Biochemical Strategies for Cancer Imaging and Phototherapy

The development of light-based therapies for clinical treatment continues to expand. Recent advances have focused on improving light delivery into deep tissue through the development of miniature light delivery systems, as well as enhancing molecular agent design to increase cellular uptake while maintaining selective activation. Traditional light delivery approaches rely on external illumination, which suffers limited tissue penetration, or wired systems that require repeated implantation which increases the risk of infection. Emerging efforts to address these limitations have focused on wireless light delivery using miniature devices that can be implanted directly into tissue. In parallel, many molecular agents used in imaging and phototherapy often exhibit limited uptake or non-selective activation in vivo. Molecular strategies to overcome these challenges include the design of bioactivatable molecules that “turn-on” only after they accumulate in the cancerous tissue. This approach reduces off target effects and allows site specific activation, improving both phototherapeutic and imaging outcomes. This thesis details the development of a novel wireless light delivery system alongside enhanced molecular agents for improved cancer imaging and phototherapy. Chapter 1 provides an introduction to phototherapy and the limitations of existing light delivery approaches, with an overview of current implantable light devices. Chapters 2 and 3 describe the design and application of a miniature wireless implantable light emitting device for photodynamic therapy. Chapter 2 focuses on wireless device development and photoinactivation of cultured cancer cells using the photosensitizer Rose Bengal while Chapter 3 evaluates the technology for an in vivo application, namely the red-light photodynamic of breast cancer using the prodrug, 5-aminolevulinic acid. Chapters 4 through 6 describe new classes of molecular agents for fluorescence imaging and phototherapy. Chapter 4 describes an esterase-activatable probe and discusses the potential problems conducting mouse studies using molecular probes with a cyclopropyl ester as the activatable functional group. Chapter 5 presents an esterase responsive derivative of 5-aminolevulinic acid with enhanced stability and cellular uptake into cancer cells. Finally, chapter 6 reports a new hypoxia responsive fluorescent molecular probe, that exhibits improved uptake and distribution within a three-dimensional multicellular tumor spheroid.