21 results on '"Bulin AL"'
Search Results
2. Spatiotemporal Tracking of Different Cell Populations in Cancer Organoid Models for Investigations on Photodynamic Therapy.
- Author
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Bulin AL and Hasan T
- Subjects
- Coculture Techniques, Humans, Organoids pathology, Neoplasms drug therapy, Neoplasms pathology, Photochemotherapy
- Abstract
Three-dimensional (3D) in vitro models of tumors are gaining interest as versatile platforms for treatment screening. In this context, heterocellular cultures in which various cell types are co-cultured are being explored to investigate whether partner cells can influence the treatment efficacies. However, when the cells are co-cultured, it is challenging to distinguish them and it becomes impossible to identify whether the treatment affects each cell line in a similar way or if there is a certain selectivity. Here, we propose a protocol in which different cell types are pre-labeled with fluorescent reporters prior to 3D culture initiation. Subsequently, the internal architecture of the 3D cancer models can be longitudinally monitored for model characterization, and to potentially detect architectural and treatment selectivity in response to therapy. This protocol employs quantum dots as non-photobleaching dyes and two-photon excited microscopy as a widely accessible imaging modality. In combination with an appropriate image analysis workflow, this protocol will help to investigate the architectural development of heterotypic microtumor/spheroid/organoid models and possibly identify treatment efficacies on individual cell populations represented within the models., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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3. Stereotaxic Implantation of F98 Cells in Fischer Rats: A Syngeneic Model to Investigate Photodynamic Therapy Response in Glioma.
- Author
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Bulin AL, Adam JF, and Elleaume H
- Subjects
- Animals, Cell Line, Tumor, Humans, Rats, Rats, Inbred F344, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Glioblastoma drug therapy, Glioblastoma pathology, Glioma drug therapy, Glioma pathology, Photochemotherapy
- Abstract
When investigating the promise of novel therapeutic modalities, the choice of an appropriate and reproducible in vivo model is critical to determine the relevance of the findings. In the case of glioblastoma, a high-grade glioma tumor that is clinically characterized by a high infiltrative pattern, no existing model exactly mimics the clinical features of these tumors. However, a syngeneic rat model of glioblastoma in which F98 cells are orthotopically implanted can recapitulate most of the characteristics of glioma as observed in patients, including a highly aggressive nature, a high degree of infiltration of cancer cells into healthy tissue, and a strong resistance to commonly used treatments including radiotherapy and chemotherapy. Here, we provide a detailed protocol to stereotaxically implant F98 cells in the rat brain and obtain a reproducible and clinically representative glioma model in rodents., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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4. Analysis of Treatment Effects on Structurally Complex Microtumor Cultures Using a Comprehensive Image Analysis Procedure.
- Author
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Bulin AL, Broekgaarden M, and Hasan T
- Subjects
- Microscopy, Fluorescence methods, Organoids
- Abstract
As three-dimensional (3D) culture models are attractive platforms to assess treatment response and expedite the development of new therapeutic regimens, appropriate methodologies to extract quantitative data from these models are required. Here, we present a live/dead staining protocol together with a recently developed analysis methodology for the multiparametric assessment of treatment effects on 3D culture models (CALYPSO: Comprehensive image AnaLYsis Procedure for Structurally complex Organoids). This methodology can process up to thousands of individual organoids within a single experiment and provides multiple informative readouts for each individual microtumor. Moreover, this protocol utilizes conventional fluorescence microscopy and commercially available dyes, allowing it to be easily implemented in most laboratories. Taken together, the methodology presented here encourages the use of microtumor models by enabling the high-throughput assessment of treatment effects, regardless of 3D culture type or microtumor architectures., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
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5. High-Throughput Examination of Therapy-Induced Alterations in Redox Metabolism in Spheroid and Microtumor Models.
- Author
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Broekgaarden M, Bulin AL, and Hasan T
- Subjects
- Flavoproteins metabolism, Homeostasis, Oxidation-Reduction, NAD metabolism, Photochemotherapy methods
- Abstract
The capacity of cancer cells to adjust their metabolism to thrive in new environments and in response to treatments has been implicated in the acquisition of treatment resistance. To optimize therapeutic strategies such as photodynamic therapy (PDT)-based combination treatments, methods to characterize the plasticity of cancer metabolism in response to treatments are required. This protocol provides a method for high-throughput and label-free tracking of metabolic redox states in cancer tissues, leveraging the autofluorescent properties of nicotinamide dinucleotide (NAD(P)H) and oxidized flavoprotein adenine dinucleotide (FAD). The methodology is optimized to be applied to 3D spheroid/microtumor/organoid cultures, regardless of the culture type (e.g., adherent or suspension cultures) and morphology. The exploitation of these methods may elucidate mechanisms of metabolic adaptation and perturbations in redox homeostasis, and chart the overall tumor health in both 3D culture models and ex vivo tissues following cancer therapies, such as PDT., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
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6. Radiation Dose-Enhancement Is a Potent Radiotherapeutic Effect of Rare-Earth Composite Nanoscintillators in Preclinical Models of Glioblastoma.
- Author
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Bulin AL, Broekgaarden M, Chaput F, Baisamy V, Garrevoet J, Busser B, Brueckner D, Youssef A, Ravanat JL, Dujardin C, Motto-Ros V, Lerouge F, Bohic S, Sancey L, and Elleaume H
- Abstract
To improve the prognosis of glioblastoma, innovative radiotherapy regimens are required to augment the effect of tolerable radiation doses while sparing surrounding tissues. In this context, nanoscintillators are emerging radiotherapeutics that down-convert X-rays into photons with energies ranging from UV to near-infrared. During radiotherapy, these scintillating properties amplify radiation-induced damage by UV-C emission or photodynamic effects. Additionally, nanoscintillators that contain high-Z elements are likely to induce another, currently unexplored effect: radiation dose-enhancement. This phenomenon stems from a higher photoelectric absorption of orthovoltage X-rays by high-Z elements compared to tissues, resulting in increased production of tissue-damaging photo- and Auger electrons. In this study, Geant4 simulations reveal that rare-earth composite LaF
3 :Ce nanoscintillators effectively generate photo- and Auger-electrons upon orthovoltage X-rays. 3D spatially resolved X-ray fluorescence microtomography shows that LaF3 :Ce highly concentrates in microtumors and enhances radiotherapy in an X-ray energy-dependent manner. In an aggressive syngeneic model of orthotopic glioblastoma, intracerebral injection of LaF3 :Ce is well tolerated and achieves complete tumor remission in 15% of the subjects receiving monochromatic synchrotron radiotherapy. This study provides unequivocal evidence for radiation dose-enhancement by nanoscintillators, eliciting a prominent radiotherapeutic effect. Altogether, nanoscintillators have invaluable properties for enhancing the focal damage of radiotherapy in glioblastoma and other radioresistant cancers., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley‐VCH GmbH.)- Published
- 2020
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7. Photodynamic Diagnosis and Therapy for Peritoneal Carcinomatosis: Emerging Perspectives.
- Author
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Xu S, Bulin AL, Hurbin A, Elleaume H, Coll JL, and Broekgaarden M
- Abstract
Peritoneal carcinomatosis occurs frequently in patients with advanced stage gastrointestinal and gynecological cancers. The wide-spread peritoneal micrometastases indicate a poor outlook, as the tumors are difficult to diagnose and challenging to completely eradicate with cytoreductive surgery and chemotherapeutics. Photodynamic diagnosis (PDD) and therapy (PDT), modalities that use photosensitizers for fluorescence detection or photochemical treatment of cancer, are promising theranostic approaches for peritoneal carcinomatosis. This review discusses the leading clinical trials, identifies the major challenges, and presents potential solutions to advance the use of PDD and PDT for the treatment of peritoneal carcinomatosis. While PDD for fluorescence-guided surgery is practically feasible and has achieved clinical success, large randomized trials are required to better evaluate the survival benefits. Although PDT is feasible and combines well with clinically used chemotherapeutics, poor tumor specificity has been associated with severe morbidity. The major challenges for both modalities are to increase the tumor specificity of the photosensitizers, to efficiently treat peritoneal microtumors regardless of their phenotypes, and to improve the ability of the excitation light to reach the cancer tissues. Substantial progress has been achieved in (1) the development of targeted photosensitizers and nanocarriers to improve tumor selectivity, (2) the design of biomodulation strategies to reduce treatment heterogeneity, and (3) the development of novel light application strategies. The use of X-ray-activated PDT during whole abdomen radiotherapy may also be considered to overcome the limited tissue penetration of light. Integrated approaches that take advantage of PDD, cytoreductive surgery, chemotherapies, PDT, and potentially radiotherapy, are likely to achieve the most effective improvement in the management of peritoneal carcinomatosis.
- Published
- 2020
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8. Cabozantinib Inhibits Photodynamic Therapy-Induced Auto- and Paracrine MET Signaling in Heterotypic Pancreatic Microtumors.
- Author
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Broekgaarden M, Alkhateeb A, Bano S, Bulin AL, Obaid G, Rizvi I, and Hasan T
- Abstract
Extensive desmoplasia is a hallmark of pancreatic ductal adenocarcinoma (PDAC), which frequently associates with treatment resistance. Recent findings indicate that a combination of photodynamic therapy and the multi-kinase inhibitor cabozantinib achieved local tumor control and a significant decrease in tumor metastases in preclinical PDAC models, but the underlying therapeutic mechanisms remain unclear. This study elucidates the molecular basis of this multi-agent regimen, focusing on the role of MET signaling. Since MET activation stems from its interaction with hepatocyte growth factor (HGF), which is typically secreted by fibroblasts, we developed heterotypic PDAC microtumor models that recapitulate these interactions. In these models, MET signaling can be constitutively activated through paracrine and autocrine mechanisms. Photodynamic therapy caused significant elevations in HGF secretion by fibroblasts, suggesting it plays a complex role in the modulation of the paracrine HGF-MET signaling cascade in desmoplastic tumors. Blocking MET phosphorylation with adjuvant cabozantinib caused a significant improvement in photodynamic therapy efficacy, most notably by elevating spheroid necrosis at low radiant exposures. These findings highlight that adjuvant photodynamic therapy can augment chemotherapy efficacies, and potentially achieve improved management of desmoplastic PDAC in a more tolerable manner.
- Published
- 2020
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9. Surface functionalization of gold nanoclusters with arginine: a trade-off between microtumor uptake and radiotherapy enhancement.
- Author
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Broekgaarden M, Bulin AL, Porret E, Musnier B, Chovelon B, Ravelet C, Sancey L, Elleaume H, Hainaut P, Coll JL, and Le Guével X
- Subjects
- Cell Line, Humans, Neoplasms metabolism, Neoplasms pathology, Gold chemistry, Gold pharmacokinetics, Gold pharmacology, Metal Nanoparticles chemistry, Metal Nanoparticles therapeutic use, Neoplasms radiotherapy, Radiation-Sensitizing Agents chemistry, Radiation-Sensitizing Agents pharmacokinetics, Radiation-Sensitizing Agents pharmacology
- Abstract
Ultra-small gold nanoclusters (AuNCs) are increasingly investigated for cancer imaging and radiotherapy enhancement. While fine-tuning the AuNC surface chemistry can optimize their pharmacokinetics, its effects on radiotherapy enhancement remain largely unexplored. This study demonstrates that optimizing the surface chemistry of AuNCs for increased tumor uptake can significantly affect its potential to augment radiotherapy outcomes.
- Published
- 2020
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10. Liquid-Crystalline Suspensions of Photosensitive Paramagnetic CeF 3 Nanodiscs.
- Author
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Chaput F, Lerouge F, Bulin AL, Amans D, Odziomek M, Faure AC, Monteil M, Dozov I, Parola S, Bouquet F, Lecouvey M, Davidson P, and Dujardin C
- Abstract
The design of high-performance energy-converting materials is an essential step for the development of sensors, but the production of the bulk materials currently used remains costly and difficult. Therefore, a different approach based on the self-assembly of nanoparticles has been explored. We report on the preparation by solvothermal synthesis of highly crystalline CeF
3 nanodiscs. Their surface modification by bisphosphonate ligands led to stable, highly concentrated, colloidal suspensions in water. Despite the low aspect ratio of the nanodiscs (∼6), a liquid-crystalline nematic phase spontaneously appeared in these colloidal suspensions. Thanks to the paramagnetic character of the nanodiscs, the nematic phase was easily aligned by a weak (0.5 T) magnetic field, which provides a simple and convenient way of orienting all of the nanodiscs in suspension in the same direction. Moreover, the more dilute, isotropic, suspensions displayed strong (electric and magnetic) field-induced orientation of the nanodiscs (Kerr and Cotton-Mouton effects), with fast enough response times to make them suitable for use in electro-optic devices. Furthermore, an emission study showed a direct relation between the luminescence intensity and magnetic-field-induced orientation of the colloids. Finally, with their fast radiative recombination decay rates, the nanodiscs show luminescence properties that compare quite favorably with those of bulk CeF3 . Therefore, these CeF3 nanodiscs are very promising building blocks for the development and processing of photosensitive materials for sensor applications.- Published
- 2019
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11. Impacting Pancreatic Cancer Therapy in Heterotypic in Vitro Organoids and in Vivo Tumors with Specificity-Tuned, NIR-Activable Photoimmunonanoconjugates: Towards Conquering Desmoplasia?
- Author
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Obaid G, Bano S, Mallidi S, Broekgaarden M, Kuriakose J, Silber Z, Bulin AL, Wang Y, Mai Z, Jin W, Simeone D, and Hasan T
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Cancer-Associated Fibroblasts drug effects, Cancer-Associated Fibroblasts pathology, Carcinoma, Pancreatic Ductal pathology, Drug Delivery Systems methods, ErbB Receptors antagonists & inhibitors, Humans, Immunoconjugates administration & dosage, Mice, Nanoconjugates administration & dosage, Nanomedicine methods, Organoids drug effects, Organoids pathology, Pancreatic Neoplasms pathology, Photochemotherapy methods, Photosensitizing Agents administration & dosage, Carcinoma, Pancreatic Ductal drug therapy, Immunoconjugates therapeutic use, Nanoconjugates therapeutic use, Pancreatic Neoplasms drug therapy, Photosensitizing Agents therapeutic use
- Abstract
Despite untiring efforts to develop therapies for pancreatic ductal adenocarcinoma (PDAC), survival statistics remain dismal, necessitating distinct approaches. Photodynamic priming (PDP), which improves drug delivery and combination regimens, as well as tumor photodestruction are key attributes of photodynamic therapy (PDT), making it a distinctive clinical option for PDAC. Localized, high-payload nanomedicine-assisted delivery of photosensitizers (PSs), with molecular specificity and controlled photoactivation, thus becomes critical in order to reduce collateral toxicity during more expansive photodynamic activation procedures with curative intent. As such, targeted photoactivable lipid-based nanomedicines are an ideal candidate but have failed to provide greater than two-fold cancer cell selectivity, if at all, due to their extensive multivariant physical, optical, and chemical complexity. Here, we report (1) a systematic multivariant tuning approach to engineer (Cet, anti-EGFR mAb) photoimmunonanoconjugates (PINs), and (2) stroma-rich heterotypic PDAC in vitro and in vivo models incorporating patient-derived pancreatic cancer-associated fibroblasts (PCAFs) that recapitulate the desmoplasia observed in the clinic. These offer a comprehensive, disease-specific framework for the development of Cet-PINs. Specificity-tuning of the PINs, in terms of PS lipid anchoring, electrostatic modulation, Cet orientation, and Cet surface densities, achieved ∼16-fold binding specificities and rapid penetration of the heterotypic organoids within 1 h, thereby providing a ∼16-fold enhancement in molecular targeted NIR photodestruction. As a demonstration of their inherent amenability for multifunctionality, encapsulation of high payloads of gemcitabine hydrochloride, 5-fluorouracil, and oxaliplatin within the Cet-PINs further improved their antitumor efficacy in the heterotypic organoids. In heterotypic desmoplastic tumors, the Cet-PINs efficiently penetrated up to 470 μm away from blood vessels, and photodynamic activation resulted in substantial tumor necrosis, which was not elicited in T47D tumors (low EGFR) or when using untargeted constructs in both tumor types. Photodynamic activation of the Cet-PINs in the heterotypic desmoplastic tumors resulted in collagen photomodulation, with a 1.5-fold reduction in collagen density, suggesting that PDP may also hold potential for conquering desmoplasia. The in vivo safety profile of photodynamic activation of the Cet-PINs was also substantially improved, as compared to the untargeted constructs. While treatment using the Cet-PINs did not cause any detriment to the mice's health or to healthy proximal tissue, photodynamic activation of untargeted constructs induced severe acute cachexia and weight loss in all treated mice, with substantial peripheral skin necrosis, muscle necrosis, and bowel perforation. This study is the first report demonstrating the true value of molecular targeting for NIR-activable PINs. These constructs integrate high payload delivery, efficient photodestruction, molecular precision, and collagen photomodulation in desmoplastic PDAC tumors in a single treatment using a single construct. Such combined PIN platforms and heterocellular models open up an array of further multiplexed combination therapies to synergistically control desmoplastic tumor progression and extend PDAC patient survival.
- Published
- 2019
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12. Modulation of redox metabolism negates cancer-associated fibroblasts-induced treatment resistance in a heterotypic 3D culture platform of pancreatic cancer.
- Author
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Broekgaarden M, Anbil S, Bulin AL, Obaid G, Mai Z, Baglo Y, Rizvi I, and Hasan T
- Subjects
- Cell Line, Tumor, Flow Cytometry, Gene Expression Regulation, Neoplastic genetics, Gene Expression Regulation, Neoplastic physiology, Humans, Oxidation-Reduction, Tumor Microenvironment, Pancreatic Neoplasms, Cancer-Associated Fibroblasts metabolism, Pancreatic Neoplasms metabolism, Photochemotherapy methods
- Abstract
The complex interplay between cancer cells and their microenvironment remains a major challenge in the design and optimization of treatment strategies for pancreatic ductal adenocarcinoma (PDAC). Recent investigations have demonstrated that mechanistically distinct combination therapies hold promise for treatment of PDAC, but effective clinical translation requires more accurate models that account for the abundant tumor-stroma and its influence on cancer growth, metabolism and treatment insensitivity. In this study, a modular 3D culture model that comprised PDAC cells and patient-derived cancer-associated fibroblasts (CAFs) was developed to assess the effects of PDAC-CAF interactions on treatment efficacies. Using newly-developed high-throughput imaging and image analysis tools, it was found that CAFs imparted a notable and statistically significant resistance to oxaliplatin chemotherapy and benzoporphyrin derivative-mediated photodynamic therapy, which associated with increased levels of basal oxidative metabolism. Increased treatment resistance and redox states were similarly observed in an orthotopic xenograft model of PDAC in which cancer cells and CAFs were co-implanted in mice. Combination therapies of oxaliplatin and PDT with the mitochondrial complex I inhibitor metformin overcame CAF-induced treatment resistance. The findings underscore that heterotypic microtumor culture models recapitulate metabolic alterations stemming from tumor-stroma interactions. The presented infrastructure can be adapted with disease-specific cell types and is compatible with patient-derived tissues to enable personalized screening and optimization of new metabolism-targeted treatment regimens for pancreatic cancer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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13. Tracking Photodynamic- and Chemotherapy-Induced Redox-State Perturbations in 3D Culture Models of Pancreatic Cancer: A Tool for Identifying Therapy-Induced Metabolic Changes.
- Author
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Broekgaarden M, Bulin AL, Frederick J, Mai Z, and Hasan T
- Abstract
The metabolic plasticity of cancer cells is considered a highly advantageous phenotype that is crucial for disease progression and acquisition of treatment resistance. A better understanding of cancer metabolism and its adaptability after treatments is vital to develop more effective therapies. To screen novel therapies and combination regimens, three-dimensional (3D) culture models of cancers are attractive platforms as they recapitulate key features of cancer. By applying non-perturbative intensity-based redox imaging combined with high-throughput image analysis, we demonstrated metabolic heterogeneity in various 3D culture models of pancreatic cancer. Photodynamic therapy and oxaliplatin chemotherapy, two cancer treatments with relevance to pancreatic cancer, induced perturbations in redox state in 3D microtumor cultures of pancreatic cancer. In an orthotopic mouse model of pancreatic cancer, a similar disruption in redox homeostasis was observed on ex vivo slices following photodynamic therapy in vivo. Taken together, redox imaging on cancer tissues combined with high-throughput analysis can elucidate dynamic spatiotemporal changes in metabolism following treatment, which will benefit the design of new metabolism-targeted therapeutic approaches.
- Published
- 2019
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14. Low dose photodynamic therapy harmonizes with radiation therapy to induce beneficial effects on pancreatic heterocellular spheroids.
- Author
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Bulin AL, Broekgaarden M, Simeone D, and Hasan T
- Abstract
Photodynamic therapy (PDT) has seen long standing interest as a therapy for resistant cancers, but the main Achilles' heel for its successful clinical exploitation is the use of poorly penetrating visible light. This limitation could be overcome by using radioluminescent nanoparticles, which can be excited during radiation therapy (RT) with penetrating X-rays. When infused in tumors, X-ray activated-nanoscintillators act as internal light sources and excite nearby photosensitizers. Recent studies demonstrated that it is realistic to achieve low dose PDT with current nanoscintillators. However, as the origin of enhanced RT efficacy with nanoscintillators may have varying origins, we aimed to answer the basic question: Is a combination of low-dose PDT beneficial to the RT efficacy in clinically relevant models of cancer? Pancreatic cancer (PanCa) remains a lethal disease for which RT is part of the palliative care and for which PDT demonstrated promising results in clinical trial. We thus evaluated the combination of low-dose PDT and RT delivered in absence of nanoscintillators on various heterocellular spheroid models that recapitulate the clinical heterogeneity of PanCa. Although therapeutic effects emerged at different timepoints in each model, the RT/PDT combination uniformly achieved favorable outcomes. With RT providing stunted tumor growth while PDT drove adjuvant apoptotic and necrotic cell death, the combination produced significantly smaller and less viable PanCa spheroids. In conclusion, the beneficial RT/PDT treatment outcomes encourage the further development of nanoscinitillators for X-ray-activated PDT. Assessment of such combination treatments should encompass multiparametric and temporally-spaced assessment of treatment effects in preclinical cancer models., Competing Interests: CONFLICTS OF INTEREST The authors have declared that no competing interest exists.
- Published
- 2019
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15. Neoadjuvant photodynamic therapy augments immediate and prolonged oxaliplatin efficacy in metastatic pancreatic cancer organoids.
- Author
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Broekgaarden M, Rizvi I, Bulin AL, Petrovic L, Goldschmidt R, Massodi I, Celli JP, and Hasan T
- Abstract
Effective treatment of advanced metastatic disease remains the primary challenge in the management of inoperable pancreatic cancer. Current therapies such as oxaliplatin (OxPt)-based chemotherapy regimens (FOLFIRINOX) provide modest short-term survival improvements, yet with significant toxicity. Photodynamic therapy (PDT), a light-activated cancer therapy, demonstrated clinical promise for pancreatic cancer treatment and enhances conventional chemotherapies with non-overlapping toxicities. This study investigates the capacity of neoadjuvant PDT using a clinically-approved photosensitizer, benzoporphyrin derivative (BPD, verteporfin), to enhance OxPt efficacy in metastatic pancreatic cancer. Treatment effects were evaluated in organotypic three-dimensional (3D) cultures, clinically representative models that bridge the gap between conventional cell cultures and in vivo models. The temporally-spaced, multiparametric analyses demonstrated a superior efficacy for combined PDT+OxPt compared to each monotherapy alone, which was recapitulated on different organotypic pancreatic cancer cultures. The therapeutic benefit of neoadjuvant PDT to OxPt chemotherapy materialized in a time-dependent manner, reducing residual viable tissue and tumor viability in a manner not achievable with OxPt or PDT alone. These findings emphasize the need for intelligent combination therapies and relevant models to evaluate the temporal kinetics of interactions between mechanistically-distinct treatments and highlight the promise of PDT as a neoadjuvant treatment for disseminated pancreatic cancer., Competing Interests: CONFLICTS OF INTEREST None.
- Published
- 2018
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16. Comprehensive high-throughput image analysis for therapeutic efficacy of architecturally complex heterotypic organoids.
- Author
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Bulin AL, Broekgaarden M, and Hasan T
- Subjects
- Antineoplastic Agents therapeutic use, Cell Line, Tumor, Fluorescent Antibody Technique, Humans, Image Processing, Computer-Assisted, Microscopy, Fluorescence, Neoplasms drug therapy, Tissue Culture Techniques, Workflow, Antineoplastic Agents pharmacology, High-Throughput Screening Assays, Molecular Imaging methods, Neoplasms pathology, Organoids drug effects, Organoids pathology
- Abstract
Bioengineered three-dimensional (3D) tumor models that incorporate heterotypic cellular communication are gaining interest as they can recapitulate key features regarding the intrinsic heterogeneity of cancer tissues. However, the architectural complexity and heterogeneous contents associated with these models pose a challenge for toxicological assays to accurately report treatment outcomes. To address this issue, we describe a comprehensive image analysis procedure for structurally complex organotypic cultures (CALYPSO) applied to fluorescence-based assays to extract multiparametric readouts of treatment effects for heterotypic tumor cultures that enables advanced analyses. The capacity of this approach is exemplified on various 3D models including adherent/suspension, mono-/heterocellular cultures and several disease types. The subsequent analysis revealed specific morphological effects of oxaliplatin chemotherapy, radiotherapy, and photodynamic therapy. The procedure can be readily implemented in most laboratories to facilitate high-throughput toxicological screening of pharmaceutical agents and treatment regimens on organotypic cultures of human disease to expedite drug and therapy development.
- Published
- 2017
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17. A Photosensitizer Lanthanide Nanoparticle Formulation that Induces Singlet Oxygen with Direct Light Excitation, But Not By Photon or X-ray Energy Transfer.
- Author
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Chouikrat R, Baros F, André JC, Vanderesse R, Viana B, Bulin AL, Dujardin C, Arnoux P, Verelst M, and Frochot C
- Abstract
We report the design and synthesis of europium-doped gadolinium oxysulfide nanoscintillators Gd
2 O2 S:Eu3+ conjugated with two different photosensitizers (PSs): a zinc chlorin (ZnTPC) and a zinc phtalocyanine (ZnPc) by covalent bonding through a layer of N-(3-trimethoxysilylpropyl)diethylenetriamine (TPDA). These conjugates were designed to be activated under X-ray excitation to allow a photodynamic effect, although this desired outcome was not achieved in this study. The monodispersed nanoparticles of ∼70 nm diameter were pegylated to be stabilized in aqueous suspension. It was shown that the PSs conserved their photophysical properties once conjugated to the nanoscintillator and efficient singlet oxygen was obtained upon photo-irradiation. However, no energy transfer was observed from the nanoscintillator to the photosensitizer neither under photo- nor X-ray irradiation., (© 2017 The American Society of Photobiology.)- Published
- 2017
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18. Beyond the Barriers of Light Penetration: Strategies, Perspectives and Possibilities for Photodynamic Therapy.
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Mallidi S, Anbil S, Bulin AL, Obaid G, Ichikawa M, and Hasan T
- Subjects
- Humans, Neoplasms therapy, Photochemotherapy trends, Light, Photochemotherapy methods, Photosensitizing Agents therapeutic use
- Abstract
Photodynamic therapy (PDT) is a photochemistry based treatment modality that involves the generation of cytotoxic species through the interactions of a photosensitizer molecule with light irradiation of an appropriate wavelength. PDT is an approved therapeutic modality for several cancers globally and in several cases has proved to be effective where traditional treatments have failed. The key parameters that determine PDT efficacy are 1. the photosensitizer (nature of the molecules, selectivity, and macroscopic and microscopic localization etc.), 2. light application (wavelength, fluence, fluence rate, irradiation regimes etc.) and 3. the microenvironment (vascularity, hypoxic regions, stromal tissue density, molecular heterogeneity etc.). Over the years, several groups aimed to monitor and manipulate the components of these critical parameters to improve the effectiveness of PDT treatments. However, PDT is still misconstrued to be a surface treatment primarily due to the limited depths of light penetration. In this review, we present the recent advances, strategies and perspectives in PDT approaches, particularly in cancer treatment, that focus on increasing the 'damage zone' beyond the reach of light in the body. This is enabled by a spectrum of approaches that range from innovative photosensitizer excitation strategies, increased specificity of phototoxicity, and biomodulatory approaches that amplify the biotherapeutic effects induced by photodynamic action. Along with the increasing depth of understanding of the underlying physical, chemical and physiological mechanisms, it is anticipated that with the convergence of these strategies, the clinical utility of PDT will be expanded to a powerful modality in the armamentarium for the management of cancer., Competing Interests: The authors have declared that no competing interest exists.
- Published
- 2016
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19. Photonanomedicine: a convergence of photodynamic therapy and nanotechnology.
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Obaid G, Broekgaarden M, Bulin AL, Huang HC, Kuriakose J, Liu J, and Hasan T
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- Photochemistry, Theranostic Nanomedicine, Nanomedicine, Neoplasms therapy, Photochemotherapy
- Abstract
As clinical nanomedicine has emerged over the past two decades, phototherapeutic advancements using nanotechnology have also evolved and impacted disease management. Because of unique features attributable to the light activation process of molecules, photonanomedicine (PNM) holds significant promise as a personalized, image-guided therapeutic approach for cancer and non-cancer pathologies. The convergence of advanced photochemical therapies such as photodynamic therapy (PDT) and imaging modalities with sophisticated nanotechnologies is enabling the ongoing evolution of fundamental PNM formulations, such as Visudyne®, into progressive forward-looking platforms that integrate theranostics (therapeutics and diagnostics), molecular selectivity, the spatiotemporally controlled release of synergistic therapeutics, along with regulated, sustained drug dosing. Considering that the envisioned goal of these integrated platforms is proving to be realistic, this review will discuss how PNM has evolved over the years as a preclinical and clinical amalgamation of nanotechnology with PDT. The encouraging investigations that emphasize the potent synergy between photochemistry and nanotherapeutics, in addition to the growing realization of the value of these multi-faceted theranostic nanoplatforms, will assist in driving PNM formulations into mainstream oncological clinical practice as a necessary tool in the medical armamentarium.
- Published
- 2016
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20. Modelling energy deposition in nanoscintillators to predict the efficiency of the X-ray-induced photodynamic effect.
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Bulin AL, Vasil'ev A, Belsky A, Amans D, Ledoux G, and Dujardin C
- Subjects
- Computer Simulation, Monte Carlo Method, Radiation Dosage, Singlet Oxygen chemistry, Energy Transfer radiation effects, Models, Statistical, Nanoparticles chemistry, Nanoparticles radiation effects, Photochemotherapy methods, X-Rays
- Abstract
Scintillating nanoparticles (NPs) in combination with X-ray or γ-radiation have a great potential for deep-tissue cancer therapy because they can be used to locally activate photosensitizers and generate singlet oxygen in tumours by means of the photodynamic effect. To understand the complex spatial distribution of energy deposition in a macroscopic volume of water loaded with nanoscintillators, we have developed a GEANT4-based Monte Carlo program. We thus obtain estimates of the maximum expected efficiency of singlet oxygen production for various materials coupled to PS, X-ray energies, NP concentrations and NP sizes. A new parameter, ηnano, is introduced to quantify the fraction of energy that is deposited in the NPs themselves, which is crucial for the efficiency of singlet oxygen production but has not been taken into account adequately so far. We furthermore emphasise the substantial contribution of primary interactions taking place in water, particularly under irradiation with high energy photons. The interplay of all these contributions to the photodynamic effect has to be taken into account in order to optimize nanoscintillators for therapeutic applications.
- Published
- 2015
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21. A molecular precursor approach to monodisperse scintillating CeF3 nanocrystals.
- Author
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Mishra S, Jeanneau E, Bulin AL, Ledoux G, Jouguet B, Amans D, Belsky A, Daniele S, and Dujardin C
- Abstract
A series of anhydrous cerium(III) trifluoroacetate complexes with neutral O-donor ligands, namely Ce2(OAc)(TFA)5(DMF)3 (1), Ce(TFA)3(L)x [x = 2, L = THF (2), DMF (3), DMSO (4); x = 1, L = diglyme (5)] and Ce2(TFA)6(DMSO)x(DMF)y [x = 6, y = 0 (6); x = 4, y = 2 (7)] (where OAc = acetate, TFA = trifluoroacetate, THF = tetrahydrofuran, DMF = dimethylformamide, DMSO = dimethylsulphoxide, and diglyme = MeO(C2H4O)2Me] were synthesized and completely characterized by elemental analysis, FT-IR spectroscopy and TG-DTA-MS studies. A partially hydrated complex [Ce(TFA)3(diglyme)(H2O)] (8) was obtained by slow evaporation of the THF solution of anhydrous 5 in the air. The single crystal X-ray diffraction analysis of 1, 3, 4, and 6–8 showed the versatile bonding mode of the TFA ligand (terminal, chelating and bridging). These complexes, on decomposition in 1-octadecene in inert atmosphere, gave CeF3 nanoparticles of 8–11 nm size. The complex 5 proved to be the best precursor in the series because of the ability of the diglyme ligand to act as capping reagent during decomposition to render the CeF3 particles monodisperse in organic solvents. The obtained CeF3 nanoparticles were characterized by FT-IR, EDX analysis and TEM studies and their luminescence and scintillation responses under UV and X-ray excitation were studied and compared with that of CeF3 single crystal.
- Published
- 2013
- Full Text
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