Towards Targeted Photodynamic Therapy: Synthesis and Characterization of Aziridine Aldehyde-Cyclized Cancer- Targeting Peptides and Bacteriochlorin Photosensitizers

This thesis presents the contributions we made towards achieving targeted photodynamic therapy (PDT) by synthesizing and characterizing new aziridine aldehyde-cyclized cancer-targeting peptides and bacteriochlorin photosensitizers (PSs). The new peptides are based on the integrin-targeting sequence, arginine-glycine-aspartic acid (RGD), and were cyclized by aziridine aldehyde-driven macrocyclization chemistry. We developed a versatile conjugation strategy, and created two useful RGD macrocycles that specifically bound to integrin receptors in vitro. Computer modeling and competitive binding studies found that this macrocyclization chemistry modulated the binding affinity of these peptides by tuning the geometry of peptides of different lengths. The new PSs described herein include bacteriochlorophyll derivatives that efficiently produced reactive oxygen species (ROS) upon illumination with red light. We discovered two simple structural modifications that enhanced the photogeneration of ROS, and suggest that future studies make use of these design parameters to create next generation bacteriochlorin PSs with superior photoactivity compared to known derivatives. In addition, we optimized a facile synthetic reaction for creating a new natural product analog with a distinct exocyclic F-ring, and found it was capable of PDT. Unlike some of its natural chlorin counterparts, our bacteriochlorin was not a potent antioxidant. Yet, we suggest that future efforts make use of our simple reaction to expand the library of F-ring containing bacteriochlorins to elucidate key structural modifications that can tune the PDT efficacy and antioxidant activity of this distinct class of bacteriochlorins. Finally, this thesis presents preliminary investigations that attempted to develop new cancer-targeting PDT agents. While the goal of achieving optimal cancer-targeted PDT was not accomplished in this work, it is envisioned that this thesis will provide useful data and insights that will contribute to the development of optimal aziridine aldehyde-cyclized peptide-bacteriochlorin PS conjugates for efficient in vivo cancer-specific PDT.