A. James Clark School of Engineering

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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.

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Subject: search.filters.subject.photodynamic therapy

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    ENGINEERING TARGETED LIGHT ACTIVATABLE NANOPLATFORMS TO MANAGE RECURRENT CANCERS
    (2024) Pang, Sumiao; Huang, Huang Chiao HH; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Cancer recurrence poses a significant challenge in various malignancies that adverselyaffect long-term survival and quality of life. Glioblastoma (GBM) and ovarian cancer exhibit particularly high recurrence rates. For GBM, tumor recurrence is nearly universal (90%) within 10 months post initial treatment due to its invasive characteristics, limited delivery of therapeutic agents, and persistent drug resistance, resulting in a 5-year survival rate of <10%. While standard chemotherapy and surgery can temporarily alleviate symptoms for both diseases, there has been no significant improvement in long-term disease management or survival extension over several decades. Therefore, it is critical to develop targeted therapies that integrates well with current standards of care strategies. Photomedicine is a promising treatment modality, and the two main phototherapies are photodynamic therapy (PDT) which involves photosensitizer administration followed by light activation resulting in non-thermal chemical damage and photothermal therapy (PTT) which involves exogenous or endogenous sensitizing agents followed by light activation resulting in thermal damage. Clinical applications of both modalities have shown its feasibility and safety; however, they face challenges due to (i) limited cancer selectivity, (ii) heterogenous treatment response, and (iii) low monotherapy treatment efficacy. Leveraging strategic therapeutic targets to advance the current sensitizing agents for targeted delivery is a potential solution to overcome these limitations. The overall objective of this dissertation is to advance and evaluate targeted light-activatable nanoplatforms for phototherapy delivery with considerations for the current clinical workflow of GBM and advanced ovarian cancer. This is achieved through the following goals, (1) engineering a novel Fn14 receptor-directed gold nanorods (DART-GNRs) to assess selectivity and PTT efficacy for GBM, and (2) evaluate safety and long-term efficacy of targeted light-activatable multi-agent nanoplatform (tLAMP) to deliver targeted PDT for peritoneal carcinomatosis. First, this work establishes a reproducible synthesis protocol for DART-GNRs, characterizes its photothermal properties, and demonstrate high selectivity towards the Fn14 receptor of cancer cells. Second half of this dissertation established and investigated a two-fiber tissue optical property (TOP) monitoring method for liquid phantoms and for peritoneal carcinomatosis mouse model to enable safer light dosimetry during PDT, established an irinotecan active loading method to reproducibly synthesize tLAMP, and determined tLAMP tumor nodule penetration depth for enhanced targeted PDT combination therapy with adjuvant chemotherapy to enhance long-term survival for ovarian cancer.
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    Systematic Evaluation of Light-Activatable Biohybrids for Anti-Glioma Photodynamic Therapy
    (MDPI, 2019-08-21) Inglut, Collin T.; Baglo, Yan; Liang, Barry J.; Cheema, Yahya; Stabile, Jillian; Woodworth, Graeme F.; Huang, Huang-Chiao
    Photosensitizing biomolecules (PSBM) represent a new generation of light-absorbing compounds with improved optical and physicochemical properties for biomedical applications. Despite numerous advances in lipid-, polymer-, and protein-based PSBMs, their effective use requires a fundamental understanding of how macromolecular structure influences the physicochemical and biological properties of the photosensitizer. Here, we prepared and characterized three well-defined PSBMs based on a clinically used photosensitizer, benzoporphyrin derivative (BPD). The PSBMs include 16:0 lysophosphocholine-BPD (16:0 Lyso PC-BPD), distearoyl-phosphoethanolamine-polyethylene-glycol-BPD (DSPE-PEG-BPD), and anti-EGFR cetuximab-BPD (Cet-BPD). In two glioma cell lines, DSPE-PEG-BPD exhibited the highest singlet oxygen yield but was the least phototoxic due to low cellular uptake. The 16:0 Lyso PC-BPD was most efficient in promoting cellular uptake but redirected BPD’s subcellular localization from mitochondria to lysosomes. At 24 h after incubation, proteolyzed Cet-BPD was localized to mitochondria and effectively disrupted the mitochondrial membrane potential upon light activation. Our results revealed the variable trafficking and end effects of PSBMs, providing valuable insights into methods of PSBM evaluation, as well as strategies to select PSBMs based on subcellular targets and cytotoxic mechanisms. We demonstrated that biologically informed combinations of PSBMs to target lysosomes and mitochondria, concurrently, may lead to enhanced therapeutic effects against gliomas.
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    Photodynamic Priming Improves the Anti-Migratory Activity of Prostaglandin E Receptor 4 Antagonist in Cancer Cells In Vitro
    (MDPI, 2021-10-20) Sorrin, Aaron J.; Liu, Cindy; Cicalo, Julia; Reader, Jocelyn; Najafali, Daniel; Zhang, Yuji; Roque, Dana M.; Huang, Huang-Chiao
    The combination of photodynamic agents and biological inhibitors is rapidly gaining attention for its promise and approval in treating advanced cancer. The activity of photodynamic treatment is mainly governed by the formation of reactive oxygen species upon light activation of photosensitizers. Exposure to reactive oxygen species above a threshold dose can induce cellular damage and cancer cell death, while the surviving cancer cells are “photodynamically primed”, or sensitized, to respond better to other drugs and biological treatments. Here, we report a new combination regimen of photodynamic priming (PDP) and prostaglandin E2 receptor 4 (EP4) inhibition that reduces the migration and invasion of two human ovarian cancer cell lines (OVCAR-5 and CAOV3) in vitro. PDP is achieved by red light activation of the FDA-approved photosensitizer, benzoporphyrin derivative (BPD), or a chemical conjugate composed of the BPD linked to cetuximab, an anti-epithelial growth factor receptor (EGFR) antibody. Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.
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    Development of an Endoscopic Auto-Fluorescent Sensing Device to Aid in the Detection of Breast Cancer and Inform Photodynamic Therapy
    (MDPI, 2022-11-11) Gaitan, Brandon; Inglut, Collin; Kanniyappan, Udayakumar; Xu, He N.; Conant, Emily F.; Frankle, Lucas; Li, Lin Z.; Chen, Yu; Huang, Huang-Chiao
    Breast cancer is the most diagnosed cancer type in women, with it being the second most deadly cancer in terms of total yearly mortality. Due to the prevalence of this disease, better methods are needed for both detection and treatment. Reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are autofluorescent biomarkers that lend insight into cell and tissue metabolism. As such, we developed an endoscopic device to measure these metabolites in tissue to differentiate between malignant tumors and normal tissue. We performed initial validations in liquid phantoms as well as compared to a previously validated redox imaging system. We also imaged ex vivo tissue samples after modulation with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) and a combination of rotenone and antimycin A. We then imaged the rim and the core of MDA-MB-231 breast cancer tumors, with our results showing that the core of a cancerous lesion has a significantly higher optical redox ratio ([FAD]/([FAD] + [NADH])) than the rim, which agrees with previously published results. The mouse muscle tissues exhibited a significantly lower FAD, higher NADH, and lower redox ratio compared to the tumor core or rim. We also used the endoscope to measure NADH and FAD after photodynamic therapy treatment, a light-activated treatment methodology. Our results found that the NADH signal increases in the malignancy rim and core, while the core of cancers demonstrated a significant increase in the FAD signal.