Theses and Dissertations from UMD

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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM

More information is available at Theses and Dissertations at University of Maryland Libraries.

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Subject: search.filters.subject.Photodynamic Therapy

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    EVALUATING THE PHOTODYNAMIC AND SONODYNAMIC POTENTIAL OF CLINICALLY RELEVANT PHOTOSENSITIZERS AND DYES
    (2024) Vig, Shruti; Chiao Huang, Huang; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Light-activable agents such as fluorophores and photosensitizers are used for fluorescenceimaging and photodynamic therapy (PDT) applications in the clinic. These agents can absorb light at specific wavelengths and generate fluorescence and/or cytotoxic reactive molecular species (RMS). Photosensitizers can also interact with ATP-binding cassette (ABC) transporters on target cells. This interaction can affect the intracellular accumulation of photosensitizers and thereby influence imaging and treatment efficacy and outcomes. Currently, there are no well-established methods for screening photoactive agents for potential phototoxicity, creating a need for reliable iii testing methods. Comprehensive screening methods are essential for ensuring safe and effective imaging and therapeutic outcomes with light activable agents. Moreover, photosensitizers are currently being explored for sonodynamic therapy (SDT) with ultrasound in patients. Just like PDT, photosensitizers are thought to be activated by ultrasound-mediated light generation (sonoluminescence) to generate RMS. However, no evidence supporting this mechanism has been published with safe, monitorable, and reproducible SDT effects. Thus, rigorous test methods must be developed to evaluate photochemical activation of photosensitizers using clinically relevant SDT parameters. The results obtained through the studies in this dissertation resulted in (1) A modified invitro test method for assessing the photo-cytotoxic potential of light-activable agents at clinically relevant concentrations and illumination parameters, (2) Updated the ABC transporter substrate status of clinically relevant using in-vitro extraction and flowcytometry methods. (3) Confirmed lack of photochemical activation of clinically relevant photosensitizers during SDT as a potential mechanism of action using a phantom model. A comprehensive understanding of the mechanisms and factors affecting the safety and efficacy of fluorophores and photosensitizers is essential for advancing the field of fluorescence imaging, PDT, and SDT for cancer and other diseases.
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    PHOTODYNAMIC THERAPIES AND ETHANOL ABLATION FOR UNRESECTABLE TUMORS AND ASSAY DEVELOPMENT
    (2024) Ma, Chen-Hua; Huang, Huang-Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Many cancers pose significant challenges due to their low survival rates, especially when tumors are deemed unresectable. These tumors are either spread diffusely or located in areas that make surgical intervention risky or impossible. This dissertation addresses innovative approaches to treating unresectable cancers, including solid and peritoneal metastasis, by using photodynamic therapy (PDT)-based combination therapy. The initial section of the dissertation reviews the atypical administration routes of photosensitizers, particularly through intratumoral, intraperitoneal, and intra-arterial injections. Next, the study evaluates the Light-Activatable Sustained-Exposure Ethanol Injection Technology (LASEIT)’s performance in xenograft models of hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). The photochemical properties of LASEIT in tissue-mimicking agarose, ex vivo swine liver, and xenograft animal models were confirmed, demonstrating its ability to maintain fluorescence and extend light propagation. Tumor-killing efficacy was shown in both single- and multi-cycle treatments, positioning LASEIT as a promising alternative for solid tumor therapy. The dissertation also investigates the potential of NanoVP, a carrier-free photosensitizer, for the treatment of peritoneal cancers. We confirmed that NanoVP was detectable in swine peritoneal organs using the ML7710 medical laser system, indicating its potential for personalized PDT in the future. However, we also discovered challenges in detecting photobleaching in pigmented organs like the spleen and liver. Finally, the dissertation employs quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) to quantify peritoneal cancer cell metastasis in a xenograft ovarian cancer model, confirming the technique’s reliability in detecting low numbers of human cells in mouse tissues.
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    Photoimmunotherapy-Based Combination Regimens and Drug Delivery Systems for Ovarian Cancer Treatment
    (2023) Sorrin, Aaron; Huang, Huang Chiao; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Ovarian cancer is among the deadliest gynecologic malignancies, accounting for over 13,000 deaths and nearly 20,000 new cases each year in the United States alone. The lethality of this disease results from several fundamental challenges, including diagnosis at advanced stages, development of resistance to standard-of-care chemotherapies, and extensive metastasis throughout the peritoneal cavity. Photodynamic therapy (PDT) is a promising treatment modality which enables spatiotemporally controlled cancer ablation upon light-activation of specialized drugs (photosensitizers). Clinical studies have demonstrated the feasibility and safety of PDT for women with peritoneally disseminated ovarian cancer, though treatment outcomes were limited by off-target toxicities and the heterogenous cellular uptake of photosensitizer. The use of antibody-conjugated photosensitizers (photoimmunoconjugates) has the potential to overcome these prior limitations, making the targeted version of PDT (photoimmunotherapy, PIT) a valuable tool for ovarian cancer treatment.The overarching objective of this dissertation is to develop PIT-based strategies for ovarian cancer management through three complimentary goals: 1) overcome metastatic behaviors in ovarian cancer using PIT-based combination therapies; 2) bolster photosensitizer drug delivery using a clinically-relevant, fluid flow-based drug delivery approach; and 3) enhance cytotoxic effects of PIT through developing a new nanocomplex for photochemotherapy. This work establishes novel PIT-based combination treatments that incorporate clinically relevant therapies, including prostaglandin E2 receptor 4 (EP4) antagonism, poly(ADP-Ribose) polymerase (PARP) inhibition, and epidermal growth factor receptor (EGFR)-targeted antibodies. Results from this dissertation reveal pronounced combination effects of PIT and EP4 antagonism, leading to cooperative reductions in metastasis- related behaviors and cell signaling in vitro. The findings of this work further demonstrate that fluid flow enhances photoimmunoconjugate delivery, modulates subcellular photosensitizer localization, and enhances the phototoxicity to ovarian cancer cells in a pump system. Lastly, we developed 1) a targeted nanocomplex for combination of PIT and PARP inhibitors; and 2) a 3- dimentional (3D) ovarian tumor spheroid coculture model for the longitudinal quantification of treatment effects and the development of multidrug resistance.
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    Development of Fluorescent Imaging Methods and Systems to Determine Photodynamic Potential and Inform Cancer Treatment Efficacy
    (2022) Gaitan, Brandon; Huang, Huang-Chiao; Chen, Yu; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Photodynamic therapy (PDT) is a treatment modality that has gained rapid popularity in both research and clinical settings over the past 20 years. PDT involves harmless red/near-infrared light excitation of non-toxic photosensitizers to generate reactive molecular species (RMS) that can induce tissue damage and/or cell death. In addition, the fluorescence signal generated from the photosensitizer can also be used for optical imaging. These effects have been harnessed for image-guided treatment of cancer and other diseases. As PDT gains popularity, it is crucial to understand and monitor different factors that could impact overall treatment efficacy. These factors include, but are not limited to, the RMS yield of photosensitizers, the distribution of photosensitizers in tissue, and the PDT activation depth in tissues. Our work focused on developing methodologies and devices to characterize and improve PDT treatment. In collaboration with the FDA, we developed a cell-free assay to rapidly and more quantitatively determine the potential phototoxicity of fluorescent probes through the measurement of singlet oxygen. We also developed a method to compare the maximal PDT activation depth of FDA-approved photosensitizers (BPD and PpIX) in the brain. We found that BPD can be activated 50% deeper into brain tissues compared to PpIX at the same radiant exposure. Next, we tested the ability of a 3D imaging system, Fluorescence Laminar Optical Tomography (FLOT), to image the distribution of photosensitizers in the rodent brain. We demonstrated that FLOT could accurately map the photosensitizer distribution up to 0.5 mm in tissues. Lastly, we developed an autofluorescent-based endoscopic imaging system to measure the metabolic impact of PDT on cancer and normal tissues, finding that PDT leads to significant changes in tissue metabolism immediately after treatment. In summary, we have developed a series of systems that can aid in PDT treatment optimization in three major ways:1) rapidly quantifying the singlet oxygen production of photosensitizers, 2) more accurately measuring a photosensitizers localization and activatable depth, and 3) developing the ability to measure a tissues response to PDT in real-time.