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WO2018134232A1 - Dispositif maldi et procédés de préparation et d'utilisation associés - Google Patents

Dispositif maldi et procédés de préparation et d'utilisation associés Download PDF

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Publication number
WO2018134232A1
WO2018134232A1 PCT/EP2018/051080 EP2018051080W WO2018134232A1 WO 2018134232 A1 WO2018134232 A1 WO 2018134232A1 EP 2018051080 W EP2018051080 W EP 2018051080W WO 2018134232 A1 WO2018134232 A1 WO 2018134232A1
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WIPO (PCT)
Prior art keywords
nanoparticles
maldi
plate
intact
biological entities
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PCT/EP2018/051080
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English (en)
Inventor
Baohong Liu
Qiao Liang
Milica JOVIC
Yingdi ZHU
Horst Pick
Hubert Girault
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École Polytechnique Fédérale de Lausanne
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Publication of WO2018134232A1 publication Critical patent/WO2018134232A1/fr

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    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • H01J49/0409—Sample holders or containers
    • H01J49/0418—Sample holders or containers for laser desorption, e.g. matrix-assisted laser desorption/ionisation [MALDI] plates or surface enhanced laser desorption/ionisation [SELDI] plates

Definitions

  • the present invention relates to a matrix-assisted laser desorption ionization (MALDI) target plate, comprising a conductive substrate covered with patterns of nanoparticles with a large hydrophilic surface area.
  • MALDI matrix-assisted laser desorption ionization
  • MALDI is a soft ionization technique used in mass spectrometry (MS), allowing analysis of biomolecules (such as DNA, proteins, peptides and sugars) 1 and large organic molecules (such as polymers and dendrimers) 2 , which are fragile and easily fragmented when ionized by other ionization methods.
  • MS mass spectrometry
  • MALDI is similar in character to electrospray ionization (ESI) in that both techniques use relatively soft ways of obtaining ions of large molecules in the gas phase, though MALDI produces far fewer multiply charged ions.
  • the sample is mixed or overlaid with a solution of a matrix that is commonly a crystallised organic acid, acting as a light absorber and a charge carrier. After drying, the sample co-crystallises with the matrix and retains its integrity.
  • the principle of MALDI ionization lies in the absorption of laser energy by the matrix (typically UV laser e.g., 337 or 355 nm), which transfers the energy to the sample and facilitates its desorption and ionization by protonation or de-protonation. 4
  • the ions are then accelerated at a fixed potential, and then separated from each other on the basis of their mass-to-charge ratio (m/z).
  • the charged sample is then detected and measured using one or more of mass analysers, for example quadrupole mass analysers, ion trap analysers, time of flight (TOF) analysers, etc. 5
  • MALDI-TOF MS has emerged as a potential tool for analysis of biological samples such as bacteria, fungi, yeasts, viruses, tissues and cancer cells. 6 8 Due to its ability to provide information about biomolecules, such as lipids, proteins, peptides, nucleic acids and metabolites, MALDI-TOF MS has been applied for characterization and identification of micro-organisms, epidemiological studies, tissue imaging, detection of biological warfare agents, and biomarker detection, and is a powerful tool for clinical diagnosis and treatment. For example, MALDI-TOF MS has been used for bacterial identification at the genus, species and even strain levels since the pioneer work of Holland et al., 9 Claydon et al. 10 and Krishnamurthy et al. 11 in 1996. Accordingly, commercial systems, such asMALDI Biotyper ® CA (Bruker Daltonics) and VITEK ® MS (bioMerieux) have been developed for routine identification of bacteria in clinical and microbiology laboratories.
  • Biological entities can be analysed by MALDI-TOF MS directly in their intact/whole state or after "preparatory" component extraction, depending on their envelope structure.
  • the approach of intact sample analysis is conducted by directly spotting the sample onto a MALDI target plate and overlaying it with matrix solution. Such is the case for bacteria like Neisseria spp., Yersinia spp., and Vibrio spp., where the bacterial cells are directly physically disrupted during MS measurements. 12 ' 13 This intact sample analysis procedure is simple and fast; however, it is not always efficient.
  • micro-organisms e.g., viruses, bacterial spores, yeast cells
  • a combination of formic acid and acetonitrile has often been used to extract proteins from bacterial cells for MS fingerprinting.
  • Matsuda et al. 15 compared the performance of both procedures for Staphylococcus spp. identification. They showed that 60.2% and 80.8% of 273 clinical strains were identified with the intact bacteria profiling method and the "preparatory" protein extraction method, respectively, while the mean process time required for 48 duplicates was 30 min for the former and 180 min for the latter.
  • MALDI matrix is often dissolved in a mixture of water, organic solvents (e.g., ethanol, methanol, acetonitrile) and a strong acid (e.g., trifluoroacetic acid).
  • organic solvents e.g., ethanol, methanol, acetonitrile
  • a strong acid e.g., trifluoroacetic acid.
  • the most frequently used matrices for biological samples are a-cyano-4- hydroxycinnamic acid (CHCA), 2,5-dihydroxy benzoic acid (DHB), and 3,5- dimethoxy-4-hydroxycinnamic acid (sinapinic acid, SA). 17
  • CHCA 2,5-dihydroxy benzoic acid
  • SA 3,5- dimethoxy-4-hydroxycinnamic acid
  • CHCA is more suitable for detection of low molecular weight molecules such as peptides and small proteins ( ⁇ 10,000 Da); DHB is more often used for phospholipids, glycopeptides and glycoproteins ( ⁇ 10,000 Da); while SA seems to be the best choice for large proteins (> 15,000 Da).
  • metal oxides e.g., TiO 2 , ZnO, ZrO 2 , SnO 2
  • metal oxides doped with different metal ions e.g., Au, Ag, Co
  • Their photocatalytic activity is based on their unique electronic structure, which is characterized by a filled valence band and an empty conduction band.
  • metal oxide particles Upon absorption of photons from the light source, metal oxide particles generate electron-hole pairs and act as photosensitizers, which drive efficient electron-transfer reactions on their surface and produce reactive oxygen species such as hydroxyl radical ("OH), superoxide radical ( * O 2 ⁇ ), and singlet oxygen ( 1 O 2 ).
  • OH hydroxyl radical
  • * O 2 ⁇ superoxide radical
  • singlet oxygen 1 O 2
  • Nanostructures have also been used to fabricate MALDI target plates.
  • the term “nanostructures” refers to structures with nanoscale size (1 - 1000 nm) in at least one dimension.
  • Niu et l. 26 have proposed to produce a nanostructured thin film (such as an alumina or aluminium thin film) on a supporting plate for MALDI MS analysis of proteins, peptides, small molecules, etc.
  • the nanostructured thin film was used to generate enhanced surface area and the appropriate structural dimensions.
  • the present invention provides a target plate according to claim 1, for enhanced MALDI MS analysis of intact biological entities such as bacteria, fungi, yeasts, virus, tissues and cancer cells.
  • the target plate comprises an electrically conductive substrate partially covered with sintered photo-reactive nanoparticles, which provide a hydrophilic surface area for homogenous sample distribution.
  • the nanoparticles absorb energy from the laser to generate electron-hole pairs and act as photosensitizers. They drive electron- transfer and radical reactions and cause in-source photo-electrochemical disruption of the biological entities' envelope structure, as well as assisting in desorption and ionization of components from the entities.
  • the invention can be applied for characterization and identification of micro-organisms, analysis of micro-organisms' resistance to antibiotics, detection of biomarkers, imaging of tissues, etc., and serve for quick clinical diagnosis and treatment.
  • the invention also provides a method of preparing a plate, according to claim 9, and a method of use of a plate, according to claim 13.
  • Optional features of the invention are set out in the dependent claims.
  • Fig. 1 schematically shows a photo-reactive MALDI plate for enhanced MS analysis of intact biological entities according to the invention
  • Fig. 2 shows the mass spectra of intact gram-negative bacteria Escherichia coli (E.coli) obtained using a classic bare metallic MALDI plate and a MALDI plate presented in Fig. 1;
  • Fig. 3 shows the mass spectra of intact gram-positive bacteria Bacillus subtilis (B. subtilis) obtained using a classic bare metallic MALDI plate and a MALDI plate presented in Fig. 1;
  • Fig. 4 shows the mass spectra of intact human melanoma cancer line wmll5 obtained using a classic bare metallic MALDI plate and a MALDI plate presented in Fig. 1;
  • Fig. 5 shows the mass spectra obtained from ampicillin-resistant E.coli XL1 and ampicillin-susceptible E.coli XL1 by using a classic bare metallic MALDI plate and a MALDI plate presented in Fig. 1;
  • Fig. 6 shows the mass spectra obtained from kanamycin-resistant E.coli BL21 and kanamycin-susceptible E.coli BL21 by using a classic bare metallic MALDI plate and a MALDI plate presented in Fig. 1;
  • Fig. 7 shows the mass spectra obtained from melanoma cell line wmll5 with or without the expression of green fluorescent protein by using a classic bare metallic MALDI plate and a MALDI plate presented in Fig. 1.
  • Fig. 1 shows a MALDI plate comprising an electrically conductive substrate 1, partially covered with immobilized photo-reactive nanoparticles 2. Nanoparticles
  • a whole detection process is conducted as following: z) a sample of biological entities 3 (e.g., bacteria, fungi, yeasts, viruses, cancer cells, tissues) in their intact state is placed on the plate in contact with the nanoparticles 2, which provide a hydrophilic surface area for the homogenous sample distribution; ii) a light-sensitive organic matrix 4 is added after the sample 3 is dried at room temperature; Hi) upon irradiation by laser 5, photo-reactive nanoparticles 2 absorb the laser energy, generate electron-hole pairs and trigger redox and radical reactions.
  • the envelope structure of the intact biological sample e.g., bacteria, fungi, yeasts, viruses, cancer cells, tissues
  • the substrate can be a commercially available MALDI plate or a homemade target plate made of any conducting material.
  • the target plate is made of aluminium, nickel, stainless steel or a conductive polymer. It can present a flat, unmodified surface, or a surface with patterned spots, dots or annular groves to assist in locating samples.
  • the substrate can be made of a non- conductive material coated with a thin layer of conductive material such as one or more evaporated metals, or a semi-conducting material.
  • the conducting substrate can be a metallic foil placed in contact with a commercially available MALDI plate. A foil with a thickness below 250 ⁇ is suitable, such as commercially available aluminium foil used for cooking or packaging food.
  • Drops of a nanoparticle suspension are deposited on substrate 1 to form a specific area, such as a set of stripes or an array of spots.
  • a specific area such as a set of stripes or an array of spots.
  • the array of spots allows a high throughput analysis of biological samples and is convenient for accurate positioning of samples.
  • inkjet printing, screen-printing, rotogravure printing or other deposition techniques can be used to prepare the specific area of nanoparticles.
  • Several layers of a nanoparticle suspension can be deposited on the substrate to form areas of different thicknesses, ranging from 50 nanometers to 50 micrometres. After the solvent evaporation, the particles can be sintered to ensure their mutual adhesion and adhesion to the substrate.
  • Sintering can be performed either by thermally heating the nanoparticles below their melting point or by low- thermal techniques such as photonic flash sintering.
  • the sintered nanoparticles provide a mesoporous structure with an extremely high surface-to-volume ratio and a high hydrophilic surface for homogeneous distribution of samples.
  • the nanoparticles can be metal oxides (e.g., Ti0 2 , ZnO, Zr0 2/ Sn0 2 ), metal oxides doped with different metal ions (e.g., Au, Ag, Co) and other materials with photo- catalytic activity. It is important that the band gap of the nanoparticles matches the laser wavelength in the MALDI mass spectrometer.
  • the sample can include whole or intact micro-organisms (e.g., bacteria, fungi, yeasts, virus), cells (e.g., cancer cells), tissues, or any other biological entities. If the sample is suspended in a liquid solution it can be deposited dropwise on the plate. If the sample is in a solid state it can be directly placed on the plate.
  • micro-organisms e.g., bacteria, fungi, yeasts, virus
  • cells e.g., cancer cells
  • tissues e.g., or any other biological entities.
  • the light sensitive organic matrix 4 can be a classic MALDI matrix containing usually a crystalline acid, such as a-cyano-4-hydroxycinnamic acid (CHCA), sinapic acid (SA), 2,5-dihydroxybenzoic acid (DHB) or 2-(4-hydroxyphenylazo)- benzoic acid (HABA).
  • a crystalline acid such as a-cyano-4-hydroxycinnamic acid (CHCA), sinapic acid (SA), 2,5-dihydroxybenzoic acid (DHB) or 2-(4-hydroxyphenylazo)- benzoic acid (HABA).
  • CHCA a-cyano-4-hydroxycinnamic acid
  • SA sinapic acid
  • DVB 2,5-dihydroxybenzoic acid
  • HABA 2-(4-hydroxyphenylazo)- benzoic acid
  • the gist of the present invention is to use photo-reactive nanoparticles for in- source photo-electrochemical disruption of the envelope of intact biological entities and for desorption/ ionization of the entities' components in the presence of an organic matrix.
  • Samples are homogeneously distributed and adsorbed on the hydrophilic surface of nanoparticles. Under the irradiation of a pulsed laser light, the nanoparticles absorb energy from the laser, generate electron-hole pairs, and induce electron-transfer and radical reactions. These reactions cause break-up of the analysed entities, facilitating desorption and ionization of inner components together with the assistance of the matrix.
  • Fig. 2 shows the comparison of mass spectra obtained from intact gram-negative bacteria E.coli by using a classic stainless steel MALDI plate and a photo-reactive MALDI plate from Fig. 1 where the immobilized nanoparticles 2 are ⁇ 1 ⁇ 2.
  • Sinapinic acid was used as the organic matrix.
  • Fig. 2a is in the mass range m/z 6,000 - 15,000 and Fig. 2b is for m/z 15,000 - 34,000.
  • the obtained results show that the photo-reactive MALDI plate brings more relevant information from intact gram-negative bacteria.
  • Fig. 3 shows the comparison of mass spectra obtained from intact gram-positive bacteria B.subtilis by using a classic stainless steel MALDI plate and a photo- reactive MALDI plate from Fig. 1 where the immobilized nanoparticles 2 are T1O2.
  • Sinapinic acid was used as the organic matrix.
  • Fig. 3a is in the mass range m/z 6,000 - 12,000 and Fig. 3b is for m/z 12,000 - 34,000.
  • the obtained results show that photo-reactive MALDI plate brings more relevant information from intact gram- positive bacteria.
  • Figs. 2 and 3 imply that identification of bacteria on the basis of protein fingerprinting can be significantly improved by using the present invention, especially at high mass range (m/z > 10,000).
  • Fig. 4 shows the comparison of mass spectra obtained from the intact human melanoma cell line ivmll5 by using a classic stainless steel MALDI plate and a photo-reactive MALDI plate from Fig. 1 where the immobilised nanoparticles 2 are T1O2.
  • Sinapinic acid was used as the organic matrix.
  • Fig. 4a is in the mass range m/z 5,000 - 15,000 and Fig. 4b is for m/z 15,000 - 50,000.
  • the obtained results show that more peaks can be obtained with the photo-reactive MALDI plate, implying that more components, especially with high molecular weight (> 10,000 Da) can be detected from intact cancer cells with the present invention.
  • Fig. 5 compares the performance of a classic stainless steel MALDI plate (Fig. 5a) and a plate from Fig. 1 where the nanoparticles 2 are ⁇ 2 (Fig. 5b) for detection of bacterial resistance to ampicillin.
  • the mass spectrum obtained from ampicillin-resistant E.coli XL1 was compared with that from ampicillin-susceptible E.coli XL1 at the mass range of m/z 27,800 - 29,800.
  • Sinapinic acid was used as the organic matrix.
  • the ampicillin-resistance gene expressed as a protein of 28,970 Da, was detected from the resistant strain using the invented plate (Fig. 5b), whereas this gene is undetectable using a classic bare MALDI plate (Fig. 5a).
  • Fig. 6 compares the performance of a classic stainless steel MALDI plate (Fig. 6a) and a plate from Fig. 1 where the immobilised nanoparticles 2 are Ti0 2 (Fig. 6b) for detection of bacterial resistance to kanamycin.
  • Fig. 6a and Fig. 6b the mass spectrum obtained from kanamycin-resistant E.coli BL21 was compared with that from kanamycin-susceptible E.coli BL21 at the mass range of m/z 19,000 - 20,000.
  • Sinapinic acid was used as organic matrix.
  • the kanamycin-resistance gene expressed as a protein of 29,050 Da, was detected from the resistant strain with the invented plate (Fig.
  • Fig. 7 compares the performance of a classic stainless steel MALDI plate (Fig. 7a) and a plate from Fig. 1 where the immobilized nanoparticles 2 are Ti0 2 (Fig. 7b), for detection of a specific marker from cancer cells. In both Fig. 7a and Fig.
  • the invented device can produce highly reproducible results, as the disruption process of the entities depends only on the photo-reactive nanomaterial.
  • this invention provides a quick way of precise profiling of biological entities with high reproducibility. It therefore helps to broaden the applications of MALDI MS for biochemical research and clinical medicine.
  • a ⁇ 1 ⁇ 2 suspension is prepared by dissolving a commercially available T1O2 paste (Solaronix Ti-Nanoxide D20/SP, Switzerland, 20 - 25 nm anatase nanoparticles; suspension Visopropanoi/Vwater/VTriton x-100 78/19.5/2.5) to reach a final concentration of 0.2 % (m/ m).
  • T1O2 paste Small Organic Chemical Vapent
  • the T1O2 suspension can also be screen-printed, rotogravure-printed, or directly deposited with a micropipette (1-10 ⁇ ,) onto the metal substrate.
  • Bacteria e.g., E.coli, B.sutilis
  • antibiotics e.g., ampicillin, carbenicillin, kanamycin, chloramphenicol, gentamicin, spectinomycin, erythromycin, hygromycin, tetracycline, etc.
  • the solution (1 - 2 L) is deposited with a micropipette onto a spot on the Ti02-modified target plate, and dried at room temperature ( ⁇ 5 min).
  • Matrix solution (1 - 2 uL, sinapinic acid, 15 mg/mL in Vacetonitriie/Vwater/ Vtrifluoroacetic acid 50/ 49.5/0.1) is added to cover the bacteria sample spot and dried at room temperature ( ⁇ 5 min).
  • MALDI-TOF MS detection was performed on a Bruker microflex ® LRF under linear positive mode.
  • the laser source used in this instrument is a nitrogen laser (337.1 nm).
  • One mass spectrum is obtained from each sample spot by accumulation of 500 laser shots. Each test is repeated for 3 times and the average mass spectrum is presented in all figures.
  • Non-pathogenic gram-negative E.coli and gram-positive B.subtilis are used as models to investigate the performance of the invented T1O2-MALDI plate for intact bacteria profiling and compare it with a classic bare MALDI plate. Results show that more peaks are obtained from the invented T1O2-MALDI plate, especially at the mass range > 10,000 Da, as shown in Fig. 2 and Fig. 3.
  • the bacterial envelope is mainly composed of lipid bilayers and peptidoglycan, which can be broken up by TiO2-induced photo-chemical redox reactions.
  • the ⁇ 2 nanoparticles also facilitate desorption and ionization of inner components together with the presence of organic matrix. Accordingly, more information about the internal components can be produced by the T1O2-MALDI plate directly from intact bacteria.
  • Antibiotic-resistant bacteria often contain special resistance genes in their genome or on plasmids, which they have acquired from other bacteria and which they can spread to make non-resistant bacteria resistant to specific antibiotic compounds. Such antibiotic resistance genes encode proteins that perform enzymatic reactions to degrade or modify antibiotic molecules making them non-functional. These proteins conferring resistance to antibiotics normally appear in the mass range higher than 10,000 Da. Ampicillin and kanamycin resistance of E.coli are firstly analysed as models. As shown in Fig. 5b, compared to the ampicillin-susceptible E.coli XLl-blue strain, an additional peak at m/z 28,970 is detected from the ampicillin-resistant strain, by using the invented Ti02-MALDI plate.
  • E.coli strains In addition to ampicillin and kanamycin, the resistance of E.coli strains to other antibiotics (e.g. carbenicillin, chloramphenicol, gentamicin, spectinomycin, erythromycin, hygromycin, tetracycline, etc.) can also be detected by the invented plate from intact bacteria.
  • antibiotics e.g. carbenicillin, chloramphenicol, gentamicin, spectinomycin, erythromycin, hygromycin, tetracycline, etc.
  • the human melanoma cell line wmll5 is employed as model.
  • a cell pellet is collected from culture media by centrifugation (2,000 rpm x 4 min), and resuspended in the same volume of deionized water.
  • the solution (1 pL) is deposited onto a T1O2 spot on the target plate and dried at room temperature.
  • the cells are covered by 1 iL of matrix solution (sinapinic acid, 15 mg/ mL in Vacetonitriie/Vwater/Vtrifiuoroacetic acid 50/49.5/0.1) and dried at room temperature prior MALDI MS detection. MS measurements are similar to those of Example 1.

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  • Optics & Photonics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

L'invention concerne une plaque cible pour une analyse par spectrométrie de masse à désorption/ionisation laser assistée par matrice améliorée (MALDI MS) d'entités biologiques intactes. La plaque cible comprend un substrat électroconducteur 1 recouvert au moins partiellement de nanoparticules photo-réactives immobilisées 2, servant de photosensibilisateur et d'un dispositif d'ionisation, qui entraîne des réactions de transfert d'électrons et de radicaux efficaces provoquant une perturbation interne de la structure d'enveloppe d'entités biologiques intactes 3 et aide à la désorption/ionisation de composants tels que des lipides, des peptides et des protéines à partir des entités biologiques intactes vers l'analyseur par spectrométrie de masse à désorption/ionisation laser assistée par matrice améliorée (MALDI MS).
PCT/EP2018/051080 2017-01-19 2018-01-17 Dispositif maldi et procédés de préparation et d'utilisation associés WO2018134232A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023157352A1 (fr) * 2022-02-16 2023-08-24 浜松ホトニクス株式会社 Support d'échantillon, procédé d'ionisation et procédé de spectrométrie de masse
CN117074503A (zh) * 2023-10-16 2023-11-17 成都泰莱医学检验实验室有限公司 用于飞行时间质谱检测的纳米复合材料及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060145068A1 (en) * 2004-12-30 2006-07-06 Yu-Chie Chen Metal oxide-assisted laser desorption/ionization mass spectrometry
WO2006118595A2 (fr) * 2004-09-17 2006-11-09 Nanosys, Inc. Films fins nanostructures et utilisations associees
WO2009003673A2 (fr) * 2007-07-02 2009-01-08 École Polytechnique Fédérale de Lausanne Extraction sur phase solide et dispositif d'ionisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006118595A2 (fr) * 2004-09-17 2006-11-09 Nanosys, Inc. Films fins nanostructures et utilisations associees
US20060145068A1 (en) * 2004-12-30 2006-07-06 Yu-Chie Chen Metal oxide-assisted laser desorption/ionization mass spectrometry
WO2009003673A2 (fr) * 2007-07-02 2009-01-08 École Polytechnique Fédérale de Lausanne Extraction sur phase solide et dispositif d'ionisation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023157352A1 (fr) * 2022-02-16 2023-08-24 浜松ホトニクス株式会社 Support d'échantillon, procédé d'ionisation et procédé de spectrométrie de masse
CN117074503A (zh) * 2023-10-16 2023-11-17 成都泰莱医学检验实验室有限公司 用于飞行时间质谱检测的纳米复合材料及其制备方法
CN117074503B (zh) * 2023-10-16 2024-01-26 成都泰莱医学检验实验室有限公司 用于飞行时间质谱检测的纳米复合材料及其制备方法

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