Advanced-stage ovarian cancer becomes extremely challenging to treat effectively using current surgical and chemotherapy methods due to factors such as peritoneal metastasis, incomplete resection, and drug resistance. While photoimmunotherapy is emerging as a promising option for unresectable metastases, its full potential often goes unrealized due to varying treatment outcomes. This research effort aims to enhance the reliability, safety, and effectiveness of photoimmunotherapy for peritoneal metastases by combining targeted nanotechnology, fluorescence-guided intervention, and a state-of-the-art medical laser system.
Peritoneal metastasis, incomplete resection, and drug resistance render advanced-stage ovarian cancer virtually incurable with current surgical and chemotherapy approaches. Photoimmunotherapy is increasingly used to treat unresectable metastases, but many innovations are lost in translation due to heterogeneous treatment effects. This study integrates targeted nanotechnology, fluorescence-guided intervention, and a medical laser system to improve the safety, efficacy, and consistency of photoimmunotherapy for peritoneal metastases.
This conference presentation was prepared for the Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXXI conference at SPIE BiOS, SPIE Photonics West 2023.
Contrast-enhanced fluorescent imaging has the potential to improve patient outcomes. A critical challenge that has not been rigorously evaluated is the potential photocytoxicity of the fluorophores used for imaging procedures. In this study, we have used a modified 3T3 Neutral Red Uptake assessment strategy to evaluate 4 imaging dyes and 2 known photosensitizers generating reactive molecular species. Results shed light on the relative photocytotoxicity of tested agents and provide strong evidence on the effectiveness of the method. These methods will provide a foundation for standardizing photo-safety testing of clinical fluorescence imaging products.
Liposomes have revolutionized the field of photomedicine. Photodynamic therapy (PDT) using Visudyne®, a liposomal photosensitizer formulation, has helped many patients globally. Since the FDA approved Visudyne® in 2002, countless studies have examined strategies to further improve the therapeutic index of lipid-based photosensitizing nanoconstructs. While liposomes can improve the pharmacokinetics of hydrophobic photosensitizers, they could also modulate cellular uptake and singlet oxygen production. Furthermore, it is evident that there are other immunological and toxicological considerations for the design of liposomal drugs. Accordingly, there is now an emerging trend to engineer carrier-free nanodrugs. Here, we developed a pure-drug nanoparticle using the clinically used verteporfin photosensitizer (termed nanoVP) for photodynamic applications. We validated the effects of nanoVP in three contexts: 1) cytotoxic PDT, 2) subtherapeutic PDT, and 3) dark toxicity. Using a brain cancer murine model, we showed that light activation of nanoVP reduced tumor volume by up to 54% compared to liposomal VP. Fluorescence imaging revealed that nanoVP had a superior tumor-to-liver tissue ratio (~0.92) compared to liposomal VP (~0.4). We further studied nanoVP-mediated PDT at subtherapeutic doses to achieve photodynamic priming (PDP). PDP has been shown to enhance drug delivery, activate antitumor immunity, and sensitize tumors to chemotherapy. This approach is particularly relevant in the brain, where high doses of PDT can result in edema, neurotoxicity, and even animal death. Using a rat model, we demonstrated that nanoVP-assisted PDP improved blood-brain barrier permeability and accumulation of a model drug (Evans Blue dye) in rat brains by >5 fold. Minimal to no brain damage was observed. Lastly, under dark conditions, we validated that nanoVP significantly reduced viability while liposomal VP stimulated cancer cell growth. Results from this work demonstrate the utility of nanoVP for cancer treatment. The development of pure-drug photosensitizing nanoparticles for photodynamic applications could further revolutionize the field of photomedicine.
KEYWORDS: Near infrared spectroscopy, Performance modeling, Monte Carlo methods, Signal detection, Sensors, Reflectivity, Oximeters, Photons, Diffuse reflectance spectroscopy, Computer simulations
Computational modeling provides a powerful tool for identifying optimal phantom-based test methods in NIRS oximetry. We implemented a Monte Carlo model to enable the simulation of NIRS devices with specific illumination-collection geometries and to identify appropriate performance test methods. Initially, we validated that our in silico approach provided adequate convergence and identified a phantom size that was optically semi-infinite. We then assessed the impact of NIRS sensor orientations and positions on a simulated channel-array phantom. Additional simulations are currently underway to extract oxygen saturation and determine the effect of phantom layer thicknesses, vessel spacing, and diameter.
Recent advances in optical imaging have the potential to significantly improve patient outcomes. Among the most promising approaches under development is contrast-enhanced fluorescence imaging, which can be performed with molecular targeting to enhance tumor visualization. One key issue that has not been rigorously addressed is the potential phototoxicity of these fluorophores. In this study, we have used a commercial cell-free assay to qualify the singlet oxygen production rate in approved (ICG, Methylene Blue) and unapproved (IRDye700, IRDye800) fluorophores. Results shed light on the relative phototoxicity of each agent and will help to establish standardized methods for photochemical safety testing.
Significance: Previous studies have been performed to image photosensitizers in certain organs and tumors using fluorescence laminar optical tomography. Currently, no work has yet been published to quantitatively compare the signal compensation of fluorescence laminar optical tomography with two-dimensional (2-D) imaging in tissues.
Aim: The purpose of this study is to quantify the benefit that fluorescence laminar optical tomography holds over 2-D imaging. We compared fluorescence laminar optical tomography with maximum intensity projection imaging to simulate 2-D imaging, as this would be the most similar and stringent comparison.
Approach: A capillary filled with a photosensitizer was placed in a phantom and ex vivo rodent brains, with fluorescence laminar optical tomography and maximum intensity projection images obtained. The signal loss in the Z direction was quantified and compared to see which methodology could compensate better for signal loss caused by tissue attenuation.
Results: The results demonstrated that we can reconstruct a capillary filled with benzoporphyrin derivative photosensitizers faithfully in phantoms and in ex vivo rodent brain tissues using fluorescence laminar optical tomography. We further demonstrated that we can better compensate for signal loss when compared with maximum intensity projection imaging.
Conclusions: Using fluorescence laminar optical tomography (FLOT), one can compensate for signal loss in deeper parts of tissue when imaging in ex vivo rodent brain tissue compared with maximum intensity projection imaging.
Glioblastoma has a high rate of recurrence due to treatment methods often failing to penetrate the blood brain barrier. To overcome this limitation, photodynamic priming (PDP) can be used to increase tissue permeability. In this study we investigate the feasibility of using fluorescence laminar optical tomography (FLOT) to provide quantitative distribution information on photodynamic drug in the brain to optimize the timing of PDP. The project will result in a non-invasive way to quantify the concentration of photodynamic drug in the brain. This would allow for optimized treatment times, leading to improved patient outcomes.
KEYWORDS: Cancer, Endoscopy, Imaging systems, Breast cancer, Luminescence, Tissues, Fluorescence spectroscopy, Spectroscopy, In vivo imaging, In vitro testing
Despite various technological advancements in cancer diagnosis, the mortality rates were not decreased significantly. We aim to develop a novel optical imaging tool to assist cancer diagnosis effectively. Fluorescence spectroscopy/imaging is a fast, rapid, and minimally invasive technique which has been successfully applied to diagnosing cancerous cells/tissues. Recently, the ratiometric imaging of intrinsic fluorescence of reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD), as pioneered by Britton Chance and the co-workers in 1950-70’s, has gained much attention to quantify the physiological parameters of living cells/tissues. The redox ratio, i.e., FAD/(FAD+NADH) or FAD/NADH, has been shown to be sensitive to various metabolic changes in in vivo and in vitro cells/tissues. Optical redox imaging has also been investigated for providing potential imaging biomarkers for cancer transformation, aggressiveness, and treatment response. Towards this goal, we have designed and developed a novel fiberoptic-based needle redox imager (NRI) that can fit into an 11G clinical coaxial biopsy needle for real time imaging during clinical cancer surgery. In the present study, the device is calibrated with tissue mimicking phantoms of FAD and NADH along with various technical parameters such as sensitivity, dynamic range, linearity, and spatial resolution of the system. We also conducted preliminary imaging of tissues ex vivo for validation. We plan to test the NRI on clinical breast cancer patients. Once validated this device may provide an effective tool for clinical cancer diagnosis.
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