Electrically conductive copolymers and their preparation

Details Electrically conductive copolymers and their preparation Electrically conductive copolymers and their preparation

1999-08-18

2001-03-06

Nutter, Nathan M. (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C525S054200, C525S054300, C435S177000, C435S180000, C435S181000, C436S528000, C436S531000, C436S532000, C530S391100, C530S391300, C530S391500, C530S391900, C530S815000, C530S816000

Reexamination Certificate

active

06197881

ABSTRACT:

FIELD OF THE INVENTION
This invention concerns copolymers useful in the preparation of biochips and biosensors, as well as the preparation of such copolymers.
BACKGROUND OF THE INVENTION
For three decades, biosensors have been the subject of increasing research efforts and constitute now a major component of mainstream analytical chemistry (see e.g. Turner et al. (Eds.), Biosensors: Fundamentals and Applications, Oxford University Press, New York, 1987; Guilbault et al. (Eds.), Uses of Immobilized Biological Compounds, vol. 252, NATO ASI, Kluver Academic Publishers, 1993; Wang, Anal. Chem. 67 (1995) 487 R.) Considerable effort has been devoted in particular to develop optimized techniques for immobilizing biomolecules on suitable supports. Since miniaturized transducers are gaining importance, much attention is focused on the development of procedures allowing the spatially controlled deposition of biomolecules (see e.g. Heiduschka et al., Chem. Eur. J. 2 (1996) 667; Jobst et al., Anal. Chem. 68 (1996) 3173.)
Among conventional immobilization procedures, only the entrapment of biomolecules in electrogenerated conducting polymer films offers a good spatial resolution (see e.g. Bartlett et al., J. Electroanal. Chem. 363 (1993) 1; Schuhmann, Mikrochim. Acta, 121 (1995) 1; Trojanowicz et al., Mikrochim. Acta, 121 (1995) 167; Cosnier, Electroanalysis, 9 (1997) 894). However, the biomolecule entrapment within electropolymerized films suffers from severe drawbacks. This method requires high concentrations of biomolecules in the aqueous electrolyte during the electropolymerization process. This is because biomolecule incorporation in the growing polymer is only due to the presence of enzyme in the immediate vicinity of the electrode surface. In addition, the physical entrapment in polymer films such as polypyrrole, polythiophene, polyacetylene or polyaniline, drastically reduces the accessibility to the immobilized biomolecule. The steric constraints generated by the surrounding polymer in particular may hinder the formation of specific antigen-antibody binding. Consequently, the electrochemical entrapment of biomolecules is not an ideal method for the fabrication of immunosensors.
Other relevant prior art is U.S. Pat. No. 5,837,859 to Teoule et al., incorporated herein by reference, and the corresponding WO 94/22889.
SUMMARY OF THE INVENTION
It is thus desired to provide an electrically conductive copolymer suitable for presenting a wide variety of biologically interesting molecules on a surface, especially in a surface array or matrix suitable for use in biosensor or biochip applications.
There is thus provided, in accordance with a preferred embodiment of the invention, an electrically conductive copolymer of the general formula I:
wherein
A is a first polymerizable monomer which produces an electrically conductive polymer when polymerized, and represents a polymerized unit of said monomer A in the electrically conductive polymer;
B is a second polymerizable monomer which when copolymerized with monomer A produces an electrically conductive polymer, and represents a polymerized unit of said monomer B in the electrically conductive polymer;
w is an integer greater than or equal to 0;
x is an integer greater than or equal to 1;
y is an integer greater than or equal to 0;
z is an integer greater than or equal to 1;
1
1
and 1
2
are each independently covalent linkers or spacer arms;
1
3
is substituent group having a desired chemical functionality; and
Bt′ is selected from the group consisting of biotin and complexes of biotin with a molecule selected from the group consisting of avidin, streptavidin, derivatives of avidin and derivatives of streptavidin,
wherein said avidin, streptavidin, derivatives of avidin or derivatives of streptavidin may optionally be substituted, and said biotin, whether in free form or in the form of a complex, is covalently bonded to 1
2
.
By the term “covalent linker or spacer arm” is meant an atom or a chain of atoms covalently bonded to one another, covalently bonded at one end to the monomer and covalently bonded at the other end to the Bt group. The covalent linker or spacer arm may be branched and may contain functional groups, such as amine, amide, or carbonyl moieties. The covalent linker or spacer arm may thus be chosen to have a desired chemical functionality.
A “desired chemical functionality” may be any chemical property desired, such as but not limited to the ability to: prevent non-specific protein binding (e.g. polyethylene glycol chains, lipophilic chains or fluorinated chains); aid in electron transfer (e.g. viologen, quinone, polyaromatics, triaryl amine); affect magnetic properties (e.g. spin labels or paramagnetic complexes of rhuthenium); affect spin resonance; affect fluorescence quenching (e.g. dinitrophenyl or other aromatics); or imparting characteristics of hydrophobicity, hydrophilicity or amphipathicity.
Derivatives of avidin and streptavidin are avidin or streptavidin molecules subustituted by, bonded to or conjugated with other moieties or molecules, especially biomolecules. Thus avidin/streptavidin derivatives include, but are not limited to, avidin/streptavidin bonded or conjugated to: proteins (e.g. enzmies, antibodies, or receptors), peptides, sugars, oligosaccharides, nucleic acids, deoxynucleic acids, metal complexes, lipids, nitro (—NO
2
) groups, and fluorophores.
The monomer A may be any polymerizable monomer which when polymerized yields an electrically conductive polymer. The monomer B may any polymerizable monomer which, when copolymerized with the monomer A, yields an electrically conductive polymer. Monomer B may thus be identical to monomer A. In accordance with a preferred embodiment of the invention, A and B are each independently selected from the group consisting of pyrrole, acetylene, azine, p-phenylene, p-phenylene vinylene, pyrene, thiophene, furan, selenophene, pyridazine, carbazole, aniline, and tyramide.
In accordance with an especially preferred embodiment of the invention, A and B are both pyrrole or both carbazole.
In accordance with a preferred embodiment of the invention, the ratio of x to y is in the range of about 1:0 to about 1:1,000,000.
In accordance with another preferred embodiment of the invention, 1
1
and 1
2
each independently contain functions selected from the group consisting of alkl groups, ether linkages, thioether linkages, carbonyl groups, carbon-carbon double bonds, carbon-carbon triple bonds, amide groups, sulfonamide groups, phosphate groups, thiophosphate groups, ketal groups and ester groups.
In accordance with a preferred embodiment of the invention, Bt is a complex of biotin with avidin or an avidin derivative, and said avidin or avidin derivative is substituted by at least one molecule selected from the group consisting of proteins, peptides, sugars, oligosaccharides, nucleic acids, deoxynucleic acids, metal complexes, lipids, nitro (—NO
2
) groups, and fluorophores.
In accordance with a preferred embodiment of the invention, the copolymer is formed on a substrate comprising a modified electrode ME, said modified electrode comprising an electrode E and an electrically conductive monolayer M deposited on E, wherein M is a monolayer consisting of monomers B′ each covalently bonded via a linker group 1
4
to a functional group selected from the group consisting of thiol, symmetric disulfide, unsymmetric disulfide, and —SiX
3
wherein X is selected from Cl, I, Br, F, and OR
3
wherein each R is independently selected from H, C
1
-C
6
alkyl, and aryl, with the proviso that when the functional group to which B′ is bonded is SiX
3
then electrode E is an indium tin oxide electrode, and when the functional group to which B′ is bonded is thiol or disulfide then E is a metallic electrode;
B′ is a monomer B as defined above; and
1
4
is a linker of 2 to 20 carbons length, optionally including ether linkages, thioether linkages, carbonyl groups, carbon-carbon double bonds, carbon-carbon triple bonds, amide groups, sulfonamide groups, phosphate groups

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