Diagnosing Lung Cancer in Exhaled Breath using Gold Nanoparticles
Reporter-curator: Tilda Barliya PhD
Authors: Gang Peng, Ulrike Tisch, Orna Adams1, Meggie Hakim, Nisrean Shehada, Yoav Y. Broza, Salem Billan, Roxolyana Abdah-Bortnyak, Abraham Kuten & Hossam Haick. (NATURE NANOTECHNOLOGY | VOL 4 | OCTOBER 2009 |)
Abstract:
Conventional diagnostic methods for lung cancer1,2 are unsuitable for widespread screening, because they are expensive and occasionally miss tumours. Gas chromatography/mass spectrometry studies have shown that several volatile organic compounds, which normally appear at levels of 1–20 ppb in healthy human breath, are elevated to levels between 10 and 100 ppb in lung cancer patients. Here we show that an array of sensors based on gold nanoparticles can rapidly distinguish the breath of lung cancer patients from the breath of healthy individuals in an atmosphere of high humidity. In combination with solidphase microextraction, gas chromatography/mass spectrometry was used to identify 42 volatile organic compounds that represent lung cancer biomarkers. Four of these were used to train and optimize the sensors, demonstrating good agreement between patient and simulated breath samples. Our results show that sensors based on gold nanoparticles could form the basis of an inexpensive and non-invasive diagnostic tool for lung cancer. (http://www.nature.com/nnano/journal/v4/n10/abs/nnano.2009.235.html) (lnbd.technion.ac.il/NanoChemistry/SendFile.asp?DBID=1…1…)
Introduction:
Lung cancer accounts for 28% of cancer-related deaths. Approximately 1.3 million people die worldwide every year. Breath testing is a fast, non-invasive diagnostic method that links specific volatile organic compounds (VOCs) in exhaled breath to medical conditions. Gas chromatography/mass spectrometry (GC-MS), ion flow tube mass spectrometry10, laser absorption spectrometry,infrared spectroscopy, polymer-coated surface acoustic wave sensors and coated quartz crystal microbalance sensors have been used for this purpose. However, these techniques are expensive, slow, require complex instruments and, furthermore, require pre-concentration of the biomarkers (that is, treating the biomarkers by a process to increase the relative concentration of the biomarkers to a level that can be detected by the specific technique) to improve detection.
Here, we report a simple, inexpensive, portable sensing technology to distinguish the breath of lung cancer patients from healthy subjects without the need to pre-treat the exhaled breath in any way (see also refs 14–16 for the diagnosis of lung cancer by sensing technology that is based on arrays of polymer/carbon black sensors). Our study consisted of four phases and included volunteers aged 28–60 years. Samples were collected from 56 healthy controls and 40 lung cancer patients after clinical diagnosis using conventional methods and before chemotherapy or other treatment.
In the first phase, we collected exhaled alveolar breath of lung cancer patients and healthy subjects using an ‘offline’ method. This method was designed to avoid potential errors arising from the failure to distinguish endogenous compounds from exogenous ones in the breath and to exclude nasal entrainment of the gas. Exogenous VOCs can be either directly absorbed through the lung via the inhaled breath or indirectly through the blood or skin. Endogenous VOCs are generated by cellular biochemical processes in the body and may provide insight into the body’s function
In the second phase, we identified the VOCs that can serve as biomarkers for lung cancer in the breath samples and determined their relative compositions, using GC-MS in combination with solidphase microextraction (SPME). GC-MS analysis identified over 300–400 different VOCs per breath sample, with .87% reproducibility for a specific volunteer examined multiple times over a period of six months. Forward stepwise discriminant analysis identified 33 common VOCs that appear in at least 83% of the patients but in fewer than 83% of the healthy subjects
The compounds that were observed in both healthy breath and lung cancer breath were presented not only at different concentrations but also in distinctively different mixture compositions.
Further forward stepwise discriminant analysis revealed nine uncommon VOCs that appear in at least 83% of the patients but not in the majority (83%) of healthy subjects. This additional class of VOCs has not been recognized in earlier GC-MS studies.
In spite of these advances in the GC-MS analysis, these data certainly do not account for all the VOCs present in the exhaled breath samples, because the pre-concentration technique can be thought of as a solid phase that extracts only part of the analytes present in the examined phase and, subsequently, releases only part of the extracted analytes.
So, it is likely that the actual mixture of VOCs to which, for example, an array of gold nanoparticle sensors would be responding is different from that obtained by GC-MS.
In the third phase of this study we designed an array of nine crossreactive chemiresistors, in which each sensor was widely responsive to a variety of odorants for the detection of lung cancer by means of breath testing. We used chemiresistors based on assemblies of 5-nm gold nanoparticles with different organic functionalities (dodecanethiol, decanethiol, 1-butanethiol, 2-ethylhexanethiol, hexanethiol, tert-dodecanethiol, 4-methoxy-toluenethiol, 2-mercaptobenzoxazole and 11-mercapto-1-undecanol).
Chemiresistors based on functionalized gold nanoparticles combine the advantages of organic specificity with the robustness and processability of inorganic materials.
The response of the nine-sensor array to both healthy and lung cancer breath samples was analysed using principal component analysis . It can be seen that there is no overlap of the lung cancer and healthy patterns.
The PCA of the healthy control group revealed that the set of gold nanoparticles sensors was not influenced by characteristics such as gender, age or smoking habits, thus strengthening the ability of the sensors to discriminate between healthy and cancerous breath. Experiments with a wider population of volunteers to thoroughly probe the influence of diet, alcohol consumption,metabolic state and genetics are under way and will be published elsewhere.
Summary:
To summarize, we have demonstrated that an array of chemiresistors based on functionalized gold nanoparticles in combination with pattern recognition methods can distinguish between the breath of lung cancer patients and healthy controls, without the need for dehumidification or pre-concentration of the lung cancer biomarkers. Our results show great promise for fast, easy and cost-effective diagnosis and screening of lung cancer. The developed devices are expected to be relatively inexpensive, portable and amenable to use in widespread screening, making them potentially valuable in saving millions of lives every year. Given the impact of the rising incidence of cancer on health budgets worldwide, the proposed technology will be a significant saving for both private and public health expenditures. The potential exists for using the proposed technology to diagnose other conditions and diseases, which could mean additional cost reductions and enhanced opportunities to save lives.
Ref:
1. Gang Peng, Ulrike Tisch, Orna Adams, Meggie Hakim, Nisrean Shehada, Yoav Y. Broza, Salem Billan, Roxolyana Abdah-Bortnyak, Abraham Kuten& Hossam Haick. Diagnosing lung cancer in exhaled breath using gold nanoparticles. Nature Nanotechnology 4, 669 – 673 (2009) http://www.nature.com/nnano/journal/v4/n10/abs/nnano.2009.235.html
2. http://lungcancer.about.com/od/diagnosisoflungcancer/a/diagnosislungca.htm
3. http://metabolomx.com/2011/12/15/metabolomx-test-detects-lung-cancer-from-breath/
4. http://www.chestnet.org/accp/pccsu/medical-applications-exhaled-breath-analysis-and-testing?page=0,3
Dr. Tilda,
Thank you very much for sharing this wonderful innovative material and prose for data collection of evidence regarding presence of Lung cancer cells in breath.
Can one use same material with other type of cell distribution, instead of aerosol, a cloud of expectorate air from one’s lungs, using a swab of cells from the nose, ear ot throut?
The diagnostic kit, if non-expensive, and the indication can be expanded, one would expect, it to be the first step rather than an chest x-ray test, which is more expansive due to the heavy equipment involved and the Radiologist who has to read the films.
The future will be bright, as far as market penetration and potential new indication.
I was informed 5 years ago about development of Raman Spectroscopy for clinical use in urinalysis by my associate and leader at Siemens, who left the company and has a successful consulting practice. It was not a good time to do a study with my colleagues in nephrology.
There’s another paper published by the same group
“Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939793/
In this paper the authors explain that: “The principle behind this approach is based on cell biology. In particular tumour growth is accompanied by gene and/or protein changes that may lead to peroxidation of the cell membrane species and, hence, to the emission of VOCs These VOCs can be detected either directly from the headspace of cancer cells or through exhaled breath as cancer-related changes in the blood chemistry lead to measurable changes in the breath by exchange through the lung.”
So this method is good for several types of cancers. So technically no need to swab nose or a throat.
Making this into a diagnostic kit will make it very efficient and non-expansive.
Emotions……….Lung cancer a very silent enemy………in front of the patient we feel deeply inside”too late…”.This great post shows that there is a new hope of better fighting this catatrophic event!
Congratulations Dr Tilda for this very high quality article!Feeling in the future “not late” or “not so late” will be very good!
I’m going to print this and show to my pneumologists!
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