Development of activatable molecular tools for applications in light-mediated cancer therapy
Forzano, Joseph A.
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Permalink
https://hdl.handle.net/2142/130089
Description
Title
Development of activatable molecular tools for applications in light-mediated cancer therapy
Author(s)
Forzano, Joseph A.
Issue Date
2025-07-10
Director of Research (if dissertation) or Advisor (if thesis)
Chan, Jefferson
Doctoral Committee Chair(s)
Chan, Jefferson
Committee Member(s)
Hergenrother, Paul
Manesis, Anastasia
Moore, Jeffrey
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemical biology
cancer therapy
photodynamic therapy
molecular imaging
Abstract
The development of novel light-based technologies has functioned as a key driver of furthering our understanding and modulation of biological phenomena. Light is an attractive stimulus for use in biology due to high levels of control of several factors: location and duration of irradiation, wavelength of the optical absorber and light source, and intensity of light shone. It allows for non-invasive studies of basic biological phenomena with minimal perturbation, bringing about deeper understanding of molecular processes within cells and tissues through molecular imaging. Light can also be used as a method for generating a therapeutic effect via several different treatment methods. Endogenous absorbers can be used for “light therapy” processes, and exogenous light-activated molecules can be used for controlled release or activation of compounds with high therapeutic efficacy.
Aldehyde dehydrogenases (ALDHs) represent an important class of enzymes that catalyze aldehyde oxidation as part of signaling pathways and cellular detoxification. One of these enzymes in particular, ALDH1A1, has been shown not only to perform these roles in healthy tissue but also to be upregulated across many cancer types. ALDH1A1 has been shown to impact drug resistance, metastasis and maintenance of a population of cancer cells with stem-like properties, and its upregulation is often linked to poor patient outcomes. As such, the development of ALDH1A1-targeted therapies that leverage its overexpression in cancer cells without inhibiting its activity in healthy cells remains an outstanding challenge. In Chapter 2, I will report on the development of a panel of novel photosensitizers that can be activated to become more cytotoxic only in the presence of light and ALDH1A1 for targeted PDT with minimal toxicity in cells with low ALDH1A1 expression. The lead compound, AAP, is shown to elicit the highest levels of toxicity in cells and in vivo only when activated by the enzyme and irradiated.
One of the predominant challenges with molecular imaging is the high background due scattering and absorption of light in biological tissues. One platform that has been developed to overcome this challenge is photoacoustic imaging, wherein relaxation of the excited state molecule produces heat that can be read as soundwaves by ultrasound transducers. Sound is less prone to attenuation in biological tissue, and therefore photoacoustic imaging can be used in deeper tissue environments than many optical techniques. Chapter 3 will discuss this modality in more detail and introduce an experiment for undergraduates exploring the photoacoustic effect.
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