WO2013057634A1 - Détection d'agrégats de particules magnétiques - Google Patents

Détection d'agrégats de particules magnétiques Download PDF

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Publication number
WO2013057634A1
WO2013057634A1 PCT/IB2012/055495 IB2012055495W WO2013057634A1 WO 2013057634 A1 WO2013057634 A1 WO 2013057634A1 IB 2012055495 W IB2012055495 W IB 2012055495W WO 2013057634 A1 WO2013057634 A1 WO 2013057634A1
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WO
WIPO (PCT)
Prior art keywords
cluster
detection
magnetic field
detection signal
clusters
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Application number
PCT/IB2012/055495
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English (en)
Inventor
Andrea Ranzoni
Jan VAN KEMENADE
Johannes Joseph Hubertina Barbara Schleipen
Menno Willem Jose Prins
Original Assignee
Koninklijke Philips Electronics N.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 EP11187706.4A external-priority patent/EP2584338A1/fr
Application filed by Koninklijke Philips Electronics N.V. filed Critical Koninklijke Philips Electronics N.V.
Publication of WO2013057634A1 publication Critical patent/WO2013057634A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • G01N33/54333—Modification of conditions of immunological binding reaction, e.g. use of more than one type of particle, use of chemical agents to improve binding, choice of incubation time or application of magnetic field during binding reaction

Definitions

  • the invention relates to a method and a device for the detection of clusters comprising at least one magnetic particle.
  • the invention relates to a method for the detection of at least one cluster in a sample, wherein the cluster comprises at least one magnetic particle.
  • the term "magnetic particle” shall comprise both permanently magnetic particles as well as magnetizable particles, for example superparamagnetic beads.
  • the size of the magnetic particles typically ranges between 3 nm and 50 ⁇ .
  • the “clusters” are agglomerates of two or more (magnetic or non-magnetic) particles which are coupled by some kind of binding. Of particular interest are specific (chemical) bindings via special chemical groups and intermediate components of interest and, in contrast thereto, nonspecific bindings that are e.g. merely caused by magnetic attraction forces between magnetized particles.
  • the method comprises the following steps, which can be executed in the listed or any other appropriate order: a) Exposing the at least one cluster to be detected to a time- variable magnetic field such that a movement of and/or in the cluster is induced by magnetic forces and/or torques that are exerted on the magnetic particle(s) within the cluster.
  • the detection signal will typically be something like a voltage, a current or a digital signal generated by a sensor.
  • the invention relates to a device for the detection of at least one cluster comprising at least one magnetic particle in a sample, said device comprising the following components:
  • a container in which the sample with the at least one cluster to be detected can be provided.
  • the sample container may for example be realized as a disposable cartridge made from plastic by injection molding.
  • a magnetic field generator comprising for example a permanent magnet or an electromagnet, for generating a time- variable magnetic field which induces movements of and/or in the cluster to be detected. Movements "in” the cluster are typically movements of its magnetic particle(s).
  • a detection unit for generating a detection signal that is related to the aforementioned induced movement of the at least one cluster.
  • An evaluation unit for evaluating the detection signal with respect to its spectrum may be realized by dedicated electronic hardware, digital data processing hardware with associated software, or a mixture of both.
  • the method and the device are realizations of a common inventive concept, i.e. the spectral evaluation of a detection signal obtained from actuated clusters. Explanations and definitions provided for one of these realizations are therefore valid for the
  • the approach realized by the method and the device allows to gain information which may help to discriminate between clusters of similar, but slightly different, constitution. Surprisingly it is for example possible to distinguish between nonspecifically and specifically bound clusters of two magnetic particles by evaluating (a part of) the frequency content of the detection signal.
  • the temporal variation of the magnetic field that acts on the clusters may in general be arbitrary. According to a preferred embodiment, the magnetic field is however varied periodically. The period of this field then provides a basic frequency which reappears in the detection signal. In typical examples, at least one component of the magnetic field may for example be a square wave or a sinusoidal wave.
  • the magnetic field rotates at least partially (i.e. at least one component of the field vector rotates at least partially in a given plane, wherein a "partially rotating" time-dependent field has orientations in a limited angular space, e.g. in an angular segment of less than 360°).
  • the spectral evaluation of the detection signal may particularly comprise the determination of the signal spectral components (Fourier coefficients) at a basic frequency and at least one higher harmonic thereof or at least two higher harmonics of the basic frequency.
  • n reflects the n-fold rotation symmetry of the rotating cluster.
  • any asymmetry in the shape of a cluster and/or properties of the individual particles making up the cluster will result in also intermediate higher harmonics at 2f, 3f, 4f, 5f, 6f, 7f, etc.
  • the evaluation of the detection signal may comprise the determination of the ratio between the mentioned signal spectral components at at least two higher harmonics of the basic frequency.
  • the ratio between the signal spectral components at 4f and 2f comprises valuable information about two-particle clusters.
  • the 4f signal seems to contain information about the gap size whereas the 2f signal does not.
  • Use of a ratio is preferable because it is independent of the number of clusters in the sample (which shows variations) and is therefore more accurately describing the properties of the sample.
  • the detection signal may originate from any detection modality. It may for example be determined from magnetic effects induced by the actuated clusters. In a preferred embodiment, the detection signal originates from an optical detection. A light detector may then be provided for detecting output light that has interacted with the clusters, particularly output light that has been scattered by the clusters.
  • the light detector may for example comprise photodiodes, photo resistors, photocells, a CCD chip, or a photo multiplier tube.
  • the scattered output light may originate from ambient light.
  • a technical light source is however provided for emitting input light into the sample. The illumination can then more precisely be controlled. If the clusters to be detected are rotated, the input light may in general come from any direction with respect to the plane of rotation, e.g. perpendicular. Preferably, the input light will however propagate in the plane of rotation.
  • the light detector is preferably disposed oblique with respect to the direction of the input light, i.e. at an angle (strictly) between 0° and 180°. Most preferably, an angle of roughly 45° is used (i.e. an angle between about 20° and 60°).
  • the clusters to be detected preferably comprise (at least) two particles each (at least one of which is a magnetic particle). Thus a symmetrical configuration is provided for which a rotational movement can be observed.
  • the two particles may be specifically bound via an intermediate target component.
  • the specificity of this binding is typically used to detect particular target components of interest in a sample by linking them to the
  • the target component can for example be a biomolecule, which can have a size between a nanometer and several tens of nanometers; or it can be a composite containing several biomolecules; or it can be a larger moiety such as a virus or a small organism; or it can be material derived from a biological cell or from tissue, e.g.
  • the distance between the particles can be used as a measure for biomarker binding, by including molecular switches between the particles to which the biomarker can bind, wherein switches with or without biomarker yield different conformations and different inter-particle distances (cf. Maye et al, "Switching binary states of nanoparticle superlattices and dimer clusters by DNA strands", Nature Nanotechnology vol. 5 , p. 116 (2010)).
  • the observed spectrum of the detection signal will usually depend on the time course of the magnetic field with which movement of the clusters is induced. Accordingly, the temporal course of the magnetic field is preferably optimized such that a high correlation between the spectral characteristics of the detection signal and a parameter of interest is achieved, for example the size of the one or more clusters, or the inter-particle distance, or the nature of the inter-particle bond, or the number of molecular bonds between the particles, or the nature of the molecular architecture on the particle, or the magnetic or optical properties of the particle, or the shape of the particle, or the viscosity or other mechanical properties of the sample. If the temporal course of the magnetic field is determined by a basic frequency, the optimization may for example comprise the determination of an optimal value of this frequency.
  • Fig. 1 schematically sketches how magnetic particles bind via a target
  • FIG. 2 is an enlarged picture of a sandwich configuration of two magnetic particles and one target molecule
  • FIG. 3 schematically sketches a device according to the present invention
  • Fig. 4 is a diagram representing the time course of a recorded optical
  • Fig. 5 shows the frequency spectrum of the signal of Figure 4;
  • Fig. 6 shows the average hydrodynamic radius for 500 nm magnetic
  • Fig. 7 shows the ratios of the 4th and 2nd harmonics of the detection signal for clusters formed from the different surface architectures of Fig. 6;
  • Fig. 8 shows the ratios of the 4th and 2nd harmonics for a blank measurement (no bBSA, right) and for low concentrations of bBSA when only doublets are present (left);
  • Fig. 9 shows the ratios of the 4th and 2nd harmonics for clusters formed via PSA from the COOH and multilayer molecular architecture
  • Fig. 10 shows the frequency dependence of higher harmonics of the detection signal.
  • Magnetic cluster assays provide a volumetric and surface-free architecture and therefore they are intrinsically rapid and cost-effective.
  • Figure 1 schematically sketches four consecutive steps of a typical magnetic cluster assay based on magnetic confinement of the magnetic (e.g. nano-) particles MP to enable effective cluster formation.
  • the magnetic particles MP coated with antibodies are provided.
  • the antigen AG is added and binds to magnetic particles.
  • the sample is exposed to a magnetic field B, causing the formation of particle chains or clusters C.
  • the sample is illuminated with a light source L, and the light scattered by the clusters is detected.
  • FIG. 2 illustrates a particular sandwich assay format where the magnetic particles MP are coated with different monoclonal antibodies AB1 and AB2.
  • the antibodies can specifically bind different sites of the antigen AG, thus forming a two-particle cluster with a sandwich configuration.
  • a typical magnetic actuation protocol consists for example in applying a uniform magnetic field to a sample containing magnetic particles that have been incubated with the target biomolecule to detect. When the field is active, the particles arrange themselves into chains and are free to vibrate and rotate while in close proximity with each others. Consequently the specific bond can be effectively formed.
  • This sensor device 100 comprises a sample container or cartridge 1 10 with a sample volume 1 1 1 in which a sample fluid with magnetic particles or beads MP can be provided.
  • the sample cartridge 1 10 is a glass tube of square cross section.
  • the sensor device 100 further comprises a reader, of which only the most relevant components are schematically sketched. These components comprise:
  • a magnetic field generator 120 which in the shown example consists of four electromagnets 120a, 120b, 120c, 120d. These magnets are arranged at the corners of a rectangle or square and are aligned with their axes towards some centre within the sample volume 1 1 1.
  • a uniform rotating magnetic field B can be generated within the sample volume that induces rotation of magnetic clusters C in the vertical plane.
  • the field vector B may for example be described by a sinusoidal temporal variation according to
  • a light source 130 for example a laser diode or an LED, which emits a collimated (laser) beam of input light LI that is focused by a lens 131 into the sample volume 1 1 1.
  • the light source 130 is arranged in the (xy-) plane in which the magnetic field B and the clusters C rotate. Arrangements oblique - particularly perpendicular - to this plane are possible, too.
  • a light detector 140 for example a photodiode or an image sensor.
  • Output light L2 coming from the sample volume 1 1 1 is focused by means of a lens 141 onto the active surface of the light detector.
  • the output light L2 consists in the shown embodiment of input light LI that was scattered by components of the sample volume, particularly by magnetic particles MP and/or clusters C of these particles.
  • the light detector 140 is arranged in this embodiment at a "detection angle" of about 90° with respect to the input light LI (in practice, smaller detection angles of about 45° will typically be preferred).
  • a control and evaluation unit 150 that is coupled to the magnetic field generator 120 and to the light detector 140 in order to control them and to process the detection signals S provided by the light detector 140.
  • the clusters C in the sample volume 111 expose a time-dependent cross-section to the incoming light LI, therefore introducing a modulation of the light intensity scattered by the sample in the output light L2.
  • the resulting detection signal S is forwarded to the control and evaluation unit 150.
  • a FFT (Fast Fourier Transform) algorithm can be applied there to the recorded signal S.
  • Figure 5 shows the Fourier Transform of the curve of Figure 4. The frequency components and the magnitude of the higher harmonics of the optical signal can be seen.
  • the (two-particle) clusters are exposing the same cross-section to the incoming light beam LI twice per period, therefore generating a modulation of the scattered light L2 at double the frequency f of the magnetic field B. Because of interference and non-linear effects, such modulation also contains features at higher frequencies, as visible in the Fourier spectrum of Figure 5.
  • the amplitude F 2 f of the FFT at twice the basic frequency f of the magnetic field is defined as signal, since it showed up as the strongest of all the harmonics.
  • the magnitude F 4 f of the harmonic at four times the applied frequency i.e. 4f
  • the ratio of the signal amplitudes F 4 f and F 2 f at four times and two times the basic frequency f respectively, i.e. the value
  • the hydrodynamic radius r of these particles was measured by dynamic light scattering. It is plotted in Figure 6 for the investigated architectures.
  • the first architecture is carboxyl- terminated (COOH) groups
  • the second is streptavidin (Strep) coating
  • the third, fourth and fifth are composed of PEG linkers of respectively 3.4 KDa, 5 KDa and 10 KDa of molecular weight.
  • Figure 7 shows the ratio R4f/2f of 4th and 2nd harmonics for the different surface architectures described in Figure 6.
  • the diagram contains the results from ten independent experiments (wavelength 658 nm, intensity 18 mW, p polarized) for two different detection angles of 45° (left bars) and 30° (right bars). It is possible to see from this a proportional relationship: for increasing gap size the ratio R4f/2f also increases.
  • each nanoparticle scatters light mostly in the forward direction with respect to the optical axis, therefore shining light into the second nanoparticle when the cluster is aligned with the optical beam.
  • Such injection of scattered light generates a stronger scattering from the second nanoparticle, which is responsible for the local smaller maximum contributing the most to the 4th harmonic.
  • the effect seems to be most pronounced when detecting the scattered light L2 at about 45° orientation with respect to the exciting laser beam LI .
  • a target component for example the biomarker antigen AG in the setup of Figure 2.
  • the physical dimensions of such a target component are typically of the order of a few nm.
  • biomolecule biotinylated BSA or bBSA
  • streptavidin coated magnetic nanoparticles Due to the strong dependence of the scattering and subsequent interference of light on the gap size, such small difference in distances could be appreciated, as shown in Figure 8.
  • This Figure shows the ratio R4f/2f of 4th to 2nd harmonic for twelve blank measurements P_0 (no bBSA) and for twelve low concentration measurements P Db at concentrations of bBSA biomolecules low enough that only doublets are present in the sample (the critical frequency - i.e. the maximum frequency at which the cluster can rotate synchronously with the field - relates to the size of the clusters in solution and was monitored as a function of the target
  • the sample is characterized by a mixture of specific and non-specific doublets in the midst of a large number of single magnetic nanoparticles.
  • a biomarker for prostate cancer Prostate Specific Antigen or PSA
  • PSA Prostate Specific Antigen
  • a more conventional surface chemistry was used, where the antibodies against PSA are coupled directly to the surface of carboxyl-terminated nanoparticles by EDC (l-ethyl-3-(3- dimethylaminopropyl) carbodiimide) chemistry.
  • EDC l-ethyl-3-(3- dimethylaminopropyl) carbodiimide
  • Figure 9 shows the ratio R4f/2f of the harmonics, where "COOH-PSA P_0" stands for the blank solution without PSA and "COOH-PSA P Db” stands for the solution with PSA in which doublets (two-particle clusters) are formed.
  • COOH-PSA P_0 stands for the blank solution without PSA
  • COOH-PSA P Db stands for the solution with PSA in which doublets (two-particle clusters) are formed.
  • the low reproducibility translates in low statistical relevance. The low
  • reproducibility may be attributed to the fact that successful binding can occur only if the target is captured by an antibody which is sterically accessible by a neighbor nanoparticle. Given the high surface roughness, the gap size can exhibit large variations, which reflects in variations in the ratio of harmonics.
  • Another feature of the invention lies in analyzing the ratio R4f/2f as a function of frequency f.
  • nanometer sensitivity in the distance between nanoparticles can be achieved by accurately monitoring the spectral content of the signal.
  • the distance determination is for example relevant in making a distinction between specific and non-specific binding, which increases the sensitivity in the low concentration limit of biosensing.
  • the detection volume of a biosensor can have different sizes with respect to the sample volume.
  • the detection volume can be as large as the total sample volume, but the detection volume can also be much smaller.
  • An advantage of having a small detection volume is that the number of magnetic particles and/or clusters in the detection volume will be low. For example, even single particles and/or single clusters can be resolved in the detection signal. Having a small detection volume will facilitate the detection of small differences between particles and/or clusters. E.g. differences between specific versus nonspecific binding.
  • a disadvantage of having a very small detection volume is that the number of magnetic particles and/or clusters may be so low that number fluctuations give an imprecise measurement outcome.
  • the detection volume may be scanned through the sample, or magnetic particles and/or clusters may be scanned through the detection volume.
  • the scanning of magnetic particles and/or clusters through the detection volume may e.g. be realized by flowing the fluid (e.g. as in a flow cytometer or in a microfluidic device) and/or by using magnetic forces.

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  • Health & Medical Sciences (AREA)
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Abstract

Cette invention concerne la détection d'agrégats (C) comprenant au moins une particule magnétique (MP). Les agrégats (C) sont déplacés par un champ magnétique variable dans le temps (B), et un signal de détection (S) relatif à ce déplacement est généré et évalué par rapport à son spectre temporel. Le champ magnétique (B) peut en particulier tourner avec une fréquence de base f, et le rapport entre les composantes du signal à cette fréquence de base f et/ou des harmoniques d'ordre supérieur peut être déterminé. Ce rapport fournit des informations sur la distance entre les particules magnétiques (MP) dans un agrégat et permet ainsi de déduire si les particules magnétiques sont liées de manière non spécifique ou sont liées de manière spécifique par un composant cible intermédiaire.
PCT/IB2012/055495 2011-10-19 2012-10-11 Détection d'agrégats de particules magnétiques WO2013057634A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161548852P 2011-10-19 2011-10-19
US61/548,852 2011-10-19
EP11187706.4A EP2584338A1 (fr) 2011-10-19 2011-11-03 Détection d'amas de particules magnétiques
EP11187706.4 2011-11-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021203201A1 (fr) 2020-04-10 2021-10-14 Alentic Microscience Inc. Analyse fondée sur des billes d'un échantillon

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EP1304542A2 (fr) * 2001-10-19 2003-04-23 Philips Corporate Intellectual Property GmbH Méthode pour déterminer la distribution spatiale des particules magnétiques
US20040126903A1 (en) * 2002-08-01 2004-07-01 Garcia Antonio A. Dynamically formed rotors for lock-in amplifier detection
WO2009037636A1 (fr) * 2007-09-21 2009-03-26 Koninklijke Philips Electronics N.V. Capteur avec un champ magnétique alternatif à haute fréquence
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US4725140A (en) * 1985-11-19 1988-02-16 Olympus Optical Co., Ltd. Method of measuring specific binding reaction with the aid of polarized light beam and magnetic field
EP1304542A2 (fr) * 2001-10-19 2003-04-23 Philips Corporate Intellectual Property GmbH Méthode pour déterminer la distribution spatiale des particules magnétiques
US20040126903A1 (en) * 2002-08-01 2004-07-01 Garcia Antonio A. Dynamically formed rotors for lock-in amplifier detection
WO2009037636A1 (fr) * 2007-09-21 2009-03-26 Koninklijke Philips Electronics N.V. Capteur avec un champ magnétique alternatif à haute fréquence
WO2010026551A1 (fr) * 2008-09-05 2010-03-11 Koninklijke Philips Electronics N.V. Champ magnétique rotatif pour améliorer la détection dans des essais sur agrégat
WO2011021142A1 (fr) * 2009-08-19 2011-02-24 Koninklijke Philips Electronics N.V. Détection de différents composants cibles par formation de groupes

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MAYE ET AL.: "Switching binary states ofnanoparticle superlattices and dimer clusters by DNA strands", NATURE NANOTECHNOLOGY, vol. 5, 2010, pages 116
RANZONI, A.; SCHLEIPEN, J.J.H.B.; VAN IJZENDOOM, L.J.; PRINS, M.W.J.: "Frequency-Selective Rotation of Two-Particle Nanoactuators for Rapid and Sensitive Detection of Biomolecules", NANO LETT, vol. 11, pages 2017 - 2022, XP002663465, DOI: doi:DOI:10.1021/NL200384P
VUPPU ANIL ET AL: "Phase sensitive enhancement for biochemical detection using rotating paramagnetic particle chains", JOURNAL OF APPLIED PHYSICS, AMERICAN INSTITUTE OF PHYSICS. NEW YORK, US, vol. 96, no. 11, 1 January 2004 (2004-01-01), pages 6831 - 6838, XP012068383, ISSN: 0021-8979, DOI: 10.1063/1.1809269 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021203201A1 (fr) 2020-04-10 2021-10-14 Alentic Microscience Inc. Analyse fondée sur des billes d'un échantillon
CN115552225A (zh) * 2020-04-10 2022-12-30 阿兰蒂克微科学股份有限公司 样品的基于球珠分析
EP4133259A4 (fr) * 2020-04-10 2023-09-27 Alentic Microscience Inc. Analyse fondée sur des billes d'un échantillon

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