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WO1998002743A1 - Detecteurs - Google Patents

Detecteurs

Info

Publication number
WO1998002743A1
WO1998002743A1 PCT/IL1997/000221 IL9700221W WO9802743A1 WO 1998002743 A1 WO1998002743 A1 WO 1998002743A1 IL 9700221 W IL9700221 W IL 9700221W WO 9802743 A1 WO9802743 A1 WO 9802743A1
Authority
WO
WIPO (PCT)
Prior art keywords
analyte
pair
sensor
analogue
cavities
Prior art date
Application number
PCT/IL1997/000221
Other languages
English (en)
Inventor
David Issachar
Original Assignee
Sensors Technology Company B.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from IL11885996A external-priority patent/IL118859A0/xx
Application filed by Sensors Technology Company B.V. filed Critical Sensors Technology Company B.V.
Priority to AU32714/97A priority Critical patent/AU3271497A/en
Publication of WO1998002743A1 publication Critical patent/WO1998002743A1/fr

Links

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
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • 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
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G01N33/5438—Electrodes

Definitions

  • the present invention is in the field of sensors, particularly biosensors for the detection of an analyte in a test medium.
  • the present invention concerns a sensor comprising a porous matrix.
  • Chemical and biochemical sensors have a great potential for application in fields such as medicine, industry and defense.
  • biosensors are useful, for example, for monitoring, clinically and biochemically important analytes both in vivo and in vitro.
  • sensors having the capacity of continuous determination of the analyte are particularly desired.
  • Sensors for continuously monitoring analytes in real time are also of great importance in industry for controlling and regulating chemical process as well as for monitoring biological and biochemical hazards.
  • U.S. Patent 5,156,972 concerns an analyte-specific sensor for determining an analyte in a test sample.
  • the sensor comprises a sensing surface to which there are linked a plurality of reversible competitive recognition units (RCRU).
  • RCRU reversible competitive recognition units
  • Each such unit contains at least one receptor and at least one ligand, one of which is an analyte-analogue.
  • the receptor and ligand are a priori connected to each other, directly or indirectly, in such a configuration that even when the analyte-analogue ligand is displaced from the receptor by an analyte ligand, the analogue is still retained in close proximity to the receptor.
  • the relative positions of the receptor and ligand in each RCRU is such that when no analyte is present in the sample, or when the analyte concentration is low, the receptor and the ligand affinity bind to each other.
  • the fluctuations in the analyte concentri- tion in the test sample affect the chemical occurrences of the RCRU, and consequently the characteristics of the sensor. The changes in the analyte concentrations are monitored continuously.
  • the advantage of the biosensor of said U.S. patent resides in the fact that the sensor is truly reversible due to the fact that the receptor and the analogue are a priori bound to each other. This means that even when the receptor is bound to the analyte, the analyte-analogue stays in a closed vicinity to the bound receptor, so that when the analyte concentration drops again, the analyte-analogue may again bind to the receptor.
  • the reversible nature of this sensor enables continuous, on-line monitoring of the analyte concentration in the sample.
  • biosensors are based on sol-gel encapsulation methods, wherein proteins are entrapped within a silicate glass matrix prepared by a sol-gel method. Research has revealed that silicate glass obtained by the sol-gel method can thus provide a host matrix so that biomolecules immobilized in this matrix retain their functional characteristics to a large extent. Moreover, these functionalized glasses can be prepared so that they are optically transparent permitting optical monitoring of the spectrometric properties of the encapsulated biomolecules (Dave et ai, Analytical Chemistry, 66(22): 1120-1127, (1994)). Enhanced evanescent wa ⁇ e sensors have been prepared based on sol-gelled-derived porous glass coating (MacCraith, Sensors and Actuators
  • sol-gel-encapsulated antibody retains its affinity for fluorescein although the encapsulation process decreased the affinity constant by about two orders of magnitude (Wang et al., Anal. Chem. , 65:2671-2677 (1993)).
  • the advantage of such encapsulated antibodies resides in the fact that they are relatively unapproachable to proteases, and thus, generally speaking, biosensors comprising an antibody entrapped within a transparent sol-gel glass are stable for long periods of time.
  • biosensor based on non-competitive binding of an antigen to an antibody, and not on competitive displacement of an analyte-analogue bound to an antibody by the analyte. Furthermore, the biosensor of Wang et al is not reversible and thus cannot enable on-line continuous monitoring of an analyte in a test medium.
  • Analyte - a molecule which presence is to be assayed or its concentration is to be determined in the test medium.
  • the analyte is a first member of a pair forming group (see below).
  • Pair forming group - two molecules which have the capability of specifically recognizing and specifically binding (see below) to each other.
  • Typical examples are antibody/antigen; receptor/ligand; lectin/glycoprotein; enzyme/substrate; two complementary strands of nucleic acid sequences and the like.
  • Second member of pair forming group - where the analyte is one memb r of the pair forming group this term refers to the other member of the same specific group, for example, where the analyte is an antigen, the second member is its specific antibody, where the analyte is a specific nucleic acid sequence, the second member is the complementary sequence, etc.
  • Analyte-analogue - a component of the detecting unit (see below) or the detecting pair (see below) which is capable of specifically binding to the second member of the pair forming group.
  • Detecting unit - a single unit in accordance with the first embodiment of the invention composed of the second member of the pair forming grot p linked (see below) to the analyte-analogue in such an orientation that specific binding between the two is possible.
  • Detecting pair - two separate molecules one being second member of the pair forming group and the other being the analyte-analogue.
  • the two molecules are entrapped within tho same cavity of the matrix having a plurality of porous cavities.
  • Link - a strong bond between the second member of the pair forming group and the analyte-analogue which like results in the detection unit.
  • the link is formed in such an orientation that enables specific binding between the analyte-analogue and the second member.
  • the link may be a covalent bond, or may be achieved by utilization of moieties having an exceptionally high affinity towards each other, such as through the biotin/avidin binding.
  • First pair - a state where the second member and the analyte are specifically bound to each other.
  • Second pair - a state where the second member and the analyte-analogue are specifically bound to each other.
  • the analyte may be present in the liquid, a priori, or may be initially present in a gaseous or solid phase.
  • the gaseous or solid phase are contacted with the liquid in order to dissolve the analyte therein.
  • the medium is brought into contact with the matrix having a plurality of porous cavities, so that it may enter each cavity and carry the analyte to the detecting unit or detecting pair present therein.
  • Signal producing moiety - compounds which are able to change a detectable signal as a result of transition between the state of the first pair and the state of the second pair.
  • the present invention concerns a sensor for detecting an analyte in a test medium.
  • the sensor is composed of a matrix having a plurality of porous cavities in which there are entrapped a plurality of detecting units each composed of a member capable of specifically binding to the analyte (termed hereinafter “the second member of the pair forming to the analyte (termed hereinafter “the second member of the pair forming unit” or “second member”) linked to an analyte-analogue which can specifically bind to the second member.
  • the linking is such as to allow the second member and the analyte-analogue to specifically bind to each other in a competitive reversible manner.
  • the analyte may competitively displace the analyte-analogue to bind specifically to said second member. Since the analyte-analogue is linked to the second member, it remains in the vicinity of the second member even when the second member is bound to the analyte. If the analyte's concentration decreases, the analyte-analogue may again specifically bind to the second member, so that the detecting units of the sensor of the invention are truly reversible.
  • the senor is composed of a matrix of porous cavities and in each cavity is entrapped a pair of two molecules, one being the second member of the pair forming group and the other being the analyte-analogue, both molecules together are termed "a detecting pair".
  • the analyte-analogue is specifically bound to the second member in a competitive-reversible manner.
  • the analyte may competitively displace :he analyte-analogue to bind specifically to the second member.
  • the analyte-analogue and the second member are in the vicinity of each other, not due to a physical link between them, but rather due to the fact that both are confined to the small space of the cavi :y.
  • the transition of the second member, in both embodiments of the invention, from a state of binding to the analyte-analogue to a state of binding the analyte and vice versa changes at least one detectable property of the sensor.
  • determination or measurement of said change is indicative to the presence or concentration, respectively, of the analyte in the test medium.
  • the pores of said matrix have properties which allow the analyte molecule to pass to the entrapped detecting units or detecting pairs, while these properties eliminate the passage of the detecting unit (in the urit - 1 -
  • the properties are size and/or electrical charge of the pores.
  • the detecting units or detecting pairs of the invention feature all the advantages of the so called “reversible competitive recognition units " (RCRUs) as specified in U.S. 5,156,972 which are: specificity to the analyte and reversibility of the detection assay, which reversibility allows for online continuous determination of analyte presence or of the analyte concentration in a test medium.
  • the detecting units or detecting pairs are not immobilized on a solid support as disclosed in U.S. 5,156,972 but rather are entrapped within the porous cavities of the matrix. Said entrapment eliminates the need to immobilize each detecting unit or each molecule of the detecting pair to the support so in accordance with the present invention the process of preparation of the sensor is simplified.
  • the pores of the matrix are typically too small to allow entrance of proteolytic enzymes to the entrapped detecting units or the entrapped molecules of the detecting pair.
  • the detecting units or detecting pairs are protected from degrada- tion by various enzymes and consequently the sensor of the invention is stable for substantially longer periods of time than the sensor of U.S. 5,156,972.
  • the present invention provides a sensor for the detection of an analyte in a test medium, the analyte being a first member of a pair forming group, the sensor comprising: a matrix having a plurality of porous cavities, entrapping within them detecting units, wherein the pore properties of the cavities are such that the detecting units are entrapped within the cavities while the analyte may move freely in and out of the cavities; each of the detecting units comprising the second member of the pair forming group linked to an analyte-analogue which can specifically bind to said second member in a reversible manner; the linking being in a manner enabling specific binding between said second - 8 -
  • the present invention further provides a sensor for the detection of an analyte in a test medium, the analyte being a first member of a pair forming group
  • the sensor comprising: a matrix having a plurality of porous cavities, a single cavity entrapping within it essentially a single detecting pair, wherein the pore properties of the cavities are such that the molecules of the detecting pair are entrapped within the cavities, while the analyte may move freely in and out of the cavities; one molecule of the detecting pair comprises the second member of the pair forming group, and the other molecule of the detecting pair comprises an analyte-analogue which can specifically bind to said second member in a reversible manner; specific binding between the analyte and said second member giving rise to the formation of a first pair and specific binding between said analyte-analogue and said second member giving rise to the formation of a second pair; transition between said first pair and said second pair resulting in a change in at least
  • the ratio of the first pair to the second pair correlates to the concentration of the analyte in the test sample. Since the level of the detectable property reflects said ratio it may be calibrated to indicate the concentration of the analyte in the test medium.
  • the present invention further provides an apparatus for detecting of an analyte in a test sample comprising the sensor of the invention and means for determining or measuring the change in said at least one detectable property of the sensor.
  • the apparatus of the invention may further comprise a signal producing moiety which is capable of transducing the transition between the first pair and the second pair and vice versa to a detectable property.
  • signal producing moieties are moieties which change their optical properties (for example refractive index or luminescence), electrochemical properties or electro chemiluminescence properties as a result of transition between the first and second pair.
  • both the sensor and the apparatus of the invention are suitable for continuous monitoring of an analyte in a liquid.
  • the analyte to be determined in accordance with the present invention is a first member of a pair forming group such as an antibody, or an antigen; an enzyme or its substrate; a ligand (such as a hormone, drug, peptide, etc.) or its soluble receptor; one strand of a nucleic acid sequence and the like.
  • the test medium containing the analyte should be a liquid medium.
  • the analyte may be present initially in the liquid, for example in a body fluid sample, or may initially be present in a solid or gaseous medium and then dissolved in the liquid which is assayed.
  • the porous sol-gel matrix may be loaded prior to the determination with a suitable liquid, and a gaseous sample is then passed on the porous sol-gel matrix so that the analyte present in the gas is dissolved in the liquid already present within the cavities of the sensor's matrix.
  • the sensor of the invention is capable of determining the presence or absence of an analyte in the test medium in a binary fashion by determining whether a change in the detectable properties did or did not take place. Alternatively, it is possible to determine the concentration of the analyte in the test sample by measuring the amount change in the detectable property and calibrating said measurement.
  • matrix having a plurality of porous cavities refers to a matrix having a plurality of spaces (cavities) within, some of the spaces being in communication with the ambient surrounding through pores wh:ch are present at the surface of said matrix.
  • the properties of the pores should be such which entrap within the cavity the detecting units (in the unit embodiment) or the detecting pair (in the pair embodiment) while enabling the analyte to more freely in and out of the cavity.
  • the property of the pore which discriminates between the analyte and the detecting unit or each molecule of the detecting pair is based usually on the pore's size. However, other pore properties such as an electric charge may also be used lor discrimination purposes.
  • one detecting unit or one detecting pair are entrapped within each cavity of the matrix due to the manner of the preparation of the matrix as will be explained hereinbelow.
  • typically one molecule of the second member and one molecule of the analyte-analogue are entrapped within each cavity. This occurs since due to the affinity between these two molecules, they form specific binding pairs already in the reaction medium, which pairs are then entrapped wtihin the pores.
  • a typical example of such a porous matrix is silicate glass, produced by a sol-gel method which proceeds by hydrolysis of the monomeric precursors of the matrix followed by polycondensation of the hydroxylated units to form a porous gel.
  • the detecting units or detecting pairs can be incorporated to the undensified sol-gel glass by adding it to the gel before gelation, substantially as described in Wang et ai, Anal. Chan. 65:2672-2675 (1993)).
  • Examples of possible matrices beyond silicate glass are cellulose nitrate, sodium alginate, polyacrylamide, agarose, dextran and gelatin.
  • the detection unit comprises the second member of the pair forming group linked to an analyte-analogue.
  • the detecting pair according to the pair embodiment of the invention comprises two separate molecules, one being the second member of the pair forming group and the other being the analyte-analogus.
  • the second member may be the full molecule, for example, where the analyte is a ligand or an antigen, the second member is the full receptor or antibody, respectively, or alternatively may be a ligand binding fragment or an antigen binding fragment of the receptor or the antibody, respectively.
  • the analyte-analogue is also a member of a pair forming group which is capable of specifically binding to said second member.
  • the analyte-analogue may have the same binding affinity to the second member as that of the analyte. However it is preferable that the affinity of the analyte-analogue to the second member will be lower than that of the analyte, in order to compensate for the fact that the analyte-analogue effective concentration near the second member is very high (since both are confined to the same cavity).
  • the analyte-analogue may be the molecule of the analyte itself, chemically modified derivatives of the analyte, fragments of the analyte (for example, antibody binding fragments of an antigen where the analyte is an antigen) or a molecule which is completely different than the analyte., but competes with the analyte for binding to the same binding site of the second member.
  • the analyte-analogue is considerably larger in size than the analyte, so that it is entrapped within the cavity while the analyte can pass freely in and out of the cavity. This can be achieved by conjugating a molecule similar to the analyte to a large inert moiety such as a bead or a molecule of human serum albumin (HSA).
  • HSA human serum albumin
  • the second member and the analyte-analogue are linked to each other in the unit embodiment of the invention.
  • the link may be a covalent linkage achieved by attaching a linker to regions of the second member and of the analyte-analogue which are not involved in the specific binding, in such a manner so that the linker does not interfere with said specific binding.
  • the linker is of a length and structure which allows under appropriate conditions, (such as absence or decrease of analyte concentration), specific binding between the second member and the binding-moiety. Examples of such linkers which cause covalent binding are polypeptidic chains such as polyalanine or chains of polyethyleneglycol, and the like.
  • the linkage between the analyte-analogue and the second member may be non-covalent, for example a link mediated by moieties having exceptionally high affinity to each other such as biotin and avidin.
  • a link mediated by moieties having exceptionally high affinity to each other such as biotin and avidin.
  • the proportion of second members which are bound to the analyte- analogue at any given condition to form the second pair is dependent on the concentration of the analyte inside the cavity, which concentration is dependent on the concentration of the analyte in the medium.
  • the detectable properties of the sensor which are changed as a result of binding or dissociation of the analyte to the second member may be photochemical, e.g. light absorption, light emission, light scattering and light polarization or electrochemical, electrochemiluminescence or piezoelectrical properties.
  • the detectable property is photochemical.
  • the physical characteristics of light which is emitted by a fluorescent labelled analyte-analogue or a labeled second member maybe designed to be different where the two are bound or unbound to each other. Accordingly the changes in the concentration of analyte may be monitored by observing the alterations of the luminescent emission, caused by association or dissociation of the analyte-analogue to said second member.
  • One way of causing and detecting luminescence in a sensor according to the invention is to design the matrix as part of a waveguide so that the evanescent light wave propagating at the solid phase/liquid or gaseous phase interface excites the luminophore binding-moiety or a luminophore second member and the emitted luminescence is conducted via the waveguide to an appropriate detector, as described in MacCraith, B.D , Sensors and Actuators, Bll:29-39 (1993).
  • the sensing is based on measurement of fluorescence intensity the distinction between the first pair state and the second pair state may be sharpened by fitting each second member (e.g.
  • the receptor of the detecting unit or detecting pair with a luminescence quencher group, for example, Rhodamine, while the analyte-analogue (e.g. ligand), contains a fluorescein group or vice versa.
  • a luminescence quencher group for example, Rhodamine
  • the analyte-analogue e.g. ligand
  • contains a fluorescein group or vice versa a luminescence in the state of the second pair wherein the analyte-analogue is specifically bound to the second member (which occurs in the absence of analyte, or in low concentrations thereof), is eliminated or reduced due to the energy transfer between the luminophore group of the labelled analyte-analogue and the quencher group of the receptor.
  • each detecting unit or one molecule of the detecting pair may be fitted with a luminescence enhancer, and in such a case, the luminescence increases upon formation of the second pair and decreases upon its dissociation to form the first pair.
  • the detectable property is electrochemical.
  • either the analyte-analogue or the second member should be fitted with a transducer which is a molecule which redox potential is substantially altered when the two are bound as compared to a situation of when the two are dissociated.
  • a transducer which is a molecule which redox potential is substantially altered when the two are bound as compared to a situation of when the two are dissociated.
  • An example of an electrochemical change due to binding and dissociation is that of nitrated derivatives of estriol (Konyves, I, and Olsson, A., Acta, Chemica Scandinavica, 18:483-487 (1964)) or by utilizing biotin labeled with an electroactive labeling group (daunomycin), which recox potential is altered as a result of binding of biotin to avidin (Sugawara et ai, Anal. Chem. , 67:299-302 (1995)).
  • the invention also provides an apparatus for determining or measuring the concentration of an analyte in a medium, comprising the sensor of the invention and a detector capable of determining or measurhg the change in the detectable property. If desired, such apparatus may be designed as monitor for continuous operation with said probing vessel being adapted for the continuous throughflow of the test medium.
  • Figs. 1 and 2 are various formulae and reaction schemes relating to preparation of the detecting units suitable for optical detection;
  • Figs. 3 and 4 are various formulae and reaction schemes relating to tie preparation of detecting units suitable for electrochemical detection. DETAILED DESCRIPTION OF THE INVENTION
  • Example 1 Preparation of Detecting unit comprising a theophylline analyte-analogue and an antibody fragment suitable for optical detection (Figs. 1 and 2)
  • the Fab fragment was prepared from monoclonal anti-theophyIl:ne IgG, following the procedure described by Prisyazhnoy et al, J. Chromatag. 424:243-253 (1988). The procedure includes digestion of the intact antibody by pepsin to get the F(ab') 2 and the F(ab') 2 was reduced further by dithiothreitol (DTT) in the presence of EDTA to get product (10).
  • DTT dithiothreitol
  • the product (12) was obtained by crosslinking (using SMBS crosslinker) the Fab fragment (10) with the labeled analyte-analogie
  • Example 2 Preparation of an electrochemical detecting unit comprising a theophylline analyte-analogue and a Fab antibody fragment (Figs. 3 and 4) A. Preparation of analyte-analogue with long-spacer and labeled with electrochemical active group
  • Daunomycin dissolved in DMF was reacted with N,N- disuccinimidyl carbonate under a similar condition described by K. Takeda et al , Tetrahedron Lett. 24:4569 ( 1983).
  • Product (18) is then obtained by removing the BOC protecting group of product (17) and redissolving the product in a phosphate buffer solution, pH 7.5.
  • the sol-gel process is a method of preparing glasses and cerarr ics at low temperature by hydrolysis and polymerization of organic precursors.
  • the process typically involves a metal alkoxide, water, a solvent and frequently a catalyst, which are mixed thoroughly to achieve homogeneity on a molecular scale.
  • Chemical reactions (hydrolysis and condensation polymerization) lead to the formation of a viscous gel, which is an amorphous porous material containing liquid solvents in the pores.
  • Low-temperature (typically ⁇ 100°C) curing expels most of the liquids and leaves he porous oxide.
  • the generic precursor solution for sol-gel-derived silica may be represented by: Si(OR) 4 + H 2 0 + ROH + acid/base catalyst, where R is an alkyl group.
  • the silica sol was prepared following the procedure described by
  • TMOS tetramethylorthosilicate
  • the coating solution was prepared by mixing 2 ml of sonicated sol with 2 ml of buffer solution (0.01 M sodium phosphate, pH 6.0) and

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
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Abstract

La présente invention concerne un détecteur d'analyte biologique dans un échantillon pour essai. L'analyte biologique est un élément d'un groupe formant une paire, par exemple de type antigène/anticorps, ligand/récepteur, etc. Ledit détecteur comporte une matrice poreuse dont chaque cavité peut piéger une molécule qui peut se lier spécifiquement à l'analyte ainsi qu'un analyte-analogue. Le déplacement compétitif de l'analyte-analogue par l'analyte objet de l'essai provoque une modification d'au moins une des propriétés détectables du détecteur.
PCT/IL1997/000221 1996-07-15 1997-07-02 Detecteurs WO1998002743A1 (fr)

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IL118859 1996-07-15
IL11885996A IL118859A0 (en) 1996-07-15 1996-07-15 Sensors

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WO2000011474A1 (fr) * 1998-08-24 2000-03-02 Therasense, Inc. Analyse d'affinite electrochimique
US6391558B1 (en) 1997-03-18 2002-05-21 Andcare, Inc. Electrochemical detection of nucleic acid sequences
US6967101B1 (en) 1999-03-24 2005-11-22 Gyros Ab Surface and its manufacture and uses
US7432330B2 (en) 2002-12-31 2008-10-07 Nektar Therapeutics Al, Corporation Hydrolytically stable maleimide-terminated polymers
US7432331B2 (en) 2002-12-31 2008-10-07 Nektar Therapeutics Al, Corporation Hydrolytically stable maleimide-terminated polymers
US7455975B2 (en) 2000-04-14 2008-11-25 Esa Biosciences, Inc. Electrochemical detection of nucleic acid sequences
WO2014013730A1 (fr) * 2012-07-20 2014-01-23 Canon Kabushiki Kaisha Composé et milieu de contraste d'imagerie photoacoustique contenant le composé
CN105688230A (zh) * 2016-02-02 2016-06-22 史春梦 七甲川吲哚花菁染料-聚乙二醇-叶酸复合物及制备方法和应用
US11559580B1 (en) 2013-09-17 2023-01-24 Blaze Bioscience, Inc. Tissue-homing peptide conjugates and methods of use thereof
US12048732B2 (en) 2016-04-15 2024-07-30 Blaze Bioscience, Inc. Methods of treating breast cancer

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