Biology subjects

Xavierselvan, M.

Publications and source records attributed to Xavierselvan, M..

4 recordsLinked to original sources

bioRxiv2024

In vivo Online label-free monitoring of heterogenous oxygen utilization during phototherapy with real-time ultrasound guided photoacoustic imaging

Understanding the tumor microenvironment, particularly the vascular density and the availability of oxygen, is key in individualizing treatment approaches and determining their efficacy. While there are many therapies including radiotherapy that are ineffective in hypoxic tumor microenvironments, here we demonstrate the heterogeneous oxygen consumption during photodynamic therapy (PDT), a non-invasive treatment method using localized light to activate a photosensitive drug in the presence of oxygen that has shown high effectiveness in the treatment of various types of tumors, including those presented in head and neck cancer (HNC) patients. While our previous work has demonstrated that blood oxygen saturation (StO2) mapped before and after treatment with ultrasound-guided photoacoustic imaging (US-PAI) can be used as a surrogate marker for the regionalized long-term efficacy of PDT, real-time monitoring of StO2 during PDT could provide additional insights on oxygen consumption and inform dose design for "on the spot" treatment decisions. Specifically, in this work, we integrated the US-PAI transducer probe with PDT light delivery fibers. We tested the setup on murine tumor models intravenously injected with liposomal benzoporphyrin derivative (BPD) photosensitizer at 0.5 mg/kg dose and photodynamic illumination at 100 and 400 mW/cm2 fluence rate. As expected, we observed with our US-PAI StO2 images that the rate of oxygen utilization increases when using a high fluence rate (HFR) light dose. Particularly in the higher fluence rate group, we observed StO2 reaching a minimum mid-light dose, followed by some degree of re-oxygenation. US-PAI added the advantage of spatial information to StO2 monitoring, which allowed us to match regions of re-oxygenation during therapy to retained vascular function with immunohistochemistry. Overall, our results have demonstrated the potential of US-PAI for applications in online dosimetry for cancer therapies such as PDT, using oxygen changes to detect regionalized physiological vascular response in the tumor microenvironment.

bioengineering↗

bioRxiv2024

Temporal dynamics of fluorescence and photoacoustic signals of a Cetuximab-IRDye800 conjugate in EGFR-overexpressing tumors

Molecular fluorescence-guided surgery has shown promise for tumor margin delineation but is limited by its depth profiling capability. Interestingly, most fluorophores, either clinically approved or in clinical trials, can also be used as photoacoustic contrast agents, yet their use is limited due to the low light fluence permitted for clinical use and the limited sensitivity of current photoacoustic imaging systems. There is therefore an urgent unmet need to establish methods for enhancing contrast in molecular targeted PA imaging which could potentially complement and overcome limitations in molecular fluorescence guided therapies. In this study, we compare the photoacoustic (PA) and fluorescence imaging capabilities of a cetuximab-IRDye800 conjugate in a subcutaneous tumor xenograft model. We demonstrate that while the fluorescence signal increases steadily over time after administration of cetuximab-IRDye800, PA signal peaks early ([~]2 fold higher at 6-hour as compared to pre-injection controls) and then decreases ([~]1.3 fold higher at 24-hour as compared to pre-injection controls). This pattern aligns with previous findings using other antibody-conjugated PA contrast agents. Mechanistically, we demonstrate that the formation of H-aggregates upon antibody conjugation enhances PA contrast of the IRDye800. The disruption of these H-aggregates, as the antibody-dye conjugate is degraded post receptor-mediated endocytosis, decreases PA signal intensity. The timeframe of maximum PA signal and decrease thereafter is consistent with the time frame of receptor-mediated endocytosis of cetuximab-IRDye800. Our data suggests that tumor cell surface binding results in peak PA signal while lysosomal localization and degradation results in a significant drop in PA signal. Our study sheds light on the distinct temporal dynamics of PA and fluorescence signals of Cetuximab-IRDye800 conjugate and we propose that optimizing IRDye800 conjugation to antibodies can further enhance PA signal intensity when timed to precisely to capture IRDye800 in an H-aggregate form.

cancer biology↗

bioRxiv2024

Vascular regional analysis unveils differential responses to anti-angiogenic therapy in pancreatic xenografts through macroscopic photoacoustic imaging

Pancreatic cancer (PC) is a highly lethal malignancy and the third leading cause of cancer deaths in the U.S. Despite major innovations in imaging technologies, there are limited surrogate radiographic indicators to aid in therapy planning and monitoring. Amongst the various imaging techniques Ultrasound-guided photoacoustic imaging (US-PAI) is a promising modality based on endogenous blood (hemoglobin) and blood oxygen saturation (StO2) contrast to monitor response to anti-angiogenic therapies. Adaptation of US-PAI to the clinical realm requires macroscopic configurations for adequate depth visualization, illuminating the need for surrogate radiographic markers, including the tumoral microvessel density (MVD). In this work, subcutaneous xenografts with PC cell lines AsPC-1 and MIA-PaCa-2 were used to investigate the effects of receptor tyrosine kinase inhibitor (sunitinib) treatment on MVD and StO2. Through histological correlation, we have shown that regions of high and low vascular density (HVD and LVD) can be identified through frequency domain filtering of macroscopic PA images which could not be garnered from purely global analysis. We utilized vascular regional analysis (VRA) of treatment-induced StO2 and total hemoglobin (HbT) changes. VRA as a tool to monitor treatment response allowed us to identify potential timepoints of vascular remodeling, highlighting its ability to provide insights into the TME not only for sunitinib treatment but also other anti-angiogenic therapies.

bioengineering↗

bioRxiv2024

Oxygen-releasing nanodroplets relieve intratumoral hypoxia in head and neck cancer spheroids.

AO_SCPLOWBSTRACTC_SCPLOWHypoxia in solid tumors, including head and neck cancer (HNC), contributes to treatment resistance, aggressive phenotypes, and poor clinical outcomes. Perfluorocarbon nanodroplets have emerged as promising oxygen carriers to alleviate tumor hypoxia. However, a thorough characterization of the hypoxia alleviation effects in terms of sustenance of oxygenated environments have not been thoroughly studied. In this study, we developed and characterized perfluoropentane nanodroplets (PFP NDs) for co-delivery of oxygen and the photoactivatable drug or photosensitizer benzoporphyrin derivative (BPD) to hypoxic HNC spheroids. The PFP NDs exhibited excellent stability, efficient oxygen loading/release, and biocompatibility. Using 3D multicellular tumor spheroids of FaDu and SCC9 HNC cells, we demonstrated the ability of oxygenated PFP NDs to penetrate the hypoxic core and alleviate hypoxia, as evidenced by reduced fluorescence of a hypoxia-sensing reagent and downregulation of hypoxia-inducible factors HIF-1 and HIF-2. BPD-loaded PFP NDs successfully delivered the photosensitizer into the spheroid core in a time-dependent manner. These findings highlight the potential of PFP NDs as a co-delivery platform to overcome hypoxia-mediated treatment resistance and improve therapy outcomes in HNC.

bioengineering↗