Tunable Fluorescent Organic Salts for Imaging and Therapy
Cancer remains a leading cause of death worldwide and many treatments still rely on non-targeted chemotherapy, which has inadequate efficacy and is plagued by toxic side effects. A promising solution is photodynamic therapy (PDT), a noninvasive clinical cancer treatment that combines a light activated photosensitizer (PS) with excitatory light to generate toxic reactive oxygen species (ROS). These photoactive agents can also produce detectable wavelengths of light upon photoactivation, which has been used clinically to image tumors in cancer diagnostics and image-guided surgery. Having uses as both diagnostic and therapeutic agents, these molecules are known as theranostics. However, current light-activated theranostics are limited by low brightness, poor tissue penetration, and nonspecific cytotoxicity independent of light excitation. Due to these obstacles, PDT is currently limited to precancerous lesions, superficial neoplastic tissue, or palliative care. Therefore, improved theranostic agents are needed. Prevailing efforts to improve existing photoactive agents focus on chemical modifications that cannot independently control electronic properties (which dictate toxicity) from optical properties. To overcome these limitations, work in this dissertation develops a novel counterion pairing platform to modulate the toxicity of organic salts composed of a photoactive cationic heptamethine cyanine (Cy+) and a non-photoactive anion. These counterion-tuned fluorescent organic salts can be designed to be either nontoxic for imaging, or phototoxic for PDT. Organic salts self-organize into nanoparticles with shifted frontier molecular orbital levels dependent on the counterion while the bandgap remains the same. This allows for tuning of electronic properties without affecting optical properties. Improvements in these areas could expand light-activated theranostics into a wider range of cancers and improve patient outcomes. This dissertation will begin with a review of current photoactive agents used in cancer therapy and ongoing challenges to the adoption of PDT as a frontline therapy. Modern PDT regimens and potential combinatorial therapies will be appraised, and recent advances in rational PS design will be highlighted. Initial in vitro studies investigated the optoelectronic tuning capabilities of counterion pairing in human lung carcinoma (A549) and melanoma (WM1158) cell lines. Viability assays establish that pairings with weakly coordinating bulky anions could generate organic salts that are non-cytotoxic and selectively phototoxic, while pairing with standard hard anions yield cytotoxic organic salts. These studies demonstrate that anion pairing can be exploited to shift energy levels and influence ROS generation to either enhance photokilling of cancer cells or improve cell imaging. Organic salts were further investigated in a metastatic breast cancer mouse model to characterize biodistribution, antitumor efficacy within a complex tumor microenvironment, and off-site toxicity. In vivo experiments confirm that counterion tuning can generate a selectively phototoxic antitumor PS which abolishes tumor growth and reduces metastasis without systemic toxicity in a breast cancer mouse model. Overall, this work demonstrates the utility of using counterion tuning to control phototoxicity, and further demonstrates the untapped potential of photoactive theranostic agents for clinical cancer therapy.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Broadwater, Deanna May
- Thesis Advisors
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Lunt, Sophia Y.
- Committee Members
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Lunt, Richard R.
TerAvest, Michaela
Zacharewski, Timothy
Neubig, Richard
- Date
- 2022
- Subjects
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Biochemistry
- Program of Study
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Biochemistry and Molecular Biology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- 214 pages
- Permalink
- https://doi.org/doi:10.25335/zzzv-0d91