Early diagnosis of cancer dramatically increases the likelihood of successful treatment. Indeed, imaging techniques have become an integral component of cancer detection. In this regard, photoacoustic imaging is a powerful new imaging modality that is based on the detection of sound waves generated by optically exciting a chromophore with light. Due to the low scattering of sound in biological tissues, this state-of-the-art approach is ideal for non-invasive, deep-tissue biomedical imaging. Our goal is to synthesize chemical probes for the early detection of cancer to facilitate staging, surgical planning, and assessment for residual cancer following tumor resection. Additionally, these versatile chemical tools will be applied to study and understand fundamental cancer processes including the mechanisms of drug resistance.

The ability to selectively kill cancer cells while sparing healthy cells is a major goal in developing new anticancer therapeutics. Our strategy involves appending photoacoustic imaging probes (blue) to chemotherapeutic agents (red) through tumor-responsive linkers (gray). These modifications render the cytotoxic drug inactive until it is released. Of note, our linkers are designed such that they are activated only by tumor microenvironments (e.g., hypoxia) or by cancer biomarkers (e.g., metalloproteinases) resulting in the release of the imaging and drug components for diagnostics and therapy, respectively. In addition to targeting cancerous cell populations, this unique approach enables us to access bio-distribution, transport mechanisms, delivery kinetics, and therapeutic efficacy of our drug-conjugates using photoacoustic imaging to expedite the drug discovery process.

Tuberculosis is a widespread infectious disease caused by the bacteria M. tuberculosis and is responsible for nearly two million deaths each year. Shockingly, most countries worldwide still rely on old inaccurate diagnostic tools from the late 1800s such as the sputum smear test. Our goal is to develop fast, reliable and affordable point-of-care diagnostic tests by exploiting pathogen-specific enzymatic activities. Specifically, M. tuberculosis expresses a beta-lactamase enzyme that can catalyze the fragmentation of cephalosporin-based antibiotics to release appended cargo. By strategically synthesizing carbon-13 labeled antibiotics, diagnosis can be made by quantifying the amount of isotopically labeled metabolites (e.g., carbon dioxide) that are produced.

Non-compliance and misuse of antibiotics have resulted in the emergence of deadly drug-resistant strains. The development of novel drugs that inhibit virulence factors rather than essential life processes is a powerful alternative to combat drug resistance because this approach provides a mechanism to disarm the bacteria without applying selective pressure for resistance. Recently, it was discovered that pathogenic bacteria such as M. tuberculosis and S. pyogenes produce toxins that cause host cell death by depleting essential NAD+ stores. Our approach is to employ multiple kinetic isotope effect measurements and computational modeling to elucidate the enzymatic transition state structure for the toxin-mediated hydrolysis of NAD+ and use this information as a blueprint to guide the design of tight-binding transition state analog inhibitors.