Developing Carbon Nanotube Optical Sensors For In Vitro And In Vivo Detection Of Biomarkers And Drugs
Diseases such as cancer can develop asymptomatically, preventing opportunities for early detection. The drive for “liquid biopsies” that can detect biomarkers in a rapid, point-of-care setting has spurred innovation in nanoparticle-based sensing schemes. One biomarker, cell-free circulating microRNA, has been a major target due to its diagnostic potential and difficulties in detecting it with standard assays. If cancer is detected, chemotherapy is often administered; unfortunately, chemotherapy can greatly decrease patient quality of life due to toxicity. Some side effects can be permanent and cumulative, as in the case of the drug doxorubicin. Sensors that can detect chemotherapy drugs in vivo would be useful as a research tool to better assess drug distribution in the organism and in cells. Clinically, an implantable cumulative sensor for doxorubicin could provide a record of lifetime exposure, minimizing chances of adverse effects. A potential nanomaterial for developing implantable sensors for biomarkers and chemotherapy drugs are single-walled carbon nanotubes. Carbon nanotubes are fluorescent in the near-infrared range, which is highly penetrant to tissue, and report their local environment via changes in their emission energy and intensity. Here, we have developed DNA-functionalized carbon nanotubes for the detection of oligonucleotide biomarkers, alkylating agents, and DNA-intercalating drugs like doxorubicin. We have discovered a method by which optical changes due to hybridization on the nanotube can be greatly enhanced, and applied it to the detection of microRNA in biofluids and in vivo. By adapting our understanding of this enhancement we were able to show directional control of nanotube solvatochromism to alkylating agents, which enabled control of sensing output signal. Mechanistic experiments allowed us to obtain new insight about the interaction of DNA-suspended nanotubes with anionic analytes, including oligonucleotides, to provide better selectivity. In detecting oligonucleotides in serum, we discovered that serum proteins can be denatured to selectively interact with nanotubes after hybridization to enhance sensing, and used this to detect viral RNA. Finally we developed a cumulative, implantable sensor for doxorubicin and other intercalating agents that enabled real-time sensing in live mice.
biomarkers; Carbon; implantable; Nanotube; sensor; solvatochromism
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International