Fischell Department of Bioengineering

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Author: search.filters.author.Vig, ShrutiStart date: 2020

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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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    Test method for evaluating the photocytotoxic potential of fluorescence imaging products
    (Wiley, 2023-07-26) Vig, Shruti; Gaitan, Brandon; Frankle, Lucas; Chen, Yu; Elespuru, Rosalie; Pfefer, T. Joshua; Huang, Huang-Chiao
    Various fluorescence imaging agents are currently under clinical studies. Despite significant benefits, phototoxicity is a barrier to the clinical translation of fluorophores. Current regulatory guidelines on medication-based phototoxicity focus on skin effects during sun exposure. However, with systemic and local administration of fluorophores and targeted illumination, there is now possibility of photochemical damage to deeper tissues during intraoperative imaging procedures. Hence, independent knowledge regarding phototoxicity is required to facilitate the development of fluorescence imaging products. Previously, we studied a cell-free assay for initial screening of reactive molecular species generation from fluorophores. The current work addresses a safety test method based on cell viability as an adjunct and a comparator with the cell-free assay. Our goal is to modify and implement an approach based on the in vitro 3T3 neutral red uptake assay of the Organization for Economic Co-Operation and Development Test Guideline 432 (OECD TG432) to evaluate the photocytotoxicity of clinically relevant fluorophores. These included indocyanine green (ICG), proflavine, methylene blue (MB), and IRDye800, as well as control photosensitizers, benzoporphyrin derivative (BPD) and rose bengal (RB). We performed measurements at agent concentrations and illumination parameters used for clinic imaging. Our results aligned with prior studies, indicating photocytotoxicity in RB and BPD and an absence of reactivity for ICG and IRDye800. DNA interactive agents, proflavine and MB, exhibited drug/light dose–response curves like photosensitizers. This study provides evidence and insights into practices useful for testing the photochemical safety of fluorescence imaging products.
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    Immunological and Toxicological Considerations for the Design of Liposomes
    (MDPI, 2020-01-22) Inglut, Collin T.; Sorrin, Aaron J.; Kuruppu, Thilinie; Vig, Shruti; Cicalo, Julia; Ahmad, Haroon; Huang, Huang-Chiao
    Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and optimizing liposomal formulations for a variety of medical applications, ranging from cancer therapeutics to analgesics. Some effort has also been made to elucidate the toxicities and immune responses that these drug formulations may elicit. Notably, intravenously injected liposomes can interact with plasma proteins, leading to opsonization, thereby altering the healthy cells they come into contact with during circulation and removal. Additionally, due to the pharmacokinetics of liposomes in circulation, drugs can end up sequestered in organs of the mononuclear phagocyte system, affecting liver and spleen function. Importantly, liposomal agents can also stimulate or suppress the immune system depending on their physiochemical properties, such as size, lipid composition, pegylation, and surface charge. Despite the surge in the clinical use of liposomal agents since 1995, there are still several drawbacks that limit their range of applications. This review presents a focused analysis of these limitations, with an emphasis on toxicity to healthy tissues and unfavorable immune responses, to shed light on key considerations that should be factored into the design and clinical use of liposomal formulations.
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    Quantifying the Photochemical Damage Potential of Contrast-Enhanced Fluorescence Imaging Products: Singlet Oxygen Production
    (Wiley, 2022-04-20) Gaitan, Brandon; Frankle, Lucas; Vig, Shruti; Oskoui, Ellen; Adwan, Miriam; Chen, Yu; Elespuru, Rosalie; Huang, Huang-Chiao; Pfefer, T. Joshua
    The benefits of contrast-enhancing imaging probes have become apparent over the past decade. However, there is a gap in the literature when it comes to the assessment of the phototoxic potential of imaging probes and systems emitting visible and/or near-infrared radiation. The primary mechanism of fluorescent agent phototoxicity is thought to involve the production of reactive molecular species (RMS), yet little has been published on the best practices for safety evaluation of RMS production levels for clinical products. We have proposed methods involving a cell-free assay to quantify singlet oxygen [(SO) a known RMS] generation of imaging probes, and performed testing of Indocyanine Green (ICG), Proflavine, Methylene Blue, IR700 and IR800 at clinically relevant concentrations and radiant exposures. Results indicated that SO production from IR800 and ICG were more than two orders of magnitude below that of the known SO generator Rose Bengal. Methylene Blue and IR700 produced much higher SO levels than ICG and IR800. These results were in good agreement with data from the literature. While agents that exhibit spectral overlap with the assay may be more prone to errors, our tests for one of these agents (Proflavine) appeared robust. Overall, our results indicate that this methodology shows promise for assessing the phototoxic potential of fluorophores due to SO production.