PhD Thesis Defense: Amogha Tadimety

Monday, March 30, 2020, 12:00pm

Zoom Meeting: https://dartmouth.zoom.us/j/340165529 / Meeting ID: 340 165 529

"Circulating Tumor DNA Capture and Detection Using Nanoplasmonic Sensors"

Abstract

Liquid biopsies, or the detection of biomarkers from a peripheral fluid sample rather than a tissue sample, offer promise for effective cancer screening, early diagnosis, and monitoring. One biomarker of significant interest, circulating tumor DNA (ctDNA), can provide insight into tumor mutational profiles and epigenetics with a very short two-hour half-life. ctDNA poses a challenge for detection, however, due to its small size and low concentration, as well as the presence of point mutations that are difficult to differentiate from wild type sequences. Nanoscale sensors, with molecular recognition and optical readout functionalities could combat these challenges through engineering high specificity and sensitivity to ctDNA in patient fluid samples.

This thesis demonstrates a platform using gold nanoparticles for plasmonic detection of sequence-specific ctDNA binding. The basic principle relies on the highly confined electric fields at the surface of gold nanoparticles, that have an ability to detect slight changes in local dielectric properties. We can functionalize the nanoparticles to be selective to biomarkers of interest, and then can read out spectral shifts to transduce binding. We demonstrate the development of plasmonic nanosensors for capture of ctDNA. Sensor arrangement is explored through studies of nanoparticles arrayed on chip through microfluidic alignment. Sequence-selective ctDNA protocols were developed for capture of clinically relevant variants in the KRAS gene, including thermodynamic modeling for enhancement of selectivity. Full integration on-chip with multiplexed capture probes and microfluidic sample delivery was demonstrated  Shape effects of particles were studied through experimental and theoretical investigation of properties of in house synthesized gold nanoparticles with multiple geometries. The platform was demonstrated for both ctDNA sensing applied to pancreatic ductal adenocarcinoma, and detection of the 16s RNA sequence relevant to bacterial detection. We provide a framework for development of rapid, minimally invasive, sample-to-answer solutions with broad medical applications from cancer to infectious disease.

Thesis Committee

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