CAREER: Biomaterials Platform for Disease Sensing using NITEC Click Chemistry

NON-TECHNICAL SUMMARY:

Chronic diseases such as organ failure are difficult to monitor and treat long-term. Unlike temporary injuries, where therapeutic progress is evaluated through a follow-up appointment, chronic diseases can change in severity unpredictably and over long periods, making periodic doctor’s visits unreliable for assessing a patient’s ongoing health. One way to address this challenge is by developing tools that allow continuous monitoring of biomarkers—molecules in the body that signal disease activity.

Peroxynitrite is a biomarker closely linked to disease severity, and this marker holds significant potential for improving the way chronic diseases are diagnosed and managed. However, current tools for detecting peroxynitrite are limited by their short lifespan and inability to work effectively in deep tissues. This project develops Extended Lifetime Peroxynitrite-Responsive Probes (xL-PRPs), a new class of materials designed for long-term, non-invasive monitoring of peroxynitrite levels in the body.

By combining innovative probe chemistries with strategies like linking small molecules together into polymers and incorporating reversible sensing mechanisms, xL-PRPs offer the potential for long-lasting and deep-tissue visualization. This will reduce the need for traditional invasive procedures, such as biopsies, to evaluate organ health. Broader impacts of this project include outreach programs to introduce high school students to hands-on demonstrations in polymer chemistry using both technical and non-technical concepts, the development of interactive biomaterials courses to bridge undergraduate and graduate education, and mentoring initiatives to promote equitable career preparation in the chemical sciences.

TECHNICAL SUMMARY:

The development of advanced biomaterials for long-term monitoring of oxidative stress is essential for addressing critical challenges in chronic disease diagnosis and treatment. Peroxynitrite (ONOO⁻), a highly reactive oxygen species strongly correlated with disease severity, presents an opportunity to revolutionize disease monitoring; however, current fluorogenic probes are hindered by single-use functionality, short in vivo activity, and inadequate imaging capabilities in deep tissues.

This CAREER project focuses on the development of Extended Lifetime Peroxynitrite-Responsive Probes (xL-PRPs), a novel class of probes designed to address these limitations. The specific objectives for these xL-PRPs are to achieve: (1) reversible ONOO⁻ responsiveness, (2) macromolecular structure for delayed in vivo tissue clearance, and (3) near-infrared fluorescence properties for enhanced imaging depth.

These materials are fabricated using NITEC click chemistry and controlled polymerization techniques, while nuclear magnetic resonance, light scattering, electron microscopy, and fluorescence microscopy are used to investigate ONOO⁻ interactions with these biomaterials. This work will establish the first reversible ONOO⁻ probes responsive to biochemical scavengers in vivo, enabling localized, long-term, and non-invasive monitoring of oxidative stress.

Anticipated outcomes include simplified synthetic methods, enhanced stability of ONOO⁻ probes, and improved imaging capabilities for chronic disease monitoring. Broader impacts include outreach programs to introduce high school students to hands-on demonstrations in polymer chemistry using both technical and non-technical concepts, the development of interactive biomaterials courses to bridge undergraduate and graduate education, and mentoring initiatives to promote equitable career preparation in the chemical sciences.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.