US20160041145A1 - Detection And Quantification Of Acetylamantadine In Urine Samples - Google Patents

Detection And Quantification Of Acetylamantadine In Urine Samples Download PDF

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Publication number
US20160041145A1
US20160041145A1 US14/776,702 US201414776702A US2016041145A1 US 20160041145 A1 US20160041145 A1 US 20160041145A1 US 201414776702 A US201414776702 A US 201414776702A US 2016041145 A1 US2016041145 A1 US 2016041145A1
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Prior art keywords
acetylamantadine
urine sample
quantification
quantifying
urine
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Abandoned
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US14/776,702
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English (en)
Inventor
Reuven Gordon
Brian Cheng
Rashid Bux
Bram Ramjiawan
Aftab Ahmed
Fraser Alan Hof
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Biomark Technologies Inc
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Biomark Technologies Inc
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Priority to US14/776,702 priority Critical patent/US20160041145A1/en
Publication of US20160041145A1 publication Critical patent/US20160041145A1/en
Assigned to BIOMARK TECHNOLOGIES INC. reassignment BIOMARK TECHNOLOGIES INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOF, Fraser Alan, RAMJIAWAN, Bram, AHMED, Aftab, CHENG, BRIAN, GORDON, REUVEN, BUX, Rashid
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    • 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
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/493—Physical analysis of biological material of liquid biological material urine
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4055—Concentrating samples by solubility techniques
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G01N21/658—Raman scattering enhancement Raman, e.g. surface plasmons
    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • 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
    • G01N15/02—Investigating particle size or size distribution
    • G01N15/0205—Investigating particle size or size distribution by optical means, e.g. by light scattering, diffraction, holography or imaging
    • 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
    • G01N15/10—Investigating individual particles
    • G01N15/14—Electro-optical investigation, e.g. flow cytometers
    • G01N15/1434—Electro-optical investigation, e.g. flow cytometers using an analyser being characterised by its optical arrangement
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/447—Systems using electrophoresis
    • G01N27/44704—Details; Accessories
    • G01N27/44717—Arrangements for investigating the separated zones, e.g. localising zones
    • G01N27/44721—Arrangements for investigating the separated zones, e.g. localising zones by optical means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/72—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables
    • G01N27/74—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids
    • 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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Definitions

  • the present invention relates to the detection and quantification of biomarkers and, in particular, to the detection and quantification of acetylamantadine in urine samples.
  • Liquid chromatography mass spectrometry has been successfully employed to detect and quantify extremely low concentrations of acetylamantadine in biological samples such as urine. This may facilitate the diagnosis of cancer at an early stage as the quantification of acetylated forms of spermidine/spermine N 1 -acetyltransferase (SSAT) including amantadine may be used to detect various pathological conditions including cancer as disclosed in U.S. Pat. No. 6,811,967 which issued to Sitar et al. on Nov. 4, 2004, and the full disclosure of which is incorporated herein by reference.
  • SSAT acetylated forms of spermidine/spermine N 1 -acetyltransferase
  • the detection and quantification of acetylamantadine using liquid chromatography mass spectrometry is relatively time consuming and costly. There is accordingly a need for an efficient and cost effective method for detecting and quantifying acetylamantadine to allow for rapid economical testing
  • the method comprises eluting acetylamantadine from the urine sample using solid phase extraction and quantifying the acetylamantadine eluted from the urine sample using Raman spectroscopy.
  • the solid phase extraction may include eluting acetylamantadine with methanol.
  • the quantification of the acetylamantadine eluted from the urine sample using Raman spectroscopy may include the use of substrate based, surface-enhanced Raman spectroscopy.
  • the method disclosed herein may be used to screen a patient for a pathological condition based on the quantification of acetylamantadine in the urine sample.
  • the method disclosed herein may also be used to screen a patient for cancer based on the quantification of acetylamantadine in the urine sample.
  • the method disclosed herein may be used to detect and quantify acetylamantadine at a low cost.
  • FIG. 1 shows the results of open air evaporation and slow evaporation of acetylamantadine in a methanol drop coated on a Surface Enhanced Raman Scattering (SERS) substrate;
  • SERS Surface Enhanced Raman Scattering
  • FIG. 2 shows quantification of acetylamantadine using a SERS substrate
  • FIG. 3 shows Raman spectra for different concentrations of acetylamantadine in a methanol
  • FIG. 4 shows a calibration curve based on the Raman spectra of FIG. 3 .
  • acetylamantadine a product of spermidine/spermine N 1 -acetyltransferase (SSAT) metabolism
  • Urine is a concentrated solution of many salts, polar metabolites and multiple non-polar steroids.
  • Expected concentration of acetylamantadine is about 1000 times smaller than that of amantadine in urine samples.
  • the distinction between amantadine and acetylamantadine can be based on the vibrational band of a carbonyl group at an approximately 1600 cm ⁇ 1 wavenumber. There are a few other differences between the spectra of amantadine and acetylamantadine, but this Raman band may be of particular interest as it is present only in the spectrum of acetylamantadine.
  • a urine sample was prepared and different constituents of the urine sample were separated using solid phase extraction (SPE).
  • SPE solid phase extraction
  • the urine sample is accordingly pre-treated using solid phase extraction to remove impurities prior to using Raman spectroscopy to identify and quantify acetylamantadine present in the urine sample.
  • the urine sample was treated using solid phase extraction to remove salts and polar impurities, increase the acetylamantadine to amantadine ratio, and minimize contamination from non-polar steroids.
  • the following protocol achieved all three aims using Strata X, Polymeric Reversed Phase from Phenomenex Inc of 411 Madrid Avenue, Torrance, Calif., 90501-1430.
  • Acetylamantadine in methanol is drop coated on the SERS substrate for Raman measurements.
  • the SERS substrate was a Klarite® SERS substrate from Renishaw Inc. of 5277 Trillium Boulevard, Hoffman Estates, Ill., 60192. Uniform coating of acetylamantadine over the SERS substrate assists in reliable quantification. It was observed that slow evaporation of methanol results in improved coating of acetylamantadine over the substrate.
  • FIG. 1 shows the results of open air evaporation and slow evaporation where the air flow is restricted. It can be seen that slow evaporation results in uniform coating.
  • FIG. 2 shows the quantification based on the 1600 cm ⁇ 1 band. The required resolution and limit of detection of 1 ng/mL is achieved with adequate signal to noise ratio. It will however be understood by a person skilled in the art that it is desirable to use a number of different peaks to create a calibration curve because different peaks will result in result in calibration curves having slightly different slopes.
  • FIG. 3 shows Raman measurements for acetylamantadine in methanol in the following concentrations 1 ng/mL, 5 g/mL, 10 ng/mL, 25 ng/mL and 50 ng/mL which were prepared using standard chemistry techniques to dissolve acetylamantadine in methanol.
  • Five peaks in the Raman spectra were chosen for each concentration, namely, 738 cm ⁇ 1 , 776.8 cm ⁇ 1 , 1198 cm ⁇ 1 , 1210 cm ⁇ 1 and 1436 cm ⁇ 1 .
  • Each peak was separated into a peak area and an adjacent area. Ten points were chosen in each peak area and adjacent area. The points were integrated and the number sum of peak area minus number sum of its adjacent area was used to get the intensity for each peak. It was then possible to get the Raman intensity for each concentration by integrating the five peaks as shown below.
  • I peak is the intensities in peak area and I adjacent is the intensities in adjacent area.
  • I peak is the intensities in peak area and I adjacent is the intensities in adjacent area.
  • the calibration curve may be used to detect and quantify the acetylamantadine in a urine sample.
  • Results demonstrate that acetylamantadine can be extracted from urine samples using solid phase extraction. Raman spectroscopy can then be used to simultaneously detect and quantify the acetylamantadine with a sensitivity of 1 ng/mL in the urine sample to screen a patient for a pathological condition such as cancer.
US14/776,702 2013-03-14 2014-03-14 Detection And Quantification Of Acetylamantadine In Urine Samples Abandoned US20160041145A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/776,702 US20160041145A1 (en) 2013-03-14 2014-03-14 Detection And Quantification Of Acetylamantadine In Urine Samples

Applications Claiming Priority (3)

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US201361785159P 2013-03-14 2013-03-14
PCT/CA2014/050273 WO2014139025A1 (fr) 2013-03-14 2014-03-14 Détection et quantification de l'acétylamantadine contenue dans des échantillons d'urine
US14/776,702 US20160041145A1 (en) 2013-03-14 2014-03-14 Detection And Quantification Of Acetylamantadine In Urine Samples

Related Parent Applications (1)

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PCT/CA2014/050273 A-371-Of-International WO2014139025A1 (fr) 2013-03-14 2014-03-14 Détection et quantification de l'acétylamantadine contenue dans des échantillons d'urine

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US15/645,994 Continuation US10175226B2 (en) 2013-03-14 2017-07-10 Detection and quantification of acetylamantadine in urine samples

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US15/645,994 Active US10175226B2 (en) 2013-03-14 2017-07-10 Detection and quantification of acetylamantadine in urine samples

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EP (1) EP2999964A4 (fr)
CN (1) CN105209910B (fr)
CA (2) CA3212686A1 (fr)
WO (1) WO2014139025A1 (fr)

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CA3198282A1 (fr) * 2015-06-26 2016-12-29 Biomark Cancer Systems Inc. Methode de detection du cancer du poumon
CN106290338B (zh) * 2016-09-10 2019-02-22 上海大学 一种检测金刚烷胺含量的方法
CN110426386A (zh) * 2019-09-11 2019-11-08 深圳网联光仪科技有限公司 一种表面增强拉曼光谱检测药物方法

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ATE412064T1 (de) * 2001-03-02 2008-11-15 Univ Manitoba Methode zur untersuchung der aktivität von spermidin/spermin n1-acetyltransferase (ssat), wobei das substrat amantadin ist
US8102525B2 (en) * 2008-10-07 2012-01-24 OptoTrace (SuZhou) Technologies, Inc. Systems and methods for detecting chemical and biological substances
WO2006113537A2 (fr) * 2005-04-14 2006-10-26 Chemimage Corporation Procede et applications pour ameliorer et imager des signaux optiques d'objets biologiques
US7656523B2 (en) * 2006-06-30 2010-02-02 Intel Corporation Multiplexed raman detection with filter set
US20100268473A1 (en) * 2008-02-19 2010-10-21 Tripp Ralph A Methods, devices, and compositions for the highly-sensitive detection and identification of diverse molecular entities
EP2561337A4 (fr) * 2010-04-20 2013-12-25 Hewlett Packard Development Co Structure multi-piliers pour analyse moléculaire
CN102947681B (zh) * 2010-04-20 2016-05-18 惠普发展公司，有限责任合伙企业 用于表面增强发光的自动布置、发光增强器件
US9410949B2 (en) * 2010-12-03 2016-08-09 Washington University In St. Louis Label-free detection of renal cancer
EP2707392A4 (fr) * 2011-05-10 2015-03-11 Biomark Technologies Inc Anticorps monoclonal pour l'acétylamantadine

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EP2999964A4 (fr) 2017-03-01
US20170328881A1 (en) 2017-11-16
EP2999964A1 (fr) 2016-03-30
CN105209910B (zh) 2019-02-15
WO2014139025A1 (fr) 2014-09-18
CN105209910A (zh) 2015-12-30
CA3212686A1 (fr) 2014-09-18
US10175226B2 (en) 2019-01-08
CA2906236C (fr) 2023-10-31
CA2906236A1 (fr) 2014-09-18

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Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GORDON, REUVEN;CHENG, BRIAN;BUX, RASHID;AND OTHERS;SIGNING DATES FROM 20130326 TO 20130410;REEL/FRAME:043817/0751