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Molecular & Cellular Analysis Technologies
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In this resubmitted application responding to Innovative Technologies for Molecular Analysis of Cancer (FOA CA-07-033), we seek to develop a novel type of sensor technology that exploits the emerging nanoscale dilute magnetic semiconductor (DMS) materials to enable ultrasensitive label-free electrical detection of DNA molecules for genetic analysis of cancer. The sensing mechanism is the following: the semiconducting properties of the properly biofunctionalized DMS nanomaterials are modulated by surface charges upon specific binding of target molecules to surface probe molecules, which leads to significant magnetic property changes that can be detected using highly sensitive giant magnetoresistance (GMR) magnetic field sensors found in computer hard disks. Outperforming any current technologies, the proposed sensors promise to be simple, specific, high throughput, robust, potentially compatible with high density arrays and multiplexing, and potentially boast low cost and good manufacturability on a large scale. In this application, we will demonstrate the proof-of-principle operation and validate the extremely high sensitivity of the proposed sensors using two families of DMS nanomaterials and model DNA samples from the p53 gene. The specific steps are: 1) synthesize and characterize nanomaterials of transition metal doped ZnO and Cr-doped ZnTe, and demonstrate robust ferromagnetism near room temperature; 2) develop and optimize strategies to attach suitable oligonucleotides onto the surface of these nanomaterials for use as the sensing elements of proposed sensors; 3) demonstrate and understand the magnetic property changes upon applying complementary target oligonucleotides from p53 genes to surface modified nanomaterials using a SQUID magnetometer; 4) construct integrated sensor devices using commercial GMR devices, and demonstrate proof-of-principle real-time electrical sensing measurements with model analytes of target oligonucleotides; and 5) evaluate and quantify the sensor response versus DNA concentrations and demonstrate the detection of complementary target p53 oligonucleotide down to concentration of 0.1 femtomolar (fM), and the differentiation of wild type and single nucleotide mismatched mutant p53 at the concentration of 10 fM through the optimization of sensors. The success of this project will enable inexpensive table-top or even handheld turn-key electrical devices that will allow heathcare professionals to perform robust high throughput but yet highly sensitive analysis of urine, serum, and blood samples for the detection and diagnosis of cancer, the monitoring of cancer progression, and the determination of response to therapy with little training and sample preparation in point-of-care settings.