Breath analysis has long been recognized as a reliable technique for diagnosing certain medical conditions through the detection of volatile organic compounds (VOCs) in exhaled breath. The diagnosis is usually performed by collecting breath samples to a container followed by subsequent measurements of specific VOCs using mass spectrometry.
The composition of VOCs in exhaled breath is dependent upon cellular metabolic processes and it includes, inter alia, saturated and unsaturated hydrocarbons, oxygen containing compounds, sulfur containing compounds, and nitrogen containing compounds. In healthy individuals, the composition provides a distinct chemical signature with relatively narrow variability between samples from a single individual and samples from different individuals.
In exhaled breath of patients with cancer, elevated levels of certain VOCs including, volatile C4-C20 alkane compounds, specific monomethylated alkanes as well as benzene derivatives were found (Phillips et al., Cancer Biomark., 3(2), 2007, 95). Hence, the composition of VOCs in exhaled breath of patients with cancer differs from that of healthy individuals, and can therefore be used to diagnose cancer. An additional advantage for diagnosing cancer through breath is the non-invasiveness of the technique which holds the potential for large-scale screening.
Gas-sensing devices for the detection of VOCs in breath samples of cancer patients have recently been applied. Such devices perform odor detection through the use of an array of cross-reactive sensors in conjunction with pattern recognition methods. In contrast to the “lock-and-key” model, each sensor in the electronic nose device is widely responsive to a variety of odorants. In this architecture, each analyte produces a distinct fingerprint from an array of broadly cross-reactive sensors. This configuration may be used to considerably widen the variety of compounds to which a given matrix is sensitive, to increase the degree of component identification and, in specific cases, to perform an analysis of individual components in complex multi-component (bio) chemical media. Pattern recognition algorithms can then be applied to the entire set of signals, obtained simultaneously from all the sensors in the array, in order to glean information on the identity, and concentration of the vapor exposed to the sensor array.
The hitherto used gas-sensing devices comprise a variety of sensor arrays including conductive polymers, nonconductive polymer/carbon black composites, metal oxide semiconductors, fluorescent dye/polymer systems, quartz microbalance sensors coated with metallo-porphyrins, polymer coated surface acoustic wave devices, and chemoresponsive dyes (Mazzone, J. Thoracic Onc., 3(7), 2008, 774). Di Natale et al. (Biosen. Bioelec., 18, 2003, 1209) disclosed the use of eight quartz microbalance gas sensors coated with different metalloporphyrins for analyzing the composition of breath of patients with lung cancer. Chen et al. (Meas. Sci. Technol., 16, 2005, 1535) used a pair of surface acoustic wave (SAW) sensors, one coated with a thin polyisobutylene (PIB) film, for detecting VOCs as markers for lung cancer. Machado et al. (Am. J. Respir. Crit. Care Med., 171, 2005, 1286) demonstrated the use of a gaseous chemical sensing device comprising a carbon polymer sensor system with 32 separate sensors for diagnosing lung cancer. Mazzone et al. (Torax, 62, 2007, 565) disclosed a colorimetric sensor array composed of chemically sensitive compounds impregnated on a disposable cartilage for analyzing breath samples of individuals with lung cancer and other lung diseases. The results presented in these disclosures have yet to provide the accuracy or consistency required for clinical use.
Sensors based on films composed of nanoparticles capped with an organic coating (“NPCOCs”) were applied as chemiresistors, quartz crystal microbalance, electrochemical sensors and the like. The advantages of NPCOCs for sensing applications stem from enhanced sensing signals which can be easily manipulated through varying the nanoparticles and/or aggregate size, inter-particle distance, composition, and periodicity. Enhanced selectivity can further be achieved through modifying the binding characteristics of the capping film as well as linker molecules. The morphology and thickness of NPCOC networks were shown to induce a dramatic influence on sensor response, wherein changes in permittivity induced a decrease in resistance of NPCOC thinner films (Joseph et al., J. Phys. Chem. C, 112, 2008, 12507). The three dimensional assembly of NPCOC structures provides additional framework for signal amplifications. Other advantages stem from the coupling of nano-structures to solid-state substrates which enable easy array integration, rapid responses, and low power-driven portable apparatuses.
Some examples for the use of NPCOCs for sensing applications are disclosed in U.S. Pat. Nos. 5,571,401, 5,698,089, 6,010,616, 6,537,498, 6,746,960, 6,773,926; Patent Application Nos. WO 00/00808, FR 2,783,051 US 2007/0114138; and in Wohltjen et al. (Anal. Chem., 70, 1998, 2856), and Evans et al. (J. Mater. Chem., 8, 2000, 183).
International patent application publication number WO 99/27357 discloses an article of manufacture suitable for use in determining whether or in what amount a chemical species is present in a target environment, which article comprises a multiplicity of particles in close-packed orientation, said particles having a core of conductive metal or conductive metal alloy, in each said particle such core being of 0.8 to 40.0 nm in maximum dimension, and on said core a ligand shell of thickness from 0.4 to 4.0 nm, which is capable of interacting with said species such that a property of said multiplicity of particles is altered.
U.S. Pat. No. 7,052,854 discloses systems and methods for ex-vivo diagnostic analysis using nanostructure-based assemblies comprising a nanoparticle, a means for detecting a target analyte/biomarker, and a surrogate marker. The sensor technology is based on the detection of the surrogate marker which indicates the presence of the target analyte/biomarker in a sample of a bodily fluid.
EP 1,215,485 discloses chemical sensors comprising a nanoparticle film formed on a substrate, the nanoparticle film comprising a nanoparticle network interlinked through linker molecules having at least two linker units. The linker units are capable of binding to the surface of the nanoparticles and at least one selectivity-enhancing unit having a binding site for reversibly binding an analyte molecule. A change of a physical property of the nanoparticle film is detected through a detection means.
WO 2009/066293 to one of the inventors of the present invention discloses a sensing apparatus for detecting volatile and non-volatile compounds, the apparatus comprises sensors of cubic nanoparticles capped with an organic coating. Further disclosed are methods of use thereof in detecting certain biomarkers for diagnosing various diseases and disorders including cancer.
There is an unmet need for a fast responsive sensor array based on a variety of sensors which provide improved sensitivity as well as selectivity for specific VOCs indicative of cancer.
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USPTO Backgrounds