Posts Tagged ‘volatile organic compounds (VOCs)’

Identifying Melanoma by Scent

Author: Tilda Barliya PhD


Researchers from the Monell Chemical Center developed a nano-sensor constructed of nano-size carbon nanotubes coated with DNA that could identify melanoma cells by scent (1).

The smell of cancer_MIT Technology

Currently, early detection of skin carcinoma is accomplished primarily through a visual exam,imaging techniques and biopsy of any suspected areas (1).

The biopsy is invasive and usually requires examination by a pathologist,  and the use of reflectance confocal microscopy and dermoscopy in situ for diagnosis of primary melanoma and other skin diseases, require specialized training.  Additionally, proteomics of caner-related biomarkers has also emerged in recent years. The discovery of cancer-related biomarkers using proteomic techniques has primarily focused on prognostic indicators of melanoma, i.e., examining the serum and plasma proteome for biomarkers indicative of metastases to distant sites (2,3).

Volatile cue however, such as those use to detect lung cancer (I), diabetes, COPD etc, have not yet been exploit in detecting melanoma. Rather volatile chemicals are released from melanoma tissues that can be differentiated from those of normal skin, posed a very interestingscientific questions.

Electronic nose that can sniff out cancer

It was no surprising that Dogs can identify by olfaction,melanoma on the skin of patients or melanoma samples hidden on healthy subjects, suggesting that volatile organic compounds (VOCs) from melanoma differ from those of normal skin. (4, 5).

D‘Amico et al. [6] employed gas chromatography/mass spectrometry (GC–MS) and a gas sensor array to investigate whether skin lesions of melanoma and nevi can be differentiated. In his paper, D’Amico had very promising results in which electronic nose sensors have been shown to have good sensitivity (with 80% accuracy) towards volatile organic compounds emitted by skin lesions, and the method seems to be effective for malign lesions identification (6).

Other attempts have been carried out to identify more closely the different VOCs of melanoma lesions compared to normal skin, however, environmental contamination rather than compounds from skin metabolism have failed to yield good detection methodology.

Kwak J et al, created an electronic nose (e-nose)  device employing functionalized DNA-coated carbon nanotube sensors, capable of sensitive and selective detection of compounds emitted from skin (1). These “single walled carbon nanotube field effect transistors (CNT FET’s), functionalized with single stranded DNA (DNACNT), have been shown to respond through a change in source drain current when exposed to VOCs” (7).

“The sensors show rapid response and recovery (seconds), very low signal drift, and chemical responses that are single strand DNA (ss-DNA) base sequence dependent. Single stranded-DNA is chosen for functionalization of the CNTs because it displays recognition for chemical vapors”.

The authors employed SPME and GC–MS to identify the VOCs that differentiate between human melanoma and normal melanocyte cells cultured in vitro, which may provide a model for in vivo human melanomas.  Same analysis were later conducted using GC–MS and DNACNT. Analysis of different normal melanocytes and melanoma cancer cell lines revealed: the growth media for normal melanocytes and cancer cells differed from each other in relative abundance of several compounds:

  • 3-hydroxy-2-butanone (acetoin),
  • 1-hexanol,
  • acetophenone,
  • phenylethyl alcohol
  • phenol

They also noted that dimethylsulfone, which has been reported, in preliminary fashion, as a significant indicator of basal cell carcinoma, was seen in significantly greater amounts in metastatic melanoma cells vs. normal cells.


It is well known that cancer cells have altered metabolisms, which are expected to yield a different profile of metabolites.The authors presented here suggest significant differences in the “volatile metabolome” of melanoma cells vs. normal melanocytes.

The authors posit that successful development of rapid screening techniques incorporating new e-nose technologies, fitted with nanosensors with high selectivity for endogenous melanoma biomarkers, may effectively scan the complex volatile fingerprints acquired from suspicious lesions and quickly provide an evaluation for the physician, regardless of their geographic location”.

Smelling a disease has also been examined in bladder cancer (8), ovarian cancer (9) as well as Parkinson and Alzheimer disease (10) and it may potentially be used to enable easy, fast and accurate method to scenting a disease.


1. Kwak J, Gallagher M, Ozdener MH, Wysocki CJ, Goldsmith BR, Isamah A, Faranda A, Fakharzadeh SS, Herlyn M, Johnson AT, Preti G. Volatile biomarkers from human melanoma cells. Journal of Chromatography B, 931 (2013) 90–96. http://www.ncbi.nlm.nih.gov/pubmed/23770738

2. S.A. Hoffman, W.A. Joo, L.A. Echan, D.W. Speicher, Higher dimensional (Hi-D) separation strategies dramatically improve the potential for cancer biomarker detection in serum and plasma.  J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci. 849 (2007) 43. http://www.ncbi.nlm.nih.gov/pubmed/17140865

3.  J. Solassol, A. Du-Thanh, T. Maudelonde, B. Guillot,  Serum proteomic profiling reveals potential biomarkers for cutaneous malignant melanoma. Int. J. Biol. Markers 26 (2011) 82. http://www.ncbi.nlm.nih.gov/pubmed/21607923

4. H. Williams, A. Pembroke, SNIFFER DOGS IN THE MELANOMA CLINIC? Lancet 333 (1989) 734.  http://www.sciencedirect.com/science/article/pii/S0140673689922575
5. J. Church, H. Williams, Another sniffer dog for the clinic?  Lancet 358 (2001) 930.  http://www.sciencedirect.com/science/article/pii/S0140673601060652

6. D’Amico A, Bono R, Pennazza G, Santonico M, Mantini G, Bernabei M, Zarlenga M, Roscioni C, Martinelli E, Paolesse R, Di Natale C.  Identification of melanoma with a gas sensor array. Skin Res Technol. 2008 May;14(2):226-36.  http://www.ncbi.nlm.nih.gov/pubmed/18412567

7. C. Staii, A.T. Johnson Jr., M. Chen, A. Gelperin, DNA-Decorated Carbon Nanotubes for Chemical Sensing. Nano Lett. 5 (2005) 1774. http://pubs.acs.org/doi/abs/10.1021/nl051261f

8. Written By: Ian Anglin. SMELLING CANCER: DEVICE DETECTS BLADDER CANCER FROM ODOR OF URINE. http://singularityhub.com/2013/07/31/smelling-cancer-device-detects-bladder-cancer-from-odor-of-urine/

9. Horvath G, Chilo J, Lindblad T. Different volatile signals emitted by human ovarian carcinoma and healthy tissue.Future Oncol. 2010 Jun;6(6):1043-1049. http://www.ncbi.nlm.nih.gov/pubmed/?term=Volatile+biomarkers+from+ovarian+cacner

10. Ulrike Tisch, Ilana Schlesinger, Radu Ionescu, Maria Nassar, Noa Axelrod, Dorina Robertman, Yael Tessler, Faris Azar, Abraham Marmur, Judith Aharon-Peretz and Hossam Haick. Detection of Alzheimer’s and Parkinson’s disease from exhaled breath using nanomaterial-based sensors. Nanomedicine January 2013, Vol. 8, No. 1, Pages 43-56   http://www.futuremedicine.com/doi/abs/10.2217/nnm.12.105?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&

Other open access article in Pharmaceutical Inteliigence

I. By: Tilda Barliya PhD. Diagnosing lung cancer in exhaled breath using gold nanoparticles.  http://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

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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 |)


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…) Nanosensors Detect Cancer Breath


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).Diagnosing lung cancer in exhaled breath

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.


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.


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


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