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United States Patent (19) 11 Patent Number: 4,758,323 Davis Et Al

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United States Patent (19) 11 Patent Number: 4,758,323 Davis Et Al United States Patent (19) 11 Patent Number: 4,758,323 Davis et al. (45) Date of Patent: Jul. 19, 1988 54 ASSAYSYSTEMS USING MORE THAN ONE 4,545,382 10/1985 Higgins et al....................... 204/403 ENZYME FOREIGN PATENT DOCUMENTS (75) Inventors: Graham Davis, Bedforshire; Hugh A. O. Hill, Oxford, both of United 0078636 11/1983 European Pat. Off. Kingdom WO82/03729 10/1982 PCT Int'l Appl. ................. 435/817 73 Assignee: Genetics International, Inc., Primary Examiner-T. Tung Cambridge, Mass. 57 ABSTRACT 21 Appl. No.: 607,698 This specification discloses methods of detection or measurement of an enzyme or of its specific substrate, 22 Filed: May 7, 1984 and sensors used in such methods. The present inven (30) Foreign Application Priority Data tion is concerned with a multi-enzyme system, and the May 5, 1983 (GB) United Kingdom ................. 831.2259 specification discloses, as one aspect of the invention a May 5, 1983 GB United Kingdom ................. 8312265 method of assay in which an electrode poised at a suit Jun. 9, 1983 GB United Kingdom ................. 8323801 able potential is contacted with a system comprising a Jun. 9, 1983 GB United Kingdom................. 8323800 first enzyme, a cofactor linked with said enzyme and a Feb. 29, 1984 GB. United Kingdom................. 8405262 mediator compound which transfers charge to the elec Feb. 29, 1984 GB United Kingdom................. 8405263 trode from the first enzyme when its electrical state is changed by reaction of cofactor material. 51 Int. Cl." ............................................. G01N 27/46 52 U.S. C. .................................... 204/403; 204/1 T; The cofactor may be NAD, NADP (both collectively 435/26; 435/288; 435/817 referred to herein as NAD(P)), cAMP, ATP, GTP, 58) Field of Search ......................... 435/26, 288, 817; TTP, or CTP. 204/403, 1 E The specification particularly illustrates a method of assay in which an electrode (1) poised at a suitable po (56) References Cited tential is contacted with a system comprising a first U.S. PATENT DOCUMENTS enzyme E a nicotinamide adenine dinucleotide com 4,224,125 9/1980 Nakamura et al. ................. 204/1 E pound N linked with said enzyme E1 and a mediator 4,225,410 9/1980 Pace ................... ... 204/1 E compound F which transfers charge to the electrodes 4,271,265 6/1981 Deneke et al..... ... 435/26 from the first enzyme when its electrical state is 4,318,980 11/1983 Boguslaski et al...................... 435/7 4,376,689 3/1983 Nakamura et al. ... ... 435/817 changed by a NAD(P) NAD(P)H reaction. The NAD 4,416,983 11/1983 Roder et al. ...... ... 435/25 compound may act as a "bridge' between the said en 4,427,771 1/1984 Misaki et al... ... 435/26 zyme/mediator system and further NAD utilizing en 4,446,231 5/1984. Self ..... ... 435/26 zyme E2. 4,463,090 7/1984 Harris...................................... 435/7 4,490,464 12/1984 Gorton et al. ...................... 435/817 7 Claims, 1 Drawing Sheet U.S. Patent Jul.19, 1988 4,758,323 1 -- - N. F N FG Y- Y 1 - 2 - F N } F. G. G. Y- S NADP 1 --- - v V M N F / GE) M N / (c) F. G. 2 Ns N1 NADPH C KG 1-N- / Sea s - NAD1 : F N \ - \ / s NADH F- G DHA F G3 4,758, 323 1. 2 ASSAY SYSTEMS USNG MORE THAN ONE ENZYME Ferrocene derivative Eo Solubility E 1, 1'-dimethyl- 100 I,D - acetic acid 124 S 370 This invention relates to methods of detection or 5 hydroxyethyl- 161 S - measurement of an enzyme or of its specific substrate, ferrocene 165 I,D 335 and to sensors used in such methods. 1,1'bis(hydroxymethyl)- 224 S 385 monocarboxylic acid 275 S 420 The following commonly owned, co-pending United 1,1'-dicarboxylic acid 385 S - States patent application filed May 7, 1984 are hereby 10 chloro- 345 I,D - incorporated by reference: methyl trimethylamino- 400 S - Sindicates water solubility; I,D means respectively insoluble and detergent-solubi lised in 3% Tween-20. Title Inventors Ser. No. E°is in mV vs a standard calomel electrode, E is measured in cm M. 1. Analytical Equipment Higgin et al. 607,599 and Sensor Electrodes 15 The E9 values of various ferrocenes in phosphate Therefor buffer at pH 7.0 given in the above table, span a range 2. Assay Techniques Hill 607,695 of potentials, E9-100 to 400 mV vs SCE. The trend in Using Specific Building Systems Evalues is in agreement with that expected on the basis 3. Assay Techniques Davis et al. 607,607 20 of substituent effects. In general electron-donating Utilizing More Than groups stabilize the positive charge and hence promote One Enzyme oxidation more so than electron withdrawing groups. Of these we find 1,1-dimethylferrocene and ferrocene monocarboxylic acid to be generally preferable because Our European Patent Application No. 82305597 de of their particularly wide range of accessible enzymes. scribes and claims a sensor electrode which comprises 25 Although the invention described in our earlier Ap at least at an external surface thereof a combination of plication was particularly adapted to the use of glucose an enzyme and a mediator compound which transfers as the substrate and of glucose oxidase or dehydro charge to the electrode when the enzyme is catatyti genase as the enzyme (thereby to provide, for example, cally active. Such an electrode, when contacting the a glucose sensor of use in the diagnosis of diabetic con specific substrate for the enzyme and poised at a suitable 30 ditions), other enzyme/substrate pairs whose electro potential gives a signal responsive to the presence of, or chemical behaviour in association with mediator com indicative of the extent of the enzyme/substrate reac pounds which have been studied by the Applicants tion, even in a complex mixture of substrates since the include the following: enzyme is specific to the desired substrate component. 35 The practical operation of such a system depends Enzyme Substrate upon the incorporation of the mediator compound. A Flavo-proteins number of types of such compounds are disclosed in Pyruvate Oxidase Pyruvate that Application, such as polyviologens, fluoranil, chlo L-Amino Acid Oxidase L-Amino Acids roanil, etc; but the mediators with best characteristics Aldehyde Oxidase Aldehydes are metallocenes. Xanthine Oxidase Xanthines Glucose Oxidase Glucose Ferrocenes (bis-cyclopentadienyl iron and its deriva Glycolate Oxidase Glycollate tives) fall within the last above named group and have Sarcosine Oxidase Sarcosine advantages over other mediators used with enzyme/- Lactate Oxidase Lactate Glutathione Reductase NAD(P)H substrate reactions for charge-transfer purposes. The 45 Lipoamide Dehydrogenase NADH unique structure and properties of ferrocene and its PQQ Enzymes derivatives have resulted in a considerable amount of Glucose Dehydrogenase Glucose theoretical and experimental study. First synthesised in Methanol Dehydrogenase Methanol and other Alkanols 1951, ferrocene was the earliest example of the now Methylamine Dehydrogenase Methylamine well-known metallocene compounds. Whilst ferrocenes 50 HAEM-Containing Enzymes had been found to be of limited value in spectrophoto Lactate Dehydrogenase Lactate metric assays as a result of their poor solubility in aque Horseradish Peroxidase Hydrogen Peroxidase ous solution and low extinction coefficients, they have Yeast Cytochrome C Peroxidase Hydrogen Peroxidase been found to be more suited to a bio-electrochemical Metalloflavoproteins 55 Carbon monoxide Carbon Monoxide system. Ferrocenes have: Oxidoreductase (a) a wide range of redox potentials accessible through Cuproproteins substitution of the cyclopentadienyl rings which can Galactose Oxidase Galactose be functionalised; (b) electrochemically reversible one-electron redox Of these, it was found clearly advantageous to utilize properties; those enzyme/substrate pairs whose behaviour was (c) the pH-independent redox potential and the slow established in most detail and which give good, prefera autoxidation of the reduced form. bly linear, response over the expected measurement These compounds lend themselves to the formation range. of derivatives, e.g. by substitution of one or both cylo- 65 That earlier Application was predominantly con pentadienyl rings and/or by polymerisation. We have cerned with sensors where mediator and enzyme were studied a number of derivatives of ferrocene such as both present on the electrode for contact with the sub those listed in the table below; strate. Useful sensors, their nature and their manufac 4,758,323 3 4. ture, and equipment for facilitating their use, are all an amount correlated with the extent of second en disclosed in more detail in our co-pending Application zyme/substrate reaction so as to permit assay of either if Ser. No. 607,599 entitled "Analytical Equipment and the other is known. Sensor Electrodes Therefor' filed of even date here As with our copending applications referred to with the disclosure of which is incorporated herewith herein, there are various modes of operation, with the by way of reference. active components variously distributed in the solution However, the system is the same if all the mediator, or on the electrode. Thus, a metal electrode may be enzyme, and substrate are in solution, or if the sensor dipped into a solution containing the mediator, both only carries mediator and enzyme, or even only media enzymes, the NAD(P) compound and the substrate. tor alone. 10 Alternatively, an electrode may be coated with media Our co-pending Application of even date Ser. No. tor, both enzymes and the NAD(P) compound and is 607695 entitled "Assay Techniques Utilising Specific dipped into solution containing the substrate to detect Binding Agents' utilises the basic system on a solution substrate or measure its concentration. Alternatively basis and assays specific binding reactions (e.g. antigen again, an electrode may be coated with mediator, the /antibody reactions or reactions of nucleic acid probe/- 15 first enzyme, the NAD(P) compound, and the substrate target sequence) by their effect on the electrochemical is dipped into a solution containing the second enzyme availability of enzyme or mediator or both.
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