Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals – Carrier is inorganic
Reexamination Certificate
2000-07-14
2004-03-02
Le, Long V. (Department: 1641)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
Carrier is inorganic
C436S518000, C436S524000, C435S007100, C428S403000
Reexamination Certificate
active
06699724
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to particles composed of a nonconducting core coated with a very thin metallic layer, and to methods of using these particles for sensing a chemical or biological analyte. More particularly, the invention relates to such particles having defined maximum absorption or scattering wavelengths, and, optionally, having one or more biomolecules conjugated to the metallic layer.
2. Description of Related Art
It has long been observed that an enormous enhancement of Raman scattering intensities is possible from many biologically significant organic molecules when they are adsorbed onto roughened silver electrodes or in a solution of aggregating colloid (Fleischmann, M. et al.
J. Chem. Soc. Commun
. 80 (1973); Duff, D. G., et al.
Langmuir
9:2301 (1993)). This effect, known as surface enhanced Raman scattering (SERS), can yield a Raman spectrum as much as a million times stronger than the spectrum of the same molecule in solution. While this approach has been popular with Raman spectroscopy using visible excitation, SERS enhancement becomes almost a requirement when a near infrared excitation source is used, as in FT-Raman spectroscopy. Although infrared excitation eliminates sample fluorescence, it also results in marked decrease in sensitivity, further motivating the need for a sensitization method. Current methods being used for SERS enhancement of near infrared FT-Raman spectroscopy are frequently plagued by difficult substrate preparation, poor reproducibility, sensitivity to contamination, or limited suitability for in vivo use.
The SERS effect is primarily related to the field strength near the surface of the substrate upon illumination, whether the substrate is a roughened metal surface or an aggregate of metallic nanoparticles. The strongest field enhancement is obtainable at the plasmon resonance of the metal substrate or particle. It is for this reason that gold colloid (plasmon resonance=520 nm) is such an efficient SERS enhancer under visible Raman excitation (typically with an argon ion laser at 514 nm). This resonance coincides with the absorption maximum of hemoglobin (Gordy, E. et al.
J. Biol. Chem
. 227:285-299 (1957)), however, which significantly restricts the use of visible excitation Raman spectroscopy on biological systems.
The idea of exploiting SERS in biosensing applications has been pursued using other strategies for quite some time. Previous workers have used SERS to measure binding between biological molecules of mutual affinity, including antibody-antigen interactions (Rohr, T. E., et al.
Anal. Biochem
. 182:388-398 (1989)). The approach in that study included the use of an avidin-coated silver film as substrate and dye-antibody conjugates to optimally enhance the SERS effect. Although that method was used in a successful sandwich immunoassay, the use of a microscopic silver substrate and the necessity for conjugation of the biomolecules with specific (carcinogenic) chromophores for resonance Raman detection severely limits the adaptability of that approach.
U.S. Pat. No. 5,567,628 (Tarcha et al.) describes an immunoassay method for performing surface enhanced Raman spectroscopy. Various substrates are described, including solid particles of gold or silver. U.S. Pat. No. 5,869,346 (Xiaoming et al) describes an apparatus and method for measuring surface-sensitized Raman scattering by an antigen-antibody complex adsorbed to solid gold, silver or copper particles.
Optical glucose monitoring is one example of an extremely important and active field of research. The goal of this research is to provide a noninvasive method of monitoring and more optimally managing diabetes, a disease that affects millions of people worldwide. A variety of approaches are currently being pursued, including near- and mid-infrared spectroscopy, photoacoustic spectroscopy, polarimetry, diffuse light scattering, and Raman spectroscopy (Waynant, R. W., et al.
IEEE
-
LEOS Newsletter
12:3-6 (1998)). In comparison to the other approaches in use, Raman spectroscopy with near infrared excitation offers the unique ability to discriminate between spectra from different analytes even when signals are small. Raman spectroscopy is the only all-optical technique currently under consideration in which the entire spectral signature of a chemical species can be obtained. The spectral signature is not obscured by water, and the significant penetration depth achieved with near-IR excitation (>1 mm) facilitates a variety of in vivo monitoring approaches. Raman spectroscopic measurements of glucose in human blood serum and ocular aqueous humor (using both conventional Raman and stimulated Raman gain spectroscopy) have also been reported (Wicksted, J. P., et al.
App. Spectroscopy
49:987-993 (1995); and U.S. Pat. No. 5,243,983 issued to Tarr et al.). Since near infrared excitation results in a dramatic decrease in sensitivity relative to visible Raman excitation, the most outstanding current limitation to Raman-based glucose monitoring is the lack of sensitivity. This results in the necessity of long data collection times and multivariate analysis techniques for signal extraction.
The use of gold colloid in biological applications began in 1971, when Faulk and Taylor invented the immunogold staining procedure. Since that time, the labeling of targeting molecules, especially proteins, with gold nanoparticles has revolutionized the visualization of cellular or tissue components by electron microscopy (M. A. Hayat, ed. Colloidal Gold: Principles, Methods and Applications Academic Press, San Diego, Calif. 1989). The optical and electron beam contrast qualities of gold colloid have provided excellent detection qualities for such techniques as immunoblotting, flow cytometry and hybridization assays. Conjugation protocols exist for the labeling of a broad range of biomolecules with gold colloid, such as protein A, avidin, streptavidin, glucose oxidase, horseradish peroxidase and IgG (M. A. Kerr et al., eds. Immunochemistry Labfax BIOS Scientific Publishers, Ltd., Oxford, U.K. 1994).
Metal nanoshells are a new type of “nanoparticle” composed of a non-conducting, semiconductor or dielectric core coated with an ultrathin metallic layer. As more fully described in co-pending U.S. patent application Ser. No. 09/038,377, metal nanoshells manifest physical properties that are truly unique. For example, it has been discovered that metal nanoshells possess attractive optical properties similar to metal colloids, i.e., a strong optical absorption and an extremely large and fast third-order nonlinear optical (NLO) polarizability associated with their plasmon resonance. At resonance, dilute solutions of conventional gold colloid possess some of the strongest electronic NLO susceptibilities of any known substance. (Hache, F. et al.
App. Phys
. 47:347-357 (1988)) However, unlike simple metal colloids, the plasmon resonance frequency of metal nanoshells depends on the relative size of the nanoparticle core and the thickness of the metallic shell (Neeves, A. E. et al.
J. Opt. Soc. Am. B
6:787 (1989); and Kreibig, U. et al. Optical Properties of Metal Clusters, Springer, N.Y. (1995)). The relative thickness or depth of each particle's constituent layers determines the wavelength of its absorption. Hence, by adjusting the relative core and shell thicknesses, and choice of materials, metal nanoshells can be fabricated that will absorb or scatter light at any wavelength across much of the ultraviolet, visible and infrared range of the electromagnetic spectrum. Whether the particle functions as an absorber or a scatterer of incident radiation depends on the ratio of the particle diameter to the wavelength of the incident light. What is highly desirable in the biomedical field are better, more sensitive devices and methods for performing in vivo sensing of chemical or biological analytes. Also desired are easier, more rapid and more sensitive methods and reagents for conducting in vitro assays for analytes such as a
Averitt Richard D.
Halas Nancy J.
Oldenburg Steven J.
West Jennifer L.
Conley & Rose, P.C.
Counts Gary W.
Le Long V.
Wm. Marsh Rice University
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