New Synthetic Approaches to Small Molecules for Imaging 

Emerging imaging applications require probes tailored to the specific demands of each method. Our approach is to define the complex reactivity of the cyanine chromophore and apply these chemistries to enable molecular design and probe discovery efforts. Through our now decade-long experience with these molecules, we have significant insight into their preparation, reactivity, and relationships between chemical structure and physical/biological properties. A major component of our efforts is to create novel synthetic methods, which allows us access to previously unknown molecules. We have developed the chemistry to assemble exceptionally bright, polycyclic pentamethine cyanines that are enabling for a variety of advanced microscopy applications. We have also worked extensively to develop novel heptamethine cyanine dyes. These molecules operate in the near-infrared (NIR) range making them applicable to in vivo live animal imaging applications. We developed a highly modified heptamethine cyanine dye, FNIR-tag, that is uniquely resistant to aggregation and provides exceptionally bright bioconjugates. We are also developing bioconjugatable nonamethine indocyanine dyes with emission beyond 1000 nm. These molecules have extended the range of wavelengths available for targeted multicolor in vivo imaging. Finally, we are developing novel turn-on or “fluorogenic” probe chemistries to enable responsive in vivo imaging applications.

Applying Optical Approaches to the Drug Delivery Problem

Recent progress establishing the clinical utility of ADCs has validated the potential of ligand-targeted small molecule delivery strategies. However, the application of these drugs has encountered significant toxicities that limits the scope of their use. Critically, these toxicities rarely result from the mAb binding to its cognate target, but rather from deleterious effects of the hydrophobic small molecule/linker combination on in vivo targeting. Consequently, the chemical components - the linker and payload - require redesign to realize the promise of these strategies. In prior studies, we developed a cyanine-based light-activated ADC strategy. Building on this work and our efforts to optimize mAb conjugates for FGS applications, we are applying optical imaging to define key criteria that determine the tumor targeting of ADCs. These efforts will identify tumor selective protease-cleavable linkers and payloads with improved physical properties. This approach builds on our expertise in optical imaging and probe design, and benefits from CCR collaborations with experts in mAb and therapeutic development.