured can comprise at least two class probes, and a class is the target probe, its target in the cell or the compound of a kind of state and/or disease association, and another kind of be a kind of medicine that is used for the treatment of disease.By this way, nanostructured as a kind ofly detect composition, to the transportation composition of interested cell with to the transportation composition of therapeutic agent.The detection of nanostructured can be used to guarantee nanostructured is transported to the destination of its expectation, and guarantees to be transported to the amount of the nanostructured of destination.
The disclosure provides the method for making nanostructured.See Current Opinion inBiotechnology 2002,13,40-46; Nature Biotechnology 2004,22,969-976 merges to herein as a reference.A kind of model's method is described in following embodiment 1.
The disclosure provide a kind of sample or experimenter (as, mammal, people, cat, dog, horse or the like) detect the method for one or more target molecules, and detect target molecule especially in vivo.For example, nanostructured can be used to detect the existence of animal tumor, as embodiment 1 in detail ground is described in detail and uses nanostructured.
It should be noted that nano-substance and segmented copolymer can self-assembly be two dimension or three-dimensional microstructures,, interact and its combination such as, but not limited to hydrophobic interaction, aqueous favoring interaction, electric charge interphase interaction, π-stack by interacting.Self-assembly can be carried out in solution or emulsion or on the matrix.Microstructure can be ordered structure or disordered structure.Microstructure can comprise at least a nanoparticle and a kind of segmented copolymer, or comprises multiple nano-substance and multiple segmented copolymer.
It should be noted that also preformed microstructure can be doped with a class or multiclass nanostructured.Especially, can doped nanometer with the preformed microstructure (as a kind of (as the sphere) porous microstructure in the multiple shape) of segmented copolymer preparation, by interacting, such as, but not limited to hydrophobic interaction, aqueous favoring interaction, electric charge interphase interaction and its combination, depend on nanostructured surface bag quilt and segmented copolymer chemical association.
As mentioned above, also it should be noted nanostructured can be used as the part of treatment (as medicament transport), as being transported to indication and its combination of one or more targets (as cancer), be used for detected state and/or disease, such as, but not limited to, cancer, tumour, neoplastic disease, autoimmune disease, inflammatory disease, metabolism state, neurology and neurodegenerative disease, virosis, dermatological diseases, angiocardiopathy, infectious disease and its combination.
At a kind of embodiment, single nano-substance of planting with segmented copolymer bag quilt, nanoparticle-the polymer composite body that perhaps comprises one or more nano-substances, can be used as probe or contrast-medium injection to the experimenter (as, people, performing animal and domestic animal) to detect primary tumor.These nanostructureds can be connected to biocompatible compound (as PEG and glucosan) with long circulation " passive target " agent, and/or are connected to biological affinity probe (as antibody, antigen, peptide, oligonucleotides, micromolecule part and medicine) with " initiatively " target primary tumor.
It should be noted that cell can be used nanostructured and/or microstructure mark (in external or body) in advance.For example, cell can be in external use nano-substance-segmented copolymer microstructure by immunostaining, absorption, microinjection, cellular uptake and similar mark.Can perhaps follow the trail of cell in vivo at external monitoring cell then, nanoparticle as tracer, fluorescence, magnetic, its combination and analog.
It should be noted that also nanostructured and/or microstructure can be used as the agent of a kind of body interimage, in blood pond, liver, spleen, heart, lung and analog.For example nanoparticle-segmented copolymer microstructure can be expelled to animal, and by changing its architectural feature, such as size and/or pan coating, these microstructures can preferentially be positioned at certain organs or rest in the blood flow as contrast preparation.
It should be noted that also segmented copolymer should be used to control the degraded of nano-substance.For example, segmented copolymer can be used for the degraded under protection (causing biocompatibility) nano-substance antibiont condition, in particular for using in the body, perhaps is used to control the degradation rate/degree of nanostructured, by changing the molecular structure of segmented copolymer.
The cancer of Shi Yonging is its ordinary meaning as it herein, is the generic term of the disease that divides uncontrollably for abnormal cell.Cancer cell can be invaded adjacent tissue and is diffused into the other parts of health by blood flow and lymphatic system.
The cancer that several main types are arranged, for example the cancer knurl is to occur in skin or the tissue, arranges or cover the cancer of internal organ.Sarcoma is the cancer that occurs in bone, cartilage, fat, muscle, blood vessel or other connective tissue or supporting tissue.Leukaemia is the cancer that occurs in blood formative tissue such as marrow, and causes producing a large amount of abnormal blood cells and enter blood flow.Lymthoma is the cancer that occurs in immune system cell.
When normal cell loses ability, in the time of can not be as specificity, controlled and collaborative unit, have just formed tumour.Usually, solid tumor is unusual a large amount of tissues, and it does not comprise tumour or liquid regions (some brain tumors have tumour, and middle necrotic zone full of liquid) usually.In the single tumour even the cell that can have different groups, it has the different lesions of having made mistakes.Solid tumor can be optimum (non-carcinous) or pernicious (carcinous).Dissimilar solid tumors is according to the cell type name that forms them.The example of solid tumor is sarcoma, cancer and lymthoma.Leukaemia (cancer of blood) does not form solid tumor usually.
Representational cancer includes but not limited to, carcinoma of urinary bladder, breast cancer, colorectal cancer, carcinoma of endometrium, head and neck cancer, leukaemia, lung cancer, lymthoma, melanoma, non-small cell lung cancer, oophoroma, prostate cancer, carcinoma of testis, the cancer of the uterus, cervix cancer, thyroid cancer, cancer of the stomach, brain stem glioma, cerebellar astrocytoma, big cerebral astrocytoma, glioblastoma, ependymoma, Ewing's sarcoma family tumour, gonioma, the outer cancer of cranium, Hodgkin's disease, leukaemia, acute lymphoblastic leukemia, acute myeloid leukaemia, liver cancer, medulloblastoma, neuroblastoma, it normally is brain tumor, non-Hodgkin lymphoma, osteosarcoma, malignant fibrous histiocytoma of bone, retinoblastoma, rhabdomyosarcoma, it normally is soft tissue sarcoma, PNET and pinealoma on the curtain, visual pathway and hypothalamus glioma, wilms' tumor, acute lymphatic leukemia, adult's acute myelocytic leukemia, adult's non-Hodgkin lymphoma, chronic lymphocytic leukemia, chronic granulocytic leukemia, the cancer of the esophagus, hairy cell, kidney, Huppert's disease, carcinoma of mouth, cancer of pancreas, primary central nervous system lymphoma, cutaneum carcinoma, small-cell carcinoma of the lung, and other.
Tumour can be divided into pernicious or optimum.Two kinds of situations, the unusual gathering and the hyperplasia of cell arranged all.In the situation of malignant tumour, cell more has aggressiveness expressively, obtains the characteristic that invasiveness increases.Finally, tumour cell in addition can capacitation with break away from they from microscopy environment, be diffused into another zone (having very different environment, is not the growth that benefits them usually) of health and continue their quick growth and division at this reposition.This is called transfer.In case pernicious cell has shifted, just more difficultly reach healing.
The trend of benign cell invasion and attack is less, is not easy to shift.Brain tumor is diffusion widely in brain, but does not transfer to outside the brain usually.Glioma is very invasive in brain, even passes through hemisphere.They are with not controlled way division.Depend on its position, they can be fatal as malignant lesion.Its example will be the benign tumour in the brain, and the space that it will be grown and take in the skull causes the brain internal pressure to increase.
The angiocardiopathy of Shi Yonging herein, should be meant the meaning that it is common, include but not limited to hypertension, diabetes, coronary heart disease, valvular heart disease, congenital heart disease, cardiac arrhythmia, cardiomyopathy, CHF, atherosclerotic, inflammatory or unsettled patch correlation behavior, the narrow again disease of blood vessel (restenosis), infraction formation, thrombosis, operation after coagulation sexual dysfunction and apoplexy.
The inflammation disease of Shi Yonging herein, should be meant the meaning that it is common, can include but not limited to that autoimmune disease such as arthritis, rheumatoid arthritis, multiple sclerosis, systemic loupus erythematosus, other disease be asthma, psoriasis, inflammatory bowel syndrome, neurodegenerative disease such as Alzheimer disease, Parkinson's, Huntington disease, vascular dementia and other pathological state such as epilepsy, antimigraine, apoplexy and wound for example.
The autoimmune disease of Shi Yonging herein, should be meant the meaning that it is common, include but not limited to, alopecia areata, ankylosing spondylitis, anti-phosphatide syndrome, the autoimmunity Addison's disease, alpastic anemia, autoimmune hemolytic anemia, autoimmunity hepatitis, Behcet, biliary cirrhosis, bullous pemphigoid, canavan's disease, cardiomyopathy, sprue-dermatitis, confirmed fatigue immune dysfunction syndrome (CFIDS), the chronic inflammation demyelinating polyneuropathy, the allergic granuloma syndrome, cicatricial pemphigoid, the CREST syndrome, cold agglutinin disease, clone disease, dermatomyositis, the Xi Erdeshi DCS, discoid lupus, essential mixed eryoglobulinemia, fibromyalgia-fibromyositis, fuchs' heterochromatic iridocyclitis, grave disease, barre-Guillaian syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, ITP (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, intermediate uveitis, juvenile arthritis, lichen planus, lupus, Mnire ' s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, nephrotic syndrome, pemphigus vulgaris, pernicious anaemia, polyarteritis nodosa, polychondritis, polyadenous body syndrome, polymyalgia rheumatica, PM-DM, primary agammaglobulinemia, PBC, psoriasis, Raynaud's phenomenon, the Lai Teer syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, chorionitis, the Si Yegelun syndrome, stiff body syndrome, aorto-arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, vasculitis, leucoderma, VKH (Vogt-Koyanagi-farmland on a plateau San Shi) disease, Wegner's granulomatosis, anti-phospholipid antibody syndrome (lupus anticoagulant), Qiu-Shi two syndromes (allergic granulomatosis), dermatomyositis/polymyositis, the Goodpasture syndrome, have arthritic matter granuloma dermatitis, lupus erythematosus (SLE, DLE, SCLE), mixed connective tissue disease, relapsing polychondritis, the HLA-B27 correlation behavior comprises ankylosing spondylitis, psoriasis, ulcerative colitis, the Lai Teer syndrome, and uveal disease.
The virosis of Shi Yonging herein, should be meant the meaning that it is common, comprise target virus such as, but not limited to, paramyxovirus, blood-shoot-eye illness virus (picoma-), rhinovirus, Coxsackie virus, influenza virus, herpesviral, adenovirus, parainfluenza virus, respiratory syncytial virus, echovirus, coronavirus, epstein-Barr virus, cytomegalovirus, varicella virus, and hepatitis (as variant, comprises hepatitis C virus (HCV), hepatitis A virus (HAV), hepatitis type B virus (HBV), Hepatitis D virus (HDV), hepatitis E virus (HEV), own Hepatitis virus (HFV), Hepatitis G Virus (HGV), human immune deficiency disease).
The neurological status of Shi Yonging should be meant the meaning that it is common herein, can be divided into three classes usually: with ischaemic or hypoxic disease; Neurodegenerative disease (is seen people such as Adams, Principlesof Neurology, 1997,6 ThEd., New York, pp 1048); Disease on the neurological and psychiatry relevant with nerve cell death.
Disease with ischaemic or the low mechanism of oxygen level can be further divided into systemic disease and cerebral ischemia.The example that relates to this systemic disease of the low mechanism of ischaemic or oxygen level comprises miocardial infarction, cardiac insufficiency, in heart failure, congestive heart failure, myocarditis, pericarditis, perimyocarditis, coronary heart disease (coronary artery stenosis), angina pectoris, congenital heart disease, shock, the epiphysis ischemic, RAS, diabetic retinopathy, thrombosis with malaria, prosthetic heart valve, anaemia (anemias), high spleen syndrome (hypersplenic syndrome), pulmonary emphysema, pulmonary fibrosis, and pulmonary edema.The example of cerebral ischemia disease comprises apoplexy (and hemorrhagic apoplexy), brain microangiopathy (small vessel disease), cerebral ischemia when producing, heartbeat stops or recover in/afterwards cerebral ischemia, because the cerebral ischemia in the cerebral ischemia of problem, the arteria carotis operation in the operation, because to thrombosis, cerebrovascular malformation and the diabetic retinopathy of cerebral ischemia, sinus thrombosis formation or the brain vein of the arteriarctia of brain supply blood.
Neurodegenerative disease can include but not limited to, amyotrophic lateral sclerosis (ALS), Parkinson's, Huntington disease, Wilson's disease, multiple system atrophy, Alzheimer disease, Pick's disease, Louis body (Lewy body) disease, Hallervorden Spatz disease, TD, heredity sensorimotor neuropathy (HMSN), Jie Ciman-Si Tuosile-Shi Yin restrains syndrome (Gerstmann-Straussler-Scheinker syndrome disease), Creutzfeldt-Jakob disease, Ma-Yue disease, Friedreich ataxia, non--Friedreich ataxia, lucky tired this moral Latourette syndrome, familial tremor, the olivopontocerebellar degeneration, secondary tumprigenicity brain syndrome, hereditary spastic paraplegia, heredity optic nerve disease (Leber), retinal pigment degeneration, recessive macular dystrophy, and Ji-Sai two syndromes.
With the example of the neurology of nerve cell death and psychiatric disorders comprise septic shock, IC hemorrhage, subarachnoid hemorrhage, multiple sclerotic dementia, inflammatory disease (vasculitis, multiple sclerosis and Ji Lan-Ba Lei syndrome), neurotrosis (as spinal cord injuries receptor and cerebral trauma), peripheral neurophaty, polyneuropathy, epilepsy, schizophrenia, metabolic encephalopathy and central nervous system infection (as, virus, bacterium, fungi).
Embodiment 1
Described the embodiment of nanostructured substantially, embodiment 1 has described some embodiments and its use of nanostructured.Below be the non-limiting example of one embodiment of the present invention, it is described in greater detail in people such as Gao, Nature Biotechnology, and 22,8 (2004), it is incorporated in herein as a reference.This embodiment is not meant the scope of restriction any embodiment of the present disclosure, and provides specific condition of experiment and result.Therefore, it will be apparent to those skilled in the art that many experiment conditions all can be changed, be intended that these and change in the scope of embodiment of the present disclosure.
The multifunctional nano microparticle probes of based semiconductor quantum dot (QD) has been developed in fixed and imaging to cancer target in live animal.Structural design relates to the ABC triblock copolymer bag quilt luminous QD, then this amphipathic nature polyalcohol is connected to fixed part of tumour target and medicament transport functionality.Target in the body that is grown in the human prostate cancer in the nude mouse is studied expression surely, and the QD probe can be transported to tumor sites, by the infiltration that strengthens with retain and by the antibody in conjunction with cancer specific cell surface biomarker.Use the cancer cell of hypodermic injection QD-label and system to inject multi-functional QD probe and cause in vivo the responsive and multicolor fluorescence imaging to cancer cell under the condition.This embodiment has also reported the big illuminator of associating whole body and has resolved the wave spectrum imaging, to remove background effectively and accurately to describe the peak light spectrum signal.These results have improved the hypersensitive and the new possibility of multiple imaging of molecule target in the body.
The result
Probe design: the QD probe that is used for the biological conjugation of the fixed and imaging of cancer target in the body is decided principle by use medicament transport and target and is designed.As schematically showing at (Fig. 3), nuclear-shell CdSe-ZnS quantum dot is by ligand (TOPO) and amphipathic nature polyalcohol coated for protecting.Because the strong hydrophobic interaction between TOPO and the polymer hydrocarbon, this two-layer " combination " mutually also forms hydrophobic protection structure, and even its antagonism hydrolysis and enzymatic degradation are under the compound condition in vivo.With the simple aggregation thing that uses in the existing research and amphipathic lipids relatively, method described herein is with high molecular (the about 100kD of MW=) multipolymer, it has 8-carbon (C-8) alkyl branches (Fig. 3 B) of meticulous ABC three block structures and grafting.This triblock polymer comprises a kind of butyl polyacrylate section (hydrophobic), a kind of polyethyl acrylate section (hydrophobic), a kind of methacrylate section (hydrophilic) and a kind of hydrophobic hydrocarbon side chain.The discovery of a key is that this polymkeric substance can be by the self-assembly process dispersion of while and the QD of Sheet TOPO-bag quilt.The result is; QD is protected to a kind of degree, and their optical characteristics (as absorption spectrum, emission spectrum and fluorescence quantum yield) is not changing with salt condition (0.01 to 1M) or after handling with 1.0M hydrochloric acid (QD that PEG-is connected) harshness at wide pH (1 to 14).
Dynamic light scattering (DLS) is measured expression, and the hydrodynamic radius of the QD probe of assembling is about 10 to 15nm (parts that depend on connection).This value is consistent with a kind of compact probe structure, and this structure comprises 5-nm QD nuclear (2.5nm radius), a 1-nm TOPO cap, a 2-nm thick polymer layer and a 4-5-nm PEG/ antibody layer.Represent that it is considerably big that the hydrodynamic radius of QD can " be done " radius than their TEM, but the TEM value of being reported is not represented the actual physical size of the QD of organic bag quilt.Reason is that organic material (such as the biomolecule of TOPO, polymkeric substance and combination) is not that enough electronics are close with observable at nanoscale TEM.Do not contacted external environment condition because QD is closely protected, their fluid mechanics behavior is mainly by surface-Bao tegillum control.Similarly, the quantum dot of polymer coating should be similar to the polymer micelle or the nanoparticle behavior of standard, and the QD of bag quilt compares with nanoparticle with big molecule can not have different hydrodynamic characteristics.
Constraint and ligand coupling efficient (about 40-50% based on geometry/size, determine by using fluorescently-labeled part experiment), estimate that each point comprises about 200TOPO molecule, about 4 to 5 triblock copolymer molecules, about 5 to 6PEG molecules and about 5 to 6 antibody molecules.Lean solution (10 when the biological conjugation of QD -12When M) spreading over glass surface, high sensitive fluorescence imaging is represented " flash of light " signal.This flash of light behavior is the feature of single quantized system such as single dye molecule and single QD, and the expression triblock copolymer is distributed to single particulate with point effectively.Preliminary TEM result has also disclosed the QD probe and has been made up of single particulate, has seldom to assemble or do not assemble.Yet it should be noted that the QD flash of light does not have adverse effect for cancer imaging in the body, because tumour cell is far from the single-point state with the QD mark of large group (up to 1,000,000).
In conjunction with level, it does not disturb antibodies at current PEG, as being confirmed by positive cell dyeing.At higher PEG density or long chain, the remarkable interference that combines with part can take place, as before pegylated liposomal being reported.In order to reduce interference, the fixed part of target can be connected to the end far away of PEG.Yet the part of Bao Luing can cause non-specific cell picked-up or immune response fully, thereby reduces the biocompatibility of probe and round-robin duration in vivo.
The tumour target is fixed: under the condition, the QD probe can be transported to tumour in vivo, by decided mechanism and active target fixed machine-processed (Fig. 3 C) by moving-target.In passive mode, the particulate of big molecule and nanometer size preferentially is collected at knub position, by enhanced permeability with retain (EPR) effect.Think that this effect is from two factors: (a) produce the angiogenesis tumour of VEGF121 (VEGF), this growth factor makes the super infiltration of neovasculature and cause big molecule of round-robin and small particle seepage; (b) lack the tumour of effective lymph excretory system, it causes subsequently big molecule or nanoparticle to be gathered.Fixed for active tumour target, the quantum dot of antibody-combination has been used for target and has decided Prostato-specificity cell surface antigen PSMA.Research has before this illustrated that PSMA is a kind of cell surface marker thing, for prostate epithelial cell and neovascular epithelial cell.PSMA is selected as a kind of attractive target, and the imaging and the treatment that are used for prostate cancer are intervened.PSMA antibody is the basis that radio-immunity scintiscanning (as ProstaScint scanning) and target are treated the human benign prostatic metastasis of cancer surely in gathering and retaining of tumor growth site.
Be incorporated into the QD probe of the PSMA monoclonal antibody J591 of the extracellular domain of discerning PSMA, at first estimated in prostate cancer cell line in conjunction with PSMA.The immunocytochemistry data acknowledgement strong and specificity in conjunction with the QD probe of PSMA Ab J591-combination in human benign prostatic cancerous cell line C4-2, known this clone is at cell surface expression PSMA (Fig. 4, upper plate).Use the comparative study of QD-PEG (no antibody) to represent to have only low-level non-specific cell to be incorporated into C4-2 cell (Fig. 4, middle plate).Use the other comparative study of PC-3 cell (a kind of human benign prostatic cancerous cell line of PSMA feminine gender) also to represent not have QD in conjunction with (Fig. 4, lower plate).These results determine that PSMA antibody-QD bond keeps their PSMA in conjunction with activity and specificity.
In order to study the behavior of probe in live animal of QD-PSMA Ab combination, below in this research, having checked: their specificity picked-up with retain, background or non-specific uptake, blood is removed and organ distributes and their related with the QD finishing.Fig. 5 A and 5B represent to obtain after single tail intravenously administrable QD-PSMA Ab bond from nude mouse, the contrast histological data of expression xenograft (Fig. 5 B) and six kinds of normal host organs (Fig. 5 A).As the characteristic from quantum dot red-fluorescent orange is being seen, non-specific QD picked-up and retaining mainly occurs in liver and the spleen, having seldom in brain, heart, kidney or lung, QD gathers or does not have.The picked-up of this intracorporeal organ and distribution mode are similar to the magnetic iron oxide nanoparticle of glucosan-Bao quilt.QD for too much COOH group polymer coating does not observe cancer target, represents non-specific organ picked-up and blood removing fast.For the QD with surface PEG group polymer coating, the speed of organ picked-up reduces, and sanguimotor length increases, and causes nanoparticle slowly to be gathered in tumour.For the QD with PEG bag quilt and biological conjugation PSMA antibody, nanoparticle betransported and is kept by tumor xenogeneic graft, but non-specific liver and spleen picked-up remain apparent.
Observing passive tumour target only has surely and increases the QD-PEG of dosage bond (6nmol injection adds preclinical probe circulation in 24-hour).By comparison, the QD-COOH bond of finding same dosage has gathering seldom in tumour since in athymic host passive target after the same length circulation.QD picked-up and the poor efficiency that retains be probably because the extra negative charge (free carboxylic acid groups on the polymer coating) on the detecting probe surface, known its reduce probe flood rate with and gathering in tumor xenogeneic graft subsequently.
Cancer imaging in the body: Fig. 6 A to 6D represents the light spectrum image-forming result, is expelled to the tail vein of the mouse that has tumour and control mice (no tumour) and obtains from PSMA-Ab QD probe.Original image (Fig. 6 A) is illustrated in the autofluorescence background (mouse skin) at the QD of tumor sites signal.Use the algorithm of the non-mixing of spectrum, fluorescence background signal (Fig. 6 B) can separate with QD signal (Fig. 6 C).Combination picture (Fig. 6 D) is clearly represented whole animal and tumor sites.The contrast that the right figure in bottom strengthens represents, the QD probe can find out from the background that essence is deceived, and has seldom or less than the interference from the mouse autofluorescence.Use other test chart of branch of the external quantum dot that excites to show that the light spectrum image-forming technology can be used for many fluorescence signals of non-mixing, it is little of 5nm (result does not show) in the peak difference.Therefore, represent that from the ability that autofluorescence is got rid of interference capability and differentiated a plurality of synchronous signals light spectrum image-forming will have sizable purposes, when with the time based on the labelling strategies combination of quantum dot.
This research has checked further how the functional group on the QD detecting probe surface influences the in-vivo imaging result.Fig. 7 has compared the in-vivo imaging result from three class finishinges: COOH group, PEG group and PEG add PSMA Ab.Consistent with histological examination, do not detect tumor signal with the COOH probe; Only observe weak tumor signal (fixed) with the PEG probe by moving-target; Detect strong signal (initiatively target is fixed) with PEG-PSMA Ab bonding probes.This relatively provides further evidence, illustrate by using the tumour-specific part active tumour target surely than based on the tumour infiltration, absorb and retain by moving-target surely more quickly and effectively.
The comparison of probe and GFP brightness and spectrum: tag and be used for cancer imaging in the body because fluorescin such as the GFP of genetic coding has been used to pair cell, so the importantly relatively detection sensitivity and the spectral signature of GFP and QD probe.For this purpose, at first QD is connected to transposition peptide (such as HIV Tat or poly arginine), and is transported to cancer cell alive.Similar peptide has been used to transport magnetic nanometer particles and has been used for monitoring cell migration and integration in the body to living cells.Fluorescence intensity measurement represents that as many as 3,000,000 QD can be transported to each cancer cell.Surprisingly, the QD of this level load does not influence cell survival degree and growth, because being implanted in of the cancer cell of QD-label causes usual tumor growth in the animal model.
Fig. 8 A represents in-vivo imaging data that the cell of the QD-label of same number (about 1000) and stably GFP-transfected cell are injected into the host mouse both sides.Although the cell of QD-label similar with the brightness in cell culture of GFP-transfected cell (two figure in the right) is only observed QD signal (orange luminescence on right side) in the body.Can not distinguish GFP signal (ring in left side) in injection site.This result can not provide to the absolute strength between GFP and the QD relatively, because a plurality of factor (such as optical density and tissue scatter) is difficult to standardization or calibration.On the contrary, this be qualitative spectrum relatively, the emission spectrum that prove QD can be converted and leave autofluorescence, permission detects in the low signal intensity beam split.By comparison, organic dyestuff and fluorescin cause little Duo conversion (strokesshift), cause GFP emission and background fluorescence in same SPECTRAL REGION.The brightness of QD and spectrum conversion advantage further are shown in Fig. 9 A and 9B and 10A and 10B.
Another key character is the big absorption coefficient of QD, and this makes them in the limited body of photon under the condition (wherein light intensity be scattered and absorption seriously undermines) become brighter probe.In order to appreciate this feature, can compare the photophysics of quantum dot and organic dyestuff.In theory, limited emissivity of the life-span of single quantum dot is than low 5-10 times of single organic dyestuff, because their long lifetime of excited states (20-50ns).Yet in fact, fluorescence imaging is operated under the limited condition of absorption usually, and wherein absorptivity is the key constraints of fluorescent emission.Because the molar extinction coefficient of QD (0.5-2 x10 6M -11cm -1) be organic dyestuff (5-10 x 10 4M -1Cm -1) about 10-50 doubly, the QD absorptivity will fast 10-50 be doubly when the same excitation photon flux than organic dyestuff.Because photoemissive speed increases, single QD shows as bright 10-20 doubly than organic dyestuff, and this is confirmed by present document experiment.
The microballon polychrome in-vivo imaging with the QD-coding has further been probed in this research.For this purpose, three kind of 0.5 μ m polymeric beads subsample mix respectively green, yellow or red QD are expelled to three diverse locations of mouse model, and being similar in advance, the use fluorescence pearl of report is used for cell differentiation and transportation research.Because common big Duo conversion (stroke shift) and the wide excitation spectrum of QD are observed all three kinds of colors (Fig. 8 B) simultaneously with single source in same mouse.
Discuss
Before this work, a plurality of seminar have reported that use QD is used for susceptibility biological detection and cell imaging, but notice significant fluorescence losses after to live animal administration quantum dot.Although the accurate source of sort signal loss is not clear, recent research represents that surface ligand is slowly degraded with being coated in the body fluid, causes surface imperfection and fluorescence quenching.This mechanism supported by following observations, and promptly surface imperfection can be excited and annealed by continuous laser, and (relating to surface structure changes) can be partly stored in the loss of QD fluorescence.The QD probe of reporting in this work is represented a kind of remarkable improvement, because they are high stability to vivo degradation.An important feature is the triblock copolymer of high molecular, and it fully wraps by TOPO-QD and forms the stable hydrophobic protective layer that centers on single QD.
On the water-wetted surface of this polymeric layer, a large amount of functional group (400 to 500 hydroxy-acid groups according to appointment) is arranged, it allows connection diagnostic agent and therapeutic agent.Have the micromolecule part such as synthetic organic molecule, small oligonucleotide and peptide, many copies of same part can be connected to single-point, cause the QD-target combination of multivalence.Research in advance represents that correctly She Ji multivalent ligand can increase by 10 orders of magnitude of binding affinity.Use is connected to the colloidal gold nanoparticle of oligomer in high superficial density, and is verified, and the sequence selective of DNA hybridization can improve 100 to 1000 times (more sharp-pointed thawing curves).Research is also represented, the sharp binding specificity of QD-peptide bond performance is most likely because be incorporated into the surface that the multivalence peptide of protein targets is distributed in tumor vascular system.This new feature is non-existent at organic dyestuff and fluorescin, and can allow density and the distribution design multivalence QD probe of target cancer cell based on the cell surface biomarker.This may provide a kind of New Policy to cancer molecular diagnosis and treatment because real unique cancer biomarker normally can't obtain or exist with extremely low concentration.
In addition, the QD probe of polymkeric substance-Bao quilt is useful on the excellent dimensional scope of in-vivo tumour target.With little peptide-dye conjugates, overflow fast and cause probe in less than 1 minute, to be removed usually by blood.By connecting little probe to big molecule or nanoparticle, circulation or retention time can be increased, and this is a widely used strategy in the medicament transport research.In fact, described work represents that the QD of PEG-protection can circulate and grow to about 48-72 hour in blood, and the half life period is about 5-8 hour.Simultaneously, these probes are enough little for the cell surface receptor that is attached to of necessity, with by endocytosis or peptide transposition and internalization and pass nucleopore to enter nucleus (peptide of position is appraised and decided in use) (Fig. 8 A, upper right).Yet the degree of depth that QD is penetrated into solid tumor will be limited, at least in part by its nano-scale.
Unique optical signature of QD also provides polychrome imaging and multiple new possibility.For example, the polychrome imaging will allow location and quantifying target measurement altogether on metastatic tumo(u)r site intensity is decided than (ratioing), space.The optical encoding strategy also may be based on using polychrome and many strength levels.The trial of this combined method is in middle proof that a large amount of genes, albumen and micromolecule storehouse are tagged.Except wavelength and intensity, the life-span fluorescence imaging has been represented a kind of new size.Because almost than (about 2-5ns) of organic dyestuff long order of magnitude, the QD probe should be suitable for the fluorescence lifetime imaging (FLIM) of cell, tissue specimen and live animal to the lifetime of excited state (about 20-50ns) of QD.
Current use orange/red-emissive quantum dots is not optimized for tissue infiltration or imaging susceptibility.The extensive work of organism optical represents, dark imaging of tissue (millimeter to centimetre) requires to use far-red light and the near infrared light of spectral range as 650-900nm.This wavelength coverage provides the view window of " clear " to optical imagery in the body, because the main absorption peak of it and blood and water is separated.Calculate based on organism optical, the quantum dot of estimated service life near infrared-emission should improve at least 10 times of tumor imaging susceptibilitys, can detect the 10-100 cancer cell sensitively.Towards this target, recent research has prepared the semiconductor-quantum-point of the new alloy of a class, is made up of cadmium telluride selenium, and adjustable fluorescent emission value height is to 850nm, quantum yield height to 60%.With nuclear-shell CdTeCdSe II section bar material, use near infrared-emission QD organizing length of penetration and cell detection susceptibility to bring main improvement.
Also has a toxicity and the body intracellular metabolic that problem is QD.Recent work represents that CdSeQD is a height toxicity at the long-term time phase pair cell of UV illumination.This is intelligible, because semiconductive particles is dissolved in the UV-radiation usually, the cadmium that discharges toxicity is in nutrient culture media.Do not have UV when radiation, the QD pair cell that this work represents to have stabilization of polymer bag quilt is nontoxic basically (pair cell division or ATP produce does not have influence).This document represents that research also confirms the nontoxic essence of the QD of protection stably in the body.This may be not astonishing, because polymer protective layer is so stable, QD nuclear can not be exposed to external environment condition.Consistent with this conclusion; research is before this represented; the ferric oxide nano particulate (up to every cell 1,000 ten thousand particulates) of picked-up glucosan-protection can significantly not reduce the cell survival degree, and the QD (up to every embryonic cell 2,000,000,000) of injection micella-protection can not influence the frog's embryo fetal hair and educate.In this work, do not reduce its survival degree or growth slightly up to 300 ten thousand QD in single cancer cell.
Yet, understand very few to the metabolism or the purge mechanism that are expelled to the QD probe in the live animal at present.For the QD of polymkeric substance-Bao quilt, the chemistry or the enzymatic degradation of semiconductor core can not take place.But the QD of polymkeric substance-protection may be removed from health, by the slow filtration and the drainage of kidney.
In a word, this research relates to a kind of new QD probe polymer coating and biological conjugation of exploitation and is used for cancer target and imaging in the body.These probes are bright, stable, and have general triblock copolymer structure, and it is suitable for well in conjunction with more diagnosis and therapeutic agent.In-vivo imaging is the result represent, the QD probe can be by passive and active mechanisms target in tumor sites, but passive target is slower and efficient is low than active target.When making up with the imaging of distinguishable ground of wavelength, the QD probe allows in live animal responsive and polychrome imaging to cancer cell.Use the near infrared emissive quantum dots to improve and organize length of penetration and imaging susceptibility.According to described research, quantum dot can be incorporated into target, imaging and therapeutic agent are used for non-invasive imaging, diagnosis and treatment cancer, cardiovascular plaque and neurodegenerative disease with exploitation " clever " nanostructured.
Method: animal uses step to be taken care of and examination of the use council and approval by the animal used as test of Emory university.
Material: unless otherwise mentioned, all (St.Louis MO) and without being further purified uses available from Sigma-Aldrich for all chemicals and biochemicals.A kind of monoclonal antibody (J591) to prostate specific membrane antigen (PSMA) is from Millennium Pharmaceuticals (Cambridge, friendship present MA).Film transposition peptide (Tat and poly arginine have and be used for the terminal biotin in conjunction with the c-of Streptavidin-QD) is by Invitrogen (Carlsbad, CA) synthetic and purifying.(CdSe of ZnS-bag quilt) is synthetic according to the document step for nuclear-shell quantum dot.The ligand solvent 3-n-octyl phosphine oxide (TOPO) of high temperature is used for this and synthesizes, and causes high-quality QD to be added cap by individual layer TOPO molecule.These points are height fluorescence (about 60% quantum yield) and single disperse (about 5% change in size).The microballon of QD-coding prepares by using 0.5 μ m mesopore microballon in the butanols, and separation and purifying as reporting before this.
By a kind of poly--the butyl acrylate section, a kind of poly--the ethyl acrylate section and a kind of poly--triblock copolymer that the methacrylate section is formed available from Sigma (St.Louis, MO).At molecular weight is about 100,000 dalton, and this polymkeric substance contains more than 1000 total monomer units, and weight distribution is the butyl acrylate and the ethyl acrylate of 23% methacrylate and 77% combination.In order to wrap by QD, about 25% free carboxylic acid groups is derived with octylame (a kind of hydrophobic side chain).Therefore, be dissolved in original polymer and n-octyl amine reaction in the dimethyl formamide (DMF), polymkeric substance/octylame mol ratio is 1:40, uses ethyl-3-dimethylaminopropyl carbodiimide (EDAC, 3 times of excessive n-octyl amines) as crosslinking chemical.Product output is usually greater than 90%, because at the high EDAC coupling efficiency of DMF (variation by the free octylame band in the thin-layered chromatography is determined).Reflection potpourri ratovap (Rotovapor R-3000, Buchi AnalyticalInc, Delaware) drying.Resulting oily liquids water sedimentation, and with water rinse 5 times to remove unnecessary EDAC and other accessory substance.After vacuum drying, octylame-polymers grafted is resuspended in ethanol/chloroform potpourri, and stores to use.
Finishing and biological conjugation: use 3:1 (v/v) chloroform/ethanol solvent mixture, the quantum dot that TOPO-adds cap is with amphipathic three block copolymer bag quilt.The ratio of polymkeric substance and QD is 5 to 10, because molecular geometry calculates expression, wraps fully by at least 4 polymer molecules of 1 quantum dot requirement.In fact, stable bag by (as, do not have and assemble) fail to reach during at a polymkeric substance/ratio less than 4:1.After vacuum drying, the point of bag quilt is suspended in the polar solvent (water-containing buffering liquid or ethanol), and is filtered and purifying by glue.Use then standard step with crosslinked free carboxylic acid groups (on each polymer molecule about 100) and contain amine part such as amine-PEGs (Sunbio, Korea), peptide and antibody.Say that briefly the point of polymer coating activates 30 minutes with 1mM EDAC at pH6.Behind the purifying, the point of activation and amine-PEG pH8 reaction 2 hours, produce the probe that PEG-connects with QD/PEG mol ratio 1:50.Replacedly, the point of activation and PEG with the QD/PEG ratio 1:6 that reduces pH8 reaction 20 minutes, then with the fixed antibody of tumour target with QD/ antibody mol ratio 1:15 reaction 2 hours.Final QD bioconjugates is filtered by post or 100,000g ultracentrifugation 30 minutes and purifying.Be resuspended in PBS damping fluid (pH7) afterwards, the particulate of gathering is removed centrifugal 10 minutes of 6000g.
The QD-Streptavidin is by using with the same crosslinking chemical (1-mMEDAC) of QD-antibody conjugates with in same experiment condition (1:15QD/ Streptavidin mol ratio, pH8, room temperature and 2 hours) preparation down.After post filtered purifying, the QD-Streptavidin mixed with QD/ peptide mol ratio 1:20 with biotinylated Tat (or poly arginine), and at room temperature cultivated accidental ultrasonic Treatment 30 minutes in the PBS damping fluid (pH7).Product is by the Filter column chromatography purification.Combining by using double-tagging peptide (biotin at one end, the organic dyestuff that is different from QD fluorescence is at the other end) of Tat or poly arginine and QD confirms.It is 20nM that peptide-QD bond is added to cell culture medium to final concentration, and cultivates 1 hour to 24 hours at 37 ℃.
Fluorescence imaging: in the body fluorescence imaging by use big-illuminator (Lightools Research, Encinitas CA) finishes, it is designed to small animal research specifically.Use two electric long-channel filtrators (Chroma Tech, Brottleboro, VT) and the color digital camera (Optronics, Magnafire SP, Olympus America, Melville NY) obtains true-Se fluoroscopic image.By using spectrum imaging system (CRI, Inc., Woburn, MA) realize the light spectrum image-forming that wavelength has been differentiated, this system comprises an optical head, it comprise the adjustable filtrator of a kind of liquid crystal (LCTF, bandwidth is 20nm, the scanning wavelength scope is 400 to 720nm), the monochromatic CCD camera of Scientific Grade of a photo-coupler and a cooling, and image obtains and analysis software.When camera when each wavelength is caught image with constant exposure, adjustable filtrator automatically from 580 to 700nm with 10nm increment substep.The acquisition time is about 10 seconds altogether.The tiff image of 13 gained is loaded onto internal memory individual data structure, forms the spectrum stack that has at the spectrum of each pixel.Use the spectrum imaging software, can detect and analyze little rapidly but significant SPECTRAL DIVERSITY.
Automatically fluorescence spectrum and quantum dot spectrum are selected from spectrum picture by the artificially, and mouse is selected suitable zone by using a computer.The algorithm of the non-mixing of application of spectral (from CRI, Inc., Woburn, MA provides) with the image of " pure " that produce non-mixing automatic fluorescence and " pure " quantum dot signal, this program is taking about 1 second on the personal computer usually.When suitably producing, the autofluorogram picture should be that intensity is uniform, does not consider whether there is the quantum dot signal (as the situation of Fig. 6 A to 6D).Differentiate effective spectrum for the purpose of non-mixing and only need primitively be carried out,, reuse in other spectrum stack because spectrum can be kept in the library of spectra.
Ultraviolet ray (330-385nm) light source (100-W mercury lamp) and the long-channel interference filter (DM400 of color digital camera (Nikon D1), wide-band are housed by use, Chroma Tech, Brattleboro, inversion Olympus microscope (IX-70) VT) is checked cell and tissue part.By use list-level spectrometer (SpectroPro 150, Roper Scientific, Trenton NJ) obtains the spectrum that wavelength has been differentiated.
Cell, tissue and intact animal research: the positive human prostate gland cancer cell of mankind mastopathy cell (MDA-MB-231) and PSMA (C4-2) is used to be transplanted to the Balb/c nude mouse of immunity-compromise.These two kinds of clones are cultivated at RPMI that has 10% hyclone respectively and T nutrient culture media.Conventional immunohistochemistry step is used for determining that the PSMAAb-QD bond is attached to the C4-2 prostate gland cancer cell, uses PEG-QD (no antigen) and PC-3 cell (no PSMA antigen) as negative control.For in advance cancer cell being tagged, QD is connected to a kind of transduction peptide, such as aforesaid HIVTat or poly arginine, and by being transported to cancer cell alive 37 ℃ of cultivations.Cultivate after 1 hour, find that each cell all contains above 100 ten thousand QD, after the incubated overnight, all QD are positioned at nucleus basically.
Use is taken care of by the animal used as test of Emory university and the step of use council approval, about 100 ten thousand tumour cells be subcutaneously injected into big nude mouse of 6-8 week (Charles River, Wilmington, MA).Monitor tumor growth every day and reach acceptable size up to it.Mouse is divided into 2 groups, is used for passive target and initiatively target research.The QD bond is expelled to the tail vein, to active target 0.4nmol, to passive target 6.0nmol (many 15 times approximately).Respectively with 95mg/kg and 5mg/kg injection Ketamine and Xylazine potpourri, mouse is placed anesthesia by intraperitoneal.In black box, provide irradiation by light transmitting fiber light, use long-channel filtrator abandons the exciting light of scattering and passes (Strokes-shifted) QD fluorescence of Duo conversion.By scientific grade CCD record fluoroscopic image.Behind whole body imaging, mouse is used CO 2Excessive dosage is put to death.Tumour and major organs are removed also freezing be used for the histology QD picked-up and the research that distributes.Tissue collecting's thing is frozen section and is the thick section of 5-10 μ m, uses acetone fixed at 0 ℃, and uses and penetrate fluorescent microscope (Olympus Axiovert, Melville, NY) inspection.
Should be emphasized that above-mentioned embodiment of the present disclosure only is the possible example of implementing, and only list for clear understanding principle of the present disclosure.Many changes and modification be can carry out to above-mentioned embodiment of the present disclosure, and marrow of the present disclosure and principle do not departed from essence.All this changes and modification all mean and are included in the scope of the present disclosure, and by following claim protection.

Claims (56)

1. nanostructured comprises:
One quantum dot; With
One hydrophobic protection structure, it comprises a kind of cap part and a kind of amphipathic multipolymer of adding, wherein said hydrophobic protection structure bag is by described quantum dot.
2. nanostructured according to claim 1, wherein said amphipathic multipolymer is selected from amphipathic nature block polymer, amphipathic random copolymers, amphipathic alternating copolymer, amphipathic periodic copolymer and its combination.
3. nanostructured according to claim 1, wherein said amphipathic multipolymer is a kind of segmented copolymer, is selected from a kind of diblock copolymer, a kind of triblock copolymer and its combination.
4. nanostructured according to claim 3, wherein said amphipathic nature block polymer comprise a kind of ABC three block structures, and it has the 8-carbon alkyl branches of grafting.
5. nanostructured according to claim 4, wherein said ABC three block structures comprise a poly--butyl acrylate section, a poly--ethyl acrylate section and polyisobutylene acid section.
6. nanostructured according to claim 1, wherein said quantum dot comprise a nuclear and a cap, and the described nuclear of wherein said quantum dot is selected from the group that IIA-VIA semiconductor, IIIA-VA semiconductor, IVA-IVA semiconductor and IVA-VIA semiconductor are formed.
7. nanostructured according to claim 6, the described nuclear of wherein said quantum dot is selected from the group of being made up of the IIA-VIA semiconductor.
8. nanostructured according to claim 6, the described nuclear of wherein said quantum dot is selected from the group by CdS, CdSe, CdTe, ZnSe, ZnS, PbS, PbSe and alloy composition.
9. nanostructured according to claim 1, wherein said quantum dot is CdTe/CdSe.
10. nanostructured according to claim 1 also comprises a kind of compound of biocompatibility, and it is arranged on the surface of described hydrophobic protection structure substantially.
11. nanostructured according to claim 10, wherein said biocompatible compound about peg molecule of 500 to 50,000 that is a kind of molecular weight.
12. nanostructured according to claim 10; also comprise a kind of probe that is arranged in substantially on the described hydrophobic protection body structure surface, wherein said probe is selected from a kind of antibody, a peptide species, a kind of polynucleotide, a kind of drug molecule, a kind of inhibitor compound and its combination.
13. nanostructured according to claim 1; also comprise being arranged in the structural a kind of probe of described hydrophobic protection, wherein said probe is selected from a kind of antibody, a peptide species, a kind of polynucleotide, a kind of drug molecule, a kind of inhibitor compound and its combination.
14. nanostructured according to claim 1, the wherein said cap part that adds comprises three-octyl group phosphine oxide.
15. a nanostructured comprises:
At least a nano-substance; With
A kind of hydrophobic protection structure, it comprises and is selected from a kind of at least a compound that adds cap part, a kind of amphipathic multipolymer and its combination that wherein said hydrophobic protection structure bag is by described nano-substance.
16. nanostructured according to claim 15 also comprises a kind of compound of biocompatibility, it is arranged on the surface of described hydrophobic protection structure substantially.
17. nanostructured according to claim 15 also comprises a kind of probe, it is arranged on the surface of described hydrophobic protection structure substantially.
18. nanostructured according to claim 15, the wherein said cap part that adds comprises three-octyl group phosphine oxide.
19. nanostructured according to claim 15, wherein said amphipathic multipolymer are a kind of amphipathic random copolymerss.
20. nanostructured according to claim 15, wherein said amphipathic multipolymer are a kind of amphipathic alternating copolymers.
21. nanostructured according to claim 15, wherein said amphipathic multipolymer are a kind of amphipathic periodic copolymers.
22. nanostructured according to claim 15, wherein said amphipathic multipolymer is selected from amphipathic nature block polymer, amphipathic random copolymers, amphipathic alternating copolymer, amphipathic periodic copolymer and its combination.
23. nanostructured according to claim 15, wherein said amphipathic multipolymer are a kind of segmented copolymers that is selected from a kind of diblock copolymer and a kind of triblock copolymer.
24. nanostructured according to claim 23, wherein said segmented copolymer comprise a kind of ABC three block structures with 8-carbon alkyl branches of grafting.
25. nanostructured according to claim 24, wherein said ABC three block structures comprise a poly--butyl acrylate section, a poly--ethyl acrylate section and polyisobutylene acid section.
26. nanostructured according to claim 17, wherein said probe comprise a kind of cancer target part.
27. nanostructured according to claim 17, wherein said probe comprise a kind of tumor of prostate target part.
28. nanostructured according to claim 15, wherein said nano-substance are selected from a kind of quantum dot, a kind of metallic nano-particle and a kind of metal oxide nanoparticles.
29. nanostructured according to claim 28, wherein said quantum dot comprise a nuclear and a cap.
30. nanostructured according to claim 29, the described nuclear of wherein said quantum dot are selected from the group that IIA-VIA semiconductor, IIIA-VA semiconductor, IVA-IVA semiconductor and IVA-VIA semiconductor are formed.
31. nanostructured according to claim 29, the described nuclear of wherein said quantum dot are selected from the group that the IIA-VIA semiconductor is formed.
32. nanostructured according to claim 29, the described nuclear of wherein said quantum dot is CdSe.
33. nanostructured according to claim 29, wherein said cap are selected from the group that high band gap IIA-VIA semiconductor is formed.
34. nanostructured according to claim 29, wherein said cap is selected from ZnS.
35. nanostructured according to claim 29, wherein said quantum dot is CdTe/CdSe.
36. a method for preparing nanostructured comprises:
A kind of nano-substance is provided; And
Form a kind of hydrophobic protection structure around described nano-substance, it comprises and is selected from a kind of at least a compound that adds cap part, a kind of amphipathic multipolymer and its combination.
37. method according to claim 36 also comprises:
A kind of biocompatible compound is connected to described hydrophobic protection structure.
38. method according to claim 36 also comprises:
A kind of probe is connected to described hydrophobic protection structure.
39. method according to claim 36, wherein said probe is selected from a kind of antibody, a peptide species, a kind of polynucleotide, a kind of drug molecule, a kind of inhibitor compound and its combination, and wherein said biocompatible compound is a kind of peg molecule.
40. method according to claim 36; wherein said nano-substance is that a kind of quantum dot and wherein said hydrophobic protection structure comprise and describedly add cap part and described amphipathic multipolymer, and wherein said amphipathic multipolymer is a kind of segmented copolymer that is selected from a kind of diblock copolymer, a kind of triblock copolymer and its combination.
41. method according to claim 36, the wherein said cap part that adds comprises three-octyl group phosphine oxide, and wherein said amphipathic multipolymer is a kind of ABC three block structures, and it comprises a poly--butyl acrylate section, a poly--ethyl acrylate section and polyisobutylene acid section.
42. a method that detects the target among the experimenter comprises:
A kind of nanostructured is provided, and it has:
At least a nano-substance,
A kind of hydrophobic protection structure, it comprises and is selected from a kind of add cap part, a kind of amphipathic copolymerization
At least a compound of thing and its combination, wherein said hydrophobic protection structure bag is received by described
The rice material,
A kind of biocompatible compound, it is arranged in described hydrophobic protection body structure surface substantially
On and
At least a probe, it is arranged on the described hydrophobic protection body structure surface substantially, and wherein
One probe has the affinity to described target;
Described nanostructured is guided to the experimenter; And
By detecting described nano-substance, determine to exist among the described experimenter described target corresponding to described probe.
43. according to the described method of claim 42, wherein said target is a kind of cancer knurl disease.
44. according to the described method of claim 43, wherein said cancer knurl disease is a kind of tumour.
45. according to the described method of claim 44, wherein said tumour is a prostate cancer.
46., wherein saidly determine to carry out in vivo according to the described method of claim 45.
47. according to the described method of claim 42, wherein said first probe is selected from a kind of polynucleotide, a peptide species, a kind of antibody, a kind of antigen and its combination.
48. according to the described method of claim 42, wherein said guiding is to be undertaken by a kind of method that is selected from the injection of hypodermic injection and general.
49., wherein saidly determine to comprise passive target process and a kind of target process of target process initiatively of being selected from according to the described method of claim 40.
50. a method for the treatment of experimenter's disease comprises:
A kind of nanostructured is provided, and it has:
At least a nano-substance,
A kind of hydrophobic protection structure, it comprises and is selected from a kind of at least a compound that adds cap part, a kind of amphipathic multipolymer and its combination, wherein said hydrophobic protection structure bag is by described nano-substance,
A kind of biocompatible compound, its be arranged in substantially on the described hydrophobic protection body structure surface and
At least a probe, it is arranged on the described hydrophobic protection body structure surface substantially, and wherein first probe can be treated described disease effectively; And
Described nanostructured guiding is treated the experimenter of described disease to needs.
51., also comprise according to the described method of claim 50:
By detecting described nano-substance, determine the existence of described disease.
52., also comprise according to the described method of claim 50:
By detecting described nano-substance, determine that described nano-substance is transported to detected described disease.
53. according to the described method of claim 50, wherein said nanostructured comprises described first probe, described first probe is a kind of drug molecule, and wherein said drug molecule can effectively be treated described disease.
54. according to the described method of claim 53, wherein said disease is a kind of cancer knurl disease.
55. according to the described method of claim 50, wherein said nanostructured comprises second probe, wherein said second probe has the affinity to described disease, and wherein said second probe is selected from a kind of polynucleotide, a peptide species, a kind of antibody, a kind of antigen and its combination.
56., also comprise according to the described method of claim 50:
By detecting described nano-substance, determine existence corresponding to the described disease of described second probe.
CN 200480041964 2003-12-22 2004-11-16 Nanostructured, its manufacture method and its using method of biological conjugation Pending CN101421623A (en)

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