Invited Talk 21st International Conference on Biological Inorganic Chemistry 2025

We have developed a new classes of enzyme-responsive magnetic resonance (MR) imaging probes that enable the non-invasive, real-time tracking of biological activity associated with gene therapy and cellular senescence. These small-molecule agents are activated by specific enzymatic processes, offering a chemical strategy for spatiotemporal imaging of otherwise silent molecular events.

Currently, there are no clinically available tools to directly assess the biodistribution or efficacy of gene therapies, particularly in tissues affected by senescence. This presents a major limitation in treatment development, as molecular responses often precede overt clinical improvement. Senescence, characterized by irreversible cell-cycle arrest and secretion of pro-inflammatory mediators, is a key driver of musculoskeletal (MSK) disorders such as osteoarthritis, where oxidative stress triggers dysfunction in synoviocytes, chondrocytes, and bone marrow cells.

To overcome this barrier, we synthesized bioresponsive Gd(III)-based MR probes that selectively respond to senescence-associated enzymes. These probes are capable of reporting activity within the central nervous system (CNS), peripheral nervous system (PNS), and MSK tissues. Their modular design enables tailored activation profiles and pharmacokinetics, opening new avenues for longitudinal imaging of therapeutic response and disease progression in vivo.

Figure 1. Top: Human osteroarthritis joints exposed to a commercial MR contrast agent (Gadavist) where senescence cells are not detected. Bottom: A bioresponsive MR agent that is enzymatically-activated by the presence of senescene cells.