Texaphyrin Architectures for Biomedical Applications

The class of texaphyrins are macrocycles with unique photophysical and chelation properties. These desirable properties have led to extensive clinical evaluations, however, FDA approval has never been obtained. We believe the fundamental properties of texaphyrins, most notably the robust metalation ability, warranted the development of novel texaphyrin architectures to potentially solve inherent limitations of previous texaphyrin entities. In the development of novel texaphyrin architectures, a texaphyrin-phospholipid conjugate was synthesized and demonstrated the capability to self-assemble into nanovesicles termed nanotexaphyrin. A library of 18 distinct metallonanotexaphyrins was synthesized, possessing strong structural and chelation capabilities. To enhance the clinical translability of these nanoparticles, a novel method was developed to enable the post-insertion of metal ions into preformed free-base nanotexaphyrin. Moreover, we demonstrate this methodology to create mix and matched metallonanotexaphyrins, offering the ability to selectively tune the multifunctionality of nanotexaphyrin for desired applications. A proof-of-concept 111In-Mn-nanotexaphyrin was developed and showed selective tumour uptake and retention for in vivo MRI-SPECT imaging in orthotopic PC3 prostate cancer mice. Additionally, we further evaluated Mn-nanotexaphyrin for MRI applications, creating a novel one-pot instantaneous chelation and self-assembly protocol for this contrast agent. Evaluations on a VX-2 head and neck tumour bearing rabbit for sentinel lymph node (SNL) mapping suggest Mn-nanotexaphyrin may serve as a contrast agent in lymphoscintigraphy procedures. Finally, the photophysical properties of texaphyrins were analyzed by creating a large library of metallotexaphyrin-antenna conjugates, using a coumarin, rhodamine B, or saturated hydrocarbon. Using classical structure-activity relationship analysis, the library emission data suggests metallotexaphyrin emission wavelengths can be tuned through the use of antenna in combination with metal ion. In doing so, the appearance or disappearance of emission bands can be precisely controlled. The work conducted in this thesis aimed to develop novel texaphyrin architectures that could serve a role in biomedical applications. The fundamental work performed here lays the foundation for others to perpetuate this field, where a multicollaborative effort can truly realize the potential of the texaphyrins.

Department dc:contributor.department

Pharmaceutical Sciences

Year dc:date.issued

2018

Author dc:creator

• Keca, Joseph Michele

Advisor dc:contributor.advisor

• Zheng, Gang

Handle dc:identifier.uri

http://hdl.handle.net/1807/91967

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/91967