Head and neck cancer (HNC) presents challenges due to its heterogeneity, high recurrence rate, and hypoxic microenvironments. Current treatments fall short, leading to high morbidity and mortality. Photodynamic therapy (PDT) offers spatiotemporal tumor control but relies on oxygenation, posing limitations in hypoxic tumors. Combining hypoxia-activated prodrugs with PDT can selectively kill hypoxic tumor cells and reduce the tumor burden. This study proposes using evofosfamide, a hypoxia-activated prodrug, in combination with benzoporphyrin derivative (BPD)-PDT in a 3D spheroids model of HNC. The growth profile, BPD uptake profile, and hypoxia development were investigated. Combination therapy enhanced PDT efficacy in hypoxic HNC spheroids.
Liquid metal nanoparticles, particularly Eutectic Gallium Indium (EGaIn), hold great potential in medical applications such as biosensors, bioelectrodes, cancer treatment, and medical imaging. This study focuses on the synthesis of EGaIn nanoparticles using sonication without harsh chemicals. The nanoparticles are surface functionalized with hyaluronan and the photosensitizer benzoporphyrin derivative (BPD) for photodynamic therapy. EGaIn nanoparticles exhibit stability, good biocompatibility, and high optical absorption for photoacoustic imaging. The singlet oxygen generation of EGaPs is compared with free BPD under physiological conditions. Additionally, in vitro and in vivo investigations confirm the photodynamic efficacy of EGaPs, making them versatile nanoparticles for targeting, imaging, drug delivery, and photodynamic therapy
KEYWORDS: Tumors, Nanodroplets, Photodynamic therapy, Oxygen, Photoacoustic spectroscopy, Hypoxia, Solids, In vivo imaging, Resistance, Real time imaging
Solid tumors face the challenge of hypoxia, resulting from an imbalance between oxygen demands and supply. Hypoxia leads to resistance to conventional cancer therapies like radiation and chemotherapy, including photodynamic therapy (PDT) that relies on oxygen radicals. To address this, we developed perfluorocarbon nanodroplets for co-delivering oxygen and a photosensitizer. In vitro and in vivo studies validated oxygen release and enhanced tumor oxygenation. Histological analysis confirmed reduced hypoxic regions in nanodroplet-treated tumors. PDT using the nanodroplets demonstrated superior efficacy compared to a liposomal formulation. Overall, oxygen-loaded nanodroplets guided by photoacoustic imaging offer a promising approach for hypoxic tumor treatment.
This Conference Presentation, “3D ultrasound guided-photoacoustic vascular imaging of pancreatic tumors to predict response to tyrosine kinase inhibitor therapy,” was recorded at SPIE Photonics West held in San Francisco, California, United States
KEYWORDS: Oxygen, Tumors, Photodynamic therapy, Nanodroplets, Image enhancement, Photoacoustic spectroscopy, Hypoxia, Solids, In vivo imaging, Real time imaging
This Conference Presentation, “Photoacoustic image guided oxygen enhanced photodynamic therapy of hypoxic tumors,” was recorded at SPIE Photonics West held in San Francisco, California, United States
This Conference Presentation, “Eutectic gallium-indium alloy based liquid metal nanoparticles for photoacoustic imaging and photodynamic therapy,” was recorded at SPIE Photonics West 2022 held in San Francisco, California, United States.
Photodynamic therapy (PDT) is a photochemistry based cytotoxic technique that imparts cellular damage via excitation of a photosensitizer with drug-specific wavelength of light. Previously we and other groups have shown the efficacy of photoacoustic imaging in predicting treatment response of vascular targeted photodynamic therapy. In this work we evaluate the efficacy of photoacoustic imaging to monitor cellular targeted photodynamic therapy and its role in predicting recurrence. The dose at the treatment site for I PDT is determined by three factors: photosensitizer (PS) concentration, oxygenation status and delivered light irradiance. Most of the FDA approved photosensitizers in their triplet-excited state generate cytotoxic species by reacting with the ground state oxygen that is available in the surrounding environment. Given the inter- and intra-subject variability in the uptake of the photosensitizer and the distribution of oxygen in the tumor, understanding the interplay between these dose parameters could aid in determining photodynamic therapy efficacy. Using various subcutaneous and orthotopic mouse models we demonstrate both oxygenation status of the tumor prior to the treatment and the change in oxygen saturation 48 hrs post treatment can predict efficacy of Aminolevulinic acid (ALA) based cellular PDT with <92% sensitivity and specificity. We further compare the predictive capability of photoacoustic imaging with the more predominantly used fluorescence imaging and immunohistochemistry techniques.
This Conference Presentation, “Photoacoustic nanodroplets for oxygen enhanced photodynamic therapy,” was recorded for the Photonics West 2021 Digital Forum.
In this study, we evaluated the capability of an LED-based photoacoustic imaging system (AcousticX, 7MHz ultrasound probe, 850 nm LED arrays) in imaging heterogenous vasculature of subcutaneous tumors in mice. For evaluating the functional imaging capability, we used AcousticX with dual-wavelength LED arrays (750/850 nm) and monitored oxygen saturation of the tumor volume. We also compared the tumor images acquired by AcousticX and a commercial laser-based photoacoustic imaging system. Our results show that LED-based photoacoustic imaging can obtain similar imaging performance as a laser-based system and thus holds good promise in preclinical cancer research in an affordable setting.
Photodynamic therapy (PDT), a spatially localized phototoxic therapy that involves irradiation of a photosensitizer (PS) with specific wavelengths of light, has shown exceptional promise in impacting cancer treatment outcomes, particularly oral cancer. To reduce PDT outcome variability, attempts toward image-guided personalized PDT are being pursued by monitoring PS uptake either via fluorescence or photoacoustic imaging (PAI), a nonionizing modality dependent on optical absorption properties of the tissue. PAI-guided PDT requires a near-infrared contrast agent for deep tissue imaging with minimal photobleaching effect. We evaluate the impact of PDT agent, benzoporphyrin derivative (BPD), on PAI agent indocyanine green (ICG) and vice versa, given that they have different optical absorption properties and singlet oxygen quantum yields for PDT. Specifically, we demonstrate in two oral squamous cell carcinoma lines (FaDu and SCC4) that ICG has minimal effect on BPD PDT efficacy when irradiated with either a continuous or pulsed laser. Furthermore, the impact of BPD on ICG photodegradation was monitored with PAI in tissue-mimicking phantoms. These studies inform us that the combination of BPD and ICG can be utilized for PAI-guided PDT. However, researchers need to consider the photodegradation effects of ICG in the presence of BPD when designing their drug delivery strategies for PAI-guided PDT.
Molecular Imaging techniques are a hotspot in oncology for their inherent ability to detect cancer early as well as characterize and stage them. The prognosis and treatment response can also be monitored with these imaging techniques. Specifically, photoacoustic imaging is a technique that recently had exponential growth in several biomedical applications, particularly for imaging tumors. Photoacoustic imaging involves excitation of the tissue with the nanosecond laser pulses and subsequent generation of acoustic waves with an ultrasound transducer. to reconstruct the image, has potential to detect and monitor cancer prognosis by using the optical contrast of hemoglobin. In this work, we evaluated the potential of LED-based photoacoustics in imaging heterogenous microvasculature in tumors.
Synovial angiogenesis and hypoxia in the joints are biomarkers of Rheumatoid Arthritis (RA). The ability to probe blood and accurately estimate the oxygen concentration make multiwavelength Photoacoustic (PA) imaging a potential tool for early detection of RA. In this work, a multiwavelength LED-based PA imaging system was characterized based on its imaging depth, resolution and accuracy of oxygen saturation estimation. A multicenter 3R (Replace, Refine and Reduce) focused small animal study was conducted. The 3R strategy was devised by reusing RA animal models, in vivo imaging of healthy animals and ex vivo studies with human blood. RA animal cadaver models with different levels of synovial angiogenesis (control, positive RA and treated) were imaged and compared against results from a previous study using the same samples. An ex vivo PA oxygen saturation imaging using human blood was validated against oximeter readings and further verified it with in vivo animal studies. An imaging depth of 8 mm with an SNR of 10 dB was achieved for RA samples. A difference in PA intensity was observed for RA models compared to control and treated group. The PA oxygen saturation estimation correlates with oximeter readings, which is confirmed with in vivo studies. The results show the efficacy of the LED-based PA imaging system in RA diagnosis based on synovial angiogenesis and hypoxia. The imaging depth, resolution and oxygen saturation estimate are sufficient to differentiate RA samples from control. Our future work will focus on validating the method using arthritis animal models and demonstrating the 3R potential.
Imaging technologies such as Ultrasound, OCT, MRI and CT are useful for diagnostics and tomographic assessment of therapy response. Fluorescence imaging with its high sensitivity is a promising approach and is extensively used for lesion localization, surgical guidance and monitoring response to therapies. While conjugating fluorophores to antibodies improves specificity, further conjugation of drugs provides a dual function, where fluorescence monitoring may simultaneously reveal drug pharmacokinetics. Fluorescence imaging, however, is limited by low penetration of light, which can be partially overcome by photoacoustic imaging (PAI). In this study, by conjugating a fluorophore and photoacoustic molecule to an antibody (Dual Function Antibody Conjugate (DFAC)), we evaluate whether PAI can significantly improve deep-tissue imaging.
To provide a systematic comparison of these imaging modalities we developed a DFAC, comprising of Cetuximab (anti-EGFR antibody) conjugated with a fluorophore (AF647) and a photoacoustic dye (IRDye800) in a 1:2:2 ratio. We hypothesize that, conjugating quantifiable probes to an antibody, would provide information about different depths within the confines of optical approaches. Such quantification is particularly important in photodynamic therapy, for determination of tissue concentration of photosensitizers and in chemotherapy for quantification of drug concentrations non-invasively. The relationship between the photoacoustic and fluorescence signals from the DFAC is demonstrated through spectroscopic techniques and their EGFR specificity along with deep tissue photoacoustic quantification is established using EGFR positive/negative cell lines and tissue mimicking phantoms.
The DFAC, presented in this study, demonstrates a combination of two complimentary imaging modalities for non-invasive determination of pharmacokinetics and in vivo drug quantification.
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