WO1999017120A1 - Preparation de conjugues au moyen de groupes de liaison polyethyleneglycol - Google Patents
Preparation de conjugues au moyen de groupes de liaison polyethyleneglycol Download PDFInfo
- Publication number
- WO1999017120A1 WO1999017120A1 PCT/US1998/019716 US9819716W WO9917120A1 WO 1999017120 A1 WO1999017120 A1 WO 1999017120A1 US 9819716 W US9819716 W US 9819716W WO 9917120 A1 WO9917120 A1 WO 9917120A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituent
- polyethylene glycol
- solid surface
- bead
- peg
- Prior art date
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6943—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a pill, a tablet, a lozenge or a capsule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
Definitions
- the predominant recognition methodology involves the use of molecular species which recognize the target.
- protein molecules that recognize a specific target can be generated as antibodies. Such antibodies can then be used to recognize the target and bind to it.
- labeling techniques By use of appropriate labeling techniques, the bound target can be identified and/or separated from the remaining population.
- flow cytometry is uniquely suited for such applications due to its capability to perform simultaneous multiparameter analysis and to separate (or sort) unique cell populations from heterogeneous mixtures of cells.
- the critical parameter is the recognition of the antigen or target. This is strongly affected by the conformation of the target, and, in general, it is essential to have the target in a confirmation resembling its native conformation.
- the instant invention presents a rapid simple method for preparing solid phases, preferably beads, with antigens or other substituents presented on the surface in such a manner that the antigens/substituents retain their original functionality and conformation, as well as much of their native structure, to permit their use in a wide array of applications.
- the substituent is attached to the surface of the solid phase by using a bifunctional derivative of polyethylene glycol.
- the polyethylene glycol (PEG) acts not only to facilitate the attachment of the substituent to the solid surface, but also acts as a buffer to prevent or reduce any interaction of the solid surface with the attached substituent or, indeed, with any other biological compounds to which it may become exposed during the use of the solid surface conjugates.
- the polyethylene glycol has a dual function, the first being that of a linking group facilitating the attachment of the substituent to the solid phase, and the second being that of maintaining, to the greatest extent possible, the native conformation of the substituent. While not wishing to be bound by theory, it is believed that this is the result of three properties conveyed by the PEG, namely: additional flexibility of the attached components due to the linking group; a reduction in the conformational distortion of the substituent due at least partially to a reduction in the "sticking" of the other portions of the substituent to the solid surface; and a reduction in the non-specific binding of other proteins and similar materials to the solid surface.
- the complexes of the instant invention are formed by attaching the substituent(s) to the solid phase by the use of the PEG as a bifunctional derivative to link the substituent to the solid phase.
- the solid phase must have a surface functional group available to facilitate the bonding of the PEG.
- the solid phase is a bead which possesses amine (NH2) functionalities.
- NH2 amine
- a preferred bead of this type is a 6 micron polymethylmethacrylate (PMMA-NH2) bead.
- PMMA-NH2 polymethylmethacrylate
- the choice of the solid phase will be governed by the specific applications intended. A variety of substituents can, thus , be attached to the solid phase by this methodology.
- substituents include, but are not limited to, fiuorophores (such as phycoeryhtrin), streptavidin (which can be used to bind biotinylated ligands), oligonucleotides, and biological compounds such as proteins and nucleic acids. Indeed, so long as the substituent will bind, or can be chemically modified to permit it to bind, to the PEG, the methodology can be utilized.
- the PEG utilized must be of a sufficient size to convey the desired properties, but not so large as to significantly hinder the kinetics of derivitization, attachment of the substituent, or the functionality of the attached substituents.
- a molecular weight of 1,000-5,000, more preferably 2,000-3,000, and even more preferably 2,000 would be used, but it is o be understood that PEG polymers of even higher and/or lower molecular weights can be used depending on the particular application.
- succimidyl propionate-PEG-2000- orthopyridyl-disulfide OPSS-PEG2000-SPA
- Shearwater Polymers Huntsville, AL
- other functional moieties on the PEG termini may be used as the particular application dictates.
- the benefits of the OPPS-PEG2000-SPA are two-fold, namely, to activate the solid surface in order to facilitate the attachment of the substituent, and to provide a "barrier layer" between the solid phase and the substituent(s) on the surface or components in the surrounding medium.
- the functional groups on the PEG reagent will be selected based on the chemistry of the solid surface and the desired functionality for substituent attachment.
- the solid phase will have a primary amine group (preferably a PMMA-NH2) and the one end of the PEG molecule will have a succinimidyl group, thereby facilitating formation of an amino ester (peptide) linkage between the solid surface and the PEG molecule.
- the PEG molecule has a protected sulfhydryl group (preferably orthopyridyl-disulfide)which can be deprotected by reduction with DTT and, thus, be available to form a thioether link with a maleimide derivatized substituent or, which could react, intact, with a sulfhydryl derivatized substituent by disulfide interchange.
- a protected sulfhydryl group preferably orthopyridyl-disulfide
- PEG attachment methodology to provide a PEG spacer between the solid phase and the substituent also will facilitate the binding of ligands or molecules to the substituent, help to retain the native properties of the bound substituents; and enhance mobility, and thus accessibility, of the attached substituents. Further, the specificity of bonding to the substituent(s) is enhanced, because the PEG linker provides a "barrier" to reduce the non-specific binding of other species to the solid surface.
- Polymethacrylate amino beads (6.1 microns PMMA-NH2), at a concentration of 1.5% w/v, were admixed with OPSS-PEG2000-SPA, at a concentration of 5 mM, in an aqueous buffer containing 50 mM sodium phosphate/ 150 mM sodium chloride/ 1 mM EDTA 0.01% w/v Tween 20, adjusted to a pH of 7.7, and reacted at room temperature for 2 hours.
- the beads were subsequently washed with reaction buffer, reduced with 25mM dithiothreitol, and subsequently washed with 50 mM MES (2-(N- morpholino)ethanesulfonic acid) /150mM sodium chloride/1 mM EDTA/0.01 %w/v Tween 20 adjusted to a pH of 6.0.
- PE phycoerythrin
- BSA-maleimide both PE and BSA maleimide were synthesized using succinimidyl 4-(N-maleimido-methyl)-cyclohexane-l-carboxylate (SMCC) (Pierce Biochemical Corp) to arrive at a protein to bead ratio of 5 micrograms per square centimeter of bead surface area.
- SCC succinimidyl 4-(N-maleimido-methyl)-cyclohexane-l-carboxylate
- the ratio of maleimide PE to maleimide BSA was adjusted to achieve the desired number of PE molecules per bead. Residual -SH groups were capped by reacting with 0.5 mM N-ethylmaleimide for 15 minutes at room temperature.
- the resultant beads were washed into PBS/0.1% sodium azide/0.2% gelatin/0.01% w/v Tween 20.
- the beads prepared by this method exhibited more uniform fluorescence and unaltered emission characteristics (essentially indistinguishable from that of PE- conjugated antibodies)and greater stability than PE beads made with shorter linkers.
- Example 2 Preparation of Streptavidin Beads with a PEG2000 Spacer The beads were prepared by the same synthetic procedure as described in Example
- biotin-PerCP as did conventional beads with a shorter spacer. While not wishing to be bound by theory, it is postulated that this is due to the greater accessibility of streptavidin on the PEG spacer, versus streptavidin held onto the bead surface with a shorter spacer.
- non-specific binding e.g. IgGl to PerCP or PE
- Example 3 Synthesis of oligonucleotide beads with a PEG2000 spacer
- the beads were prepared by the same synthetic procedure as described in Example 1, except that the OPSS-PEG2000-SPA labeled, reduced, and washed beads were reacted with 120 pmole/cm2 of 5'-maleimido oligonucleotide, which was previously synthesized by the reaction of the 5' NH2-22 mer oligonucleotide with SMCC.
- the beads prepared by this method bound FITC labeled complimentary oligonucleotide with a low CV and low non-specific binding.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Polyethers (AREA)
- Peptides Or Proteins (AREA)
Abstract
La présente invention concerne un procédé simple et rapide de préparation de phases solides, de préférence de perles, dont la surface présente des antigènes ou d'autres substituants de telle manière que les antigènes/substituants gardent leur fonctionnalité et leur conformation originales, ainsi qu'une grande part de leur structure originelle, pour permettre leur utilisation dans un large éventail d'applications. Plus particulièrement, le substituant est fixé à la surface de la phase solide au moyen d'un dérivé bifonctionnel de polyéthylèneglycol. On a découvert que le polyéthylèneglycol (PEG) sert non seulement à faciliter la fixation du substituant à la surface solide, mais aussi en tant que tampon permettant d'éviter ou de réduire toute interaction de la surface solide avec le substituant fixé ou, en réalité, avec tout autre composé biologique auquel il pourrait être exposé lors de l'utilisation des conjugués à surface solide.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU94021/98A AU9402198A (en) | 1997-09-26 | 1998-09-21 | Preparing conjugates using polyethylene glycol linkers |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US93898697A | 1997-09-26 | 1997-09-26 | |
US08/938,986 | 1997-09-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999017120A1 true WO1999017120A1 (fr) | 1999-04-08 |
Family
ID=25472336
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/019716 WO1999017120A1 (fr) | 1997-09-26 | 1998-09-21 | Preparation de conjugues au moyen de groupes de liaison polyethyleneglycol |
Country Status (2)
Country | Link |
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AU (1) | AU9402198A (fr) |
WO (1) | WO1999017120A1 (fr) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004050919A2 (fr) * | 2002-12-04 | 2004-06-17 | International Business Machines Corporation | Traitement de surface |
WO2005041859A2 (fr) | 2003-04-30 | 2005-05-12 | Sirna Therapeutics, Inc. | Conjugues et compositions |
US6921669B2 (en) * | 2000-05-16 | 2005-07-26 | Micronas Holding Gmbh | Linker system for activating surfaces for bioconjugation |
US7491805B2 (en) | 2001-05-18 | 2009-02-17 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
US7517864B2 (en) | 2001-05-18 | 2009-04-14 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US7833992B2 (en) | 2001-05-18 | 2010-11-16 | Merck Sharpe & Dohme | Conjugates and compositions for cellular delivery |
EP2415486A2 (fr) | 2001-05-18 | 2012-02-08 | Sirna Therapeutics, Inc. | Conjugués et compositions pour la fourniture cellulaire |
US20140213641A1 (en) * | 2011-05-09 | 2014-07-31 | Institut Quimic De Sarria | Polymeric nanoparticles for drug delivery |
US8962342B2 (en) | 2007-06-06 | 2015-02-24 | Beckton, Dickinson And Company | Near-infrared dyes as surface enhanced raman scattering reporters |
US8993614B2 (en) | 2012-03-15 | 2015-03-31 | F. Hoffmann-La Roche Ag | Substituted pyrrolidine-2-carboxamides |
US9181551B2 (en) | 2002-02-20 | 2015-11-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9260471B2 (en) | 2010-10-29 | 2016-02-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA) |
US9657294B2 (en) | 2002-02-20 | 2017-05-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9994853B2 (en) | 2001-05-18 | 2018-06-12 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
CN109142759A (zh) * | 2018-08-31 | 2019-01-04 | 江苏力博医药生物技术股份有限公司 | 一种高质量血型检测卡用微柱凝胶的制备方法 |
US10508277B2 (en) | 2004-05-24 | 2019-12-17 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1364663A1 (fr) * | 2002-05-21 | 2003-11-26 | Commonwealth Scientific And Industrial Research Organisation | Dispositifs oculaires avec surface fonctionalisée conférant des propriétés adhésives |
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EP0476545A1 (fr) * | 1990-09-14 | 1992-03-25 | Tosoh Corporation | Procédé et ensemble pour immunoessai |
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EP0806250A2 (fr) * | 1996-05-10 | 1997-11-12 | Roche Diagnostics GmbH | Surfaces revêtues avec des groupes amines |
WO1998032466A1 (fr) * | 1997-01-29 | 1998-07-30 | Polymasc Pharmaceuticals Plc | Procede de p.e.g.ylation |
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-
1998
- 1998-09-21 AU AU94021/98A patent/AU9402198A/en not_active Abandoned
- 1998-09-21 WO PCT/US1998/019716 patent/WO1999017120A1/fr active Application Filing
Patent Citations (7)
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S. ZALIPSKY: "Functionalized poly(ethylene glycol) for preparation of biologically relevant conjugates", BIOCONJUGATE CHEM., vol. 6, 1995, pages 150 - 165, XP002068523 * |
Cited By (34)
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US6921669B2 (en) * | 2000-05-16 | 2005-07-26 | Micronas Holding Gmbh | Linker system for activating surfaces for bioconjugation |
US9994853B2 (en) | 2001-05-18 | 2018-06-12 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
US7964578B2 (en) | 2001-05-18 | 2011-06-21 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
EP3231445A1 (fr) | 2001-05-18 | 2017-10-18 | Sirna Therapeutics, Inc. | Conjugués et compositions pour la fourniture cellulaire |
EP2415486A2 (fr) | 2001-05-18 | 2012-02-08 | Sirna Therapeutics, Inc. | Conjugués et compositions pour la fourniture cellulaire |
US7491805B2 (en) | 2001-05-18 | 2009-02-17 | Sirna Therapeutics, Inc. | Conjugates and compositions for cellular delivery |
US7517864B2 (en) | 2001-05-18 | 2009-04-14 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US7833992B2 (en) | 2001-05-18 | 2010-11-16 | Merck Sharpe & Dohme | Conjugates and compositions for cellular delivery |
US9657294B2 (en) | 2002-02-20 | 2017-05-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9738899B2 (en) | 2002-02-20 | 2017-08-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9771588B2 (en) | 2002-02-20 | 2017-09-26 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US10662428B2 (en) | 2002-02-20 | 2020-05-26 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US10351852B2 (en) | 2002-02-20 | 2019-07-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9181551B2 (en) | 2002-02-20 | 2015-11-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US10000754B2 (en) | 2002-02-20 | 2018-06-19 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9957517B2 (en) | 2002-02-20 | 2018-05-01 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US10889815B2 (en) | 2002-02-20 | 2021-01-12 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9732344B2 (en) | 2002-02-20 | 2017-08-15 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
WO2004050919A2 (fr) * | 2002-12-04 | 2004-06-17 | International Business Machines Corporation | Traitement de surface |
WO2004050919A3 (fr) * | 2002-12-04 | 2004-08-26 | Ibm | Traitement de surface |
US7070922B2 (en) | 2002-12-04 | 2006-07-04 | International Business Machines Corporation | Surface treatment |
WO2005041859A2 (fr) | 2003-04-30 | 2005-05-12 | Sirna Therapeutics, Inc. | Conjugues et compositions |
EP3222294A1 (fr) | 2003-04-30 | 2017-09-27 | Sirna Therapeutics, Inc. | Conjugués et compositions pour délivrer des composés au niveau cellulaire |
US10508277B2 (en) | 2004-05-24 | 2019-12-17 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
US9546957B2 (en) | 2007-06-06 | 2017-01-17 | Becton, Dickinson And Company | Near-infrared dyes as surface enhanced raman scattering reporters |
US8962342B2 (en) | 2007-06-06 | 2015-02-24 | Beckton, Dickinson And Company | Near-infrared dyes as surface enhanced raman scattering reporters |
US9970005B2 (en) | 2010-10-29 | 2018-05-15 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA) |
US9260471B2 (en) | 2010-10-29 | 2016-02-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA) |
US11193126B2 (en) | 2010-10-29 | 2021-12-07 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA) |
US11932854B2 (en) | 2010-10-29 | 2024-03-19 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA) |
US20140213641A1 (en) * | 2011-05-09 | 2014-07-31 | Institut Quimic De Sarria | Polymeric nanoparticles for drug delivery |
US8993614B2 (en) | 2012-03-15 | 2015-03-31 | F. Hoffmann-La Roche Ag | Substituted pyrrolidine-2-carboxamides |
CN109142759B (zh) * | 2018-08-31 | 2021-08-06 | 江苏力博医药生物技术股份有限公司 | 一种高质量血型检测卡用微柱凝胶的制备方法 |
CN109142759A (zh) * | 2018-08-31 | 2019-01-04 | 江苏力博医药生物技术股份有限公司 | 一种高质量血型检测卡用微柱凝胶的制备方法 |
Also Published As
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