Cancer is recognized as a highly complex disease involving myriad molecular processes and arises as the result of gradual accumulation of multiple genetic and proteomic alterations, which also serve as cancer biomarkers. A major focus of current cancer research is how to correlate these underlying molecular events with cancer development and progression. Recent advances in cancer molecular analysis and bioanalytical sciences have led to the development of DNA chips, ELISA, miniaturized biosensors, microfluidic devices (e.g., bioMEMS or microelectromechanical systems, and mass spectrometry. These enabling technologies have substantially influenced the way that we detect and analyze cancer, such as gene expression profiling, drug discovery, and clinical diagnostics. However, none of these technical platforms are sufficiently flexible to allow detection of both genetic alterations and protein profiles with sensitivity down to single molecule level. As current research in genomics and proteomics produces more sequence data, there is a strong need for new technologies that can rapidly screen a large number of nucleic acids and proteins. In this context, the primary goal of this proposal is to develop a versatile and sensitive technology that can quickly analyze cancer molecular profiles (such as DNAs, RNAs and proteins) in a highly multiplexed manner for accurate diagnostics, prognostics and effective therapeutics. The innovation and basic rationale of this technology lies in the novel optical properties of semiconductor quantum dots or QDs (e.g., tunable light emission, improved signal brightness, resistance against photobleaching, and simultaneous excitation of multiple colors) and our ability to make optical barcodes using these nanoparticles. Different from single QD based imaging, we propose to prepare QD encoded optical barcodes of both micrometer sizes and nanometer sizes. The micro-barcodes will be used to tag biomolecular probes, whereas the nanospheres will be used as reporters to enhance the current detection sensitivity by 2-3 orders of magnitude. We will also explore new surface encapsulation and pore sealing approaches to stabilize the optical barcodes, and chemical conjugation approaches to optimize biomolecular probe immobilization. We will further carry out experiments to detect mutations on both DNA and RNA level as well as the profiles of protein cancer biomarkers, which can be isolated from serum or homogenized cell and tissue specimens.

Public Health Relevance

We describe a new generation of QD-based optical barcoding technology for molecular analysis of cancer. The innovation arises from three levels: (1) the concept of using QDs for intensity-color based multiplexing, which has significantly higher multiplexing capability than traditional technology and simplified detection instrumentation;(2) the technique of using mesoporous material for micro barcodes and block-copolymer self assembly for nanobeads; and (3) the selection of clinically important biomarkers for cancer molecular analysis. It is built on our considerable expertise and strength in QD probe chemistry, optical imaging and cancer research. The major advantage of this versatile platform is that it allows simultaneous analysis of DNA, RNA as well as protein cancer markers with unprecedented sensitivity, which is not possible with other approaches.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BST-M (50))
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Patriotis, Christos F
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University of Washington
Biomedical Engineering
Schools of Engineering
United States
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Shang, Jing; Gao, Xiaohu (2014) Nanoparticle counting: towards accurate determination of the molar concentration. Chem Soc Rev 43:7267-78
Zrazhevskiy, Pavel; Gao, Xiaohu (2013) Quantum dot imaging platform for single-cell molecular profiling. Nat Commun 4:1619
O'Donnell, Matthew; Wei, Chen-Wei; Xia, Jinjun et al. (2013) Can molecular imaging enable personalized diagnostics? An example using magnetomotive photoacoustic imaging. Ann Biomed Eng 41:2237-47
Wei, Chen-wei; Xia, Jinjun; Pelivanov, Ivan et al. (2013) Magnetomotive photoacoustic imaging: in vitro studies of magnetic trapping with simultaneous photoacoustic detection of rare circulating tumor cells. J Biophotonics 6:513-22
Zrazhevskiy, Pavel; True, Lawrence D; Gao, Xiaohu (2013) Multicolor multicycle molecular profiling with quantum dots for single-cell analysis. Nat Protoc 8:1852-69
Hu, Shang-Hsiu; Chen, San-Yuan; Gao, Xiaohu (2012) Multifunctional nanocapsules for simultaneous encapsulation of hydrophilic and hydrophobic compounds and on-demand release. ACS Nano 6:2558-65
Liu, Hong Yan; Gao, Xiaohu (2011) Engineering monovalent quantum dot-antibody bioconjugates with a hybrid gel system. Bioconjug Chem 22:510-7
Probst, Christine E; Zrazhevskiy, Pavel; Gao, Xiaohu (2011) Rapid multitarget immunomagnetic separation through programmable DNA linker displacement. J Am Chem Soc 133:17126-9
Hu, Xiaoge; Gao, Xiaohu (2011) Multilayer coating of gold nanorods for combined stability and biocompatibility. Phys Chem Chem Phys 13:10028-35
Hu, Xiaoge; Gao, Xiaohu (2010) Silica-polymer dual layer-encapsulated quantum dots with remarkable stability. ACS Nano 4:6080-6

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