Live Microscopy of Multicellular Spheroids with the Multimodal Near-Infrared Nanoparticles Reveals Differences in Oxygenation Gradients
Assessment of hypoxia, nutrients, metabolite gradients, and other hallmarks of the tumor microenvironment within 3D multicellular spheroid and organoid models represents a challenging analytical task. Here, we report red/near-infrared (NIR) emitting cell staining with O2-sensitive nanoparticles, whi...
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| Veröffentlicht in: | ACS nano Jg. 18; H. 19; S. 12168 - 12186 |
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| Sprache: | Englisch |
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14.05.2024
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| Abstract | Assessment of hypoxia, nutrients, metabolite gradients, and other hallmarks of the tumor microenvironment within 3D multicellular spheroid and organoid models represents a challenging analytical task. Here, we report red/near-infrared (NIR) emitting cell staining with O2-sensitive nanoparticles, which enable measurements of spheroid oxygenation on a conventional fluorescence microscope. Nanosensor probes, termed “MMIR” (multimodal infrared), incorporate an NIR O2-sensitive metalloporphyrin (PtTPTBPF) and deep red aza-BODIPY reference dyes within a biocompatible polymer shell, allowing for oxygen gradient quantification via fluorescence ratio and phosphorescence lifetime readouts. We optimized staining techniques and evaluated the nanosensor probe characteristics and cytotoxicity. Subsequently, we applied nanosensors to the live spheroid models based on HCT116, DPSCs, and SKOV3 cells, at rest, and treated with drugs affecting cell respiration. We found that the growth medium viscosity, spheroid size, and formation method influenced spheroid oxygenation. Some spheroids produced from HCT116 and dental pulp stem cells exhibited “inverted” oxygenation gradients, with higher core oxygen levels than the periphery. This contrasted with the frequently encountered “normal” gradient of hypoxia toward the core caused by diffusion. Further microscopy analysis of spheroids with an “inverted” gradient demonstrated metabolic stratification of cells within spheroids: thus, autofluorescence FLIM of NAD(P)H indicated the formation of a glycolytic core and localization of OxPhos-active cells at the periphery. Collectively, we demonstrate a strong potential of NIR-emitting ratiometric nanosensors for advanced microscopy studies targeting live and quantitative real-time monitoring of cell metabolism and hypoxia in complex 3D tissue models. |
|---|---|
| AbstractList | Assessment of hypoxia,
nutrients, metabolite gradients, and other
hallmarks of the tumor microenvironment within 3D multicellular spheroid
and organoid models represents a challenging analytical task. Here,
we report red/near-infrared (NIR) emitting cell staining with O2-sensitive nanoparticles, which enable measurements of spheroid
oxygenation on a conventional fluorescence microscope. Nanosensor
probes, termed “MMIR” (multimodal infrared), incorporate
an NIR O2-sensitive metalloporphyrin (PtTPTBPF) and deep
red aza-BODIPY reference dyes within a biocompatible polymer shell,
allowing for oxygen gradient quantification via fluorescence ratio
and phosphorescence lifetime readouts. We optimized staining techniques
and evaluated the nanosensor probe characteristics and cytotoxicity.
Subsequently, we applied nanosensors to the live spheroid models based
on HCT116, DPSCs, and SKOV3 cells, at rest, and treated with drugs
affecting cell respiration. We found that the growth medium viscosity,
spheroid size, and formation method influenced spheroid oxygenation.
Some spheroids produced from HCT116 and dental pulp stem cells exhibited
“inverted” oxygenation gradients, with higher core oxygen
levels than the periphery. This contrasted with the frequently encountered
“normal” gradient of hypoxia toward the core caused
by diffusion. Further microscopy analysis of spheroids with an “inverted”
gradient demonstrated metabolic stratification of cells within spheroids:
thus, autofluorescence FLIM of NAD(P)H indicated the formation of
a glycolytic core and localization of OxPhos-active cells at the periphery.
Collectively, we demonstrate a strong potential of NIR-emitting ratiometric
nanosensors for advanced microscopy studies targeting live and quantitative
real-time monitoring of cell metabolism and hypoxia in complex 3D
tissue models. Assessment of hypoxia, nutrients, metabolite gradients, and other hallmarks of the tumor microenvironment within 3D multicellular spheroid and organoid models represents a challenging analytical task. Here, we report red/near-infrared (NIR) emitting cell staining with O2-sensitive nanoparticles, which enable measurements of spheroid oxygenation on a conventional fluorescence microscope. Nanosensor probes, termed "MMIR" (multimodal infrared), incorporate an NIR O2-sensitive metalloporphyrin (PtTPTBPF) and deep red aza-BODIPY reference dyes within a biocompatible polymer shell, allowing for oxygen gradient quantification via fluorescence ratio and phosphorescence lifetime readouts. We optimized staining techniques and evaluated the nanosensor probe characteristics and cytotoxicity. Subsequently, we applied nanosensors to the live spheroid models based on HCT116, DPSCs, and SKOV3 cells, at rest, and treated with drugs affecting cell respiration. We found that the growth medium viscosity, spheroid size, and formation method influenced spheroid oxygenation. Some spheroids produced from HCT116 and dental pulp stem cells exhibited "inverted" oxygenation gradients, with higher core oxygen levels than the periphery. This contrasted with the frequently encountered "normal" gradient of hypoxia toward the core caused by diffusion. Further microscopy analysis of spheroids with an "inverted" gradient demonstrated metabolic stratification of cells within spheroids: thus, autofluorescence FLIM of NAD(P)H indicated the formation of a glycolytic core and localization of OxPhos-active cells at the periphery. Collectively, we demonstrate a strong potential of NIR-emitting ratiometric nanosensors for advanced microscopy studies targeting live and quantitative real-time monitoring of cell metabolism and hypoxia in complex 3D tissue models.Assessment of hypoxia, nutrients, metabolite gradients, and other hallmarks of the tumor microenvironment within 3D multicellular spheroid and organoid models represents a challenging analytical task. Here, we report red/near-infrared (NIR) emitting cell staining with O2-sensitive nanoparticles, which enable measurements of spheroid oxygenation on a conventional fluorescence microscope. Nanosensor probes, termed "MMIR" (multimodal infrared), incorporate an NIR O2-sensitive metalloporphyrin (PtTPTBPF) and deep red aza-BODIPY reference dyes within a biocompatible polymer shell, allowing for oxygen gradient quantification via fluorescence ratio and phosphorescence lifetime readouts. We optimized staining techniques and evaluated the nanosensor probe characteristics and cytotoxicity. Subsequently, we applied nanosensors to the live spheroid models based on HCT116, DPSCs, and SKOV3 cells, at rest, and treated with drugs affecting cell respiration. We found that the growth medium viscosity, spheroid size, and formation method influenced spheroid oxygenation. Some spheroids produced from HCT116 and dental pulp stem cells exhibited "inverted" oxygenation gradients, with higher core oxygen levels than the periphery. This contrasted with the frequently encountered "normal" gradient of hypoxia toward the core caused by diffusion. Further microscopy analysis of spheroids with an "inverted" gradient demonstrated metabolic stratification of cells within spheroids: thus, autofluorescence FLIM of NAD(P)H indicated the formation of a glycolytic core and localization of OxPhos-active cells at the periphery. Collectively, we demonstrate a strong potential of NIR-emitting ratiometric nanosensors for advanced microscopy studies targeting live and quantitative real-time monitoring of cell metabolism and hypoxia in complex 3D tissue models. Assessment of hypoxia, nutrients, metabolite gradients, and other hallmarks of the tumor microenvironment within 3D multicellular spheroid and organoid models represents a challenging analytical task. Here, we report red/near-infrared (NIR) emitting cell staining with O2-sensitive nanoparticles, which enable measurements of spheroid oxygenation on a conventional fluorescence microscope. Nanosensor probes, termed “MMIR” (multimodal infrared), incorporate an NIR O2-sensitive metalloporphyrin (PtTPTBPF) and deep red aza-BODIPY reference dyes within a biocompatible polymer shell, allowing for oxygen gradient quantification via fluorescence ratio and phosphorescence lifetime readouts. We optimized staining techniques and evaluated the nanosensor probe characteristics and cytotoxicity. Subsequently, we applied nanosensors to the live spheroid models based on HCT116, DPSCs, and SKOV3 cells, at rest, and treated with drugs affecting cell respiration. We found that the growth medium viscosity, spheroid size, and formation method influenced spheroid oxygenation. Some spheroids produced from HCT116 and dental pulp stem cells exhibited “inverted” oxygenation gradients, with higher core oxygen levels than the periphery. This contrasted with the frequently encountered “normal” gradient of hypoxia toward the core caused by diffusion. Further microscopy analysis of spheroids with an “inverted” gradient demonstrated metabolic stratification of cells within spheroids: thus, autofluorescence FLIM of NAD(P)H indicated the formation of a glycolytic core and localization of OxPhos-active cells at the periphery. Collectively, we demonstrate a strong potential of NIR-emitting ratiometric nanosensors for advanced microscopy studies targeting live and quantitative real-time monitoring of cell metabolism and hypoxia in complex 3D tissue models. Assessment of hypoxia, nutrients, metabolite gradients, and other hallmarks of the tumor microenvironment within 3D multicellular spheroid and organoid models represents a challenging analytical task. Here, we report red/near-infrared (NIR) emitting cell staining with O -sensitive nanoparticles, which enable measurements of spheroid oxygenation on a conventional fluorescence microscope. Nanosensor probes, termed "MMIR" (multimodal infrared), incorporate an NIR O -sensitive metalloporphyrin (PtTPTBPF) and deep red aza-BODIPY reference dyes within a biocompatible polymer shell, allowing for oxygen gradient quantification via fluorescence ratio and phosphorescence lifetime readouts. We optimized staining techniques and evaluated the nanosensor probe characteristics and cytotoxicity. Subsequently, we applied nanosensors to the live spheroid models based on HCT116, DPSCs, and SKOV3 cells, at rest, and treated with drugs affecting cell respiration. We found that the growth medium viscosity, spheroid size, and formation method influenced spheroid oxygenation. Some spheroids produced from HCT116 and dental pulp stem cells exhibited "inverted" oxygenation gradients, with higher core oxygen levels than the periphery. This contrasted with the frequently encountered "normal" gradient of hypoxia toward the core caused by diffusion. Further microscopy analysis of spheroids with an "inverted" gradient demonstrated metabolic stratification of cells within spheroids: thus, autofluorescence FLIM of NAD(P)H indicated the formation of a glycolytic core and localization of OxPhos-active cells at the periphery. Collectively, we demonstrate a strong potential of NIR-emitting ratiometric nanosensors for advanced microscopy studies targeting live and quantitative real-time monitoring of cell metabolism and hypoxia in complex 3D tissue models. |
| Author | Heymans, Nina Nobis, Max Borisov, Sergey M. Pinheiro, Cláudio Hendrix, An Debruyne, Angela C. Dmitriev, Ruslan I. Okkelman, Irina A. |
| AuthorAffiliation | Ghent University Institute of Analytical Chemistry and Food Chemistry Intravital Imaging Expertise Center, VIB Center for Cancer Biology Cancer Research Institute Ghent (CRIG) Tissue Engineering and Biomaterials Group, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences Laboratory of Experimental Cancer Research, Department of Human Structure and Repair Ghent Light Microscopy Core |
| AuthorAffiliation_xml | – name: Tissue Engineering and Biomaterials Group, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences – name: Cancer Research Institute Ghent (CRIG) – name: Ghent University – name: Laboratory of Experimental Cancer Research, Department of Human Structure and Repair – name: Ghent Light Microscopy Core – name: Institute of Analytical Chemistry and Food Chemistry – name: Intravital Imaging Expertise Center, VIB Center for Cancer Biology |
| Author_xml | – sequence: 1 givenname: Angela C. surname: Debruyne fullname: Debruyne, Angela C. organization: Tissue Engineering and Biomaterials Group, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences – sequence: 2 givenname: Irina A. surname: Okkelman fullname: Okkelman, Irina A. organization: Ghent University – sequence: 3 givenname: Nina surname: Heymans fullname: Heymans, Nina organization: Tissue Engineering and Biomaterials Group, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences – sequence: 4 givenname: Cláudio surname: Pinheiro fullname: Pinheiro, Cláudio organization: Cancer Research Institute Ghent (CRIG) – sequence: 5 givenname: An surname: Hendrix fullname: Hendrix, An organization: Cancer Research Institute Ghent (CRIG) – sequence: 6 givenname: Max orcidid: 0000-0002-1861-1390 surname: Nobis fullname: Nobis, Max organization: Intravital Imaging Expertise Center, VIB Center for Cancer Biology – sequence: 7 givenname: Sergey M. orcidid: 0000-0001-9318-8273 surname: Borisov fullname: Borisov, Sergey M. email: sergey.borisov@tugraz.at organization: Institute of Analytical Chemistry and Food Chemistry – sequence: 8 givenname: Ruslan I. orcidid: 0000-0002-0347-8718 surname: Dmitriev fullname: Dmitriev, Ruslan I. email: Ruslan.dmitriev@ugent.be organization: Ghent University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38687976$$D View this record in MEDLINE/PubMed |
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| Keywords | hypoxia nanoparticles cancer FLIM oxygenation fluorescence microscopy multicellular spheroids |
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| SubjectTerms | Humans Infrared Rays Metalloporphyrins - chemistry Metalloporphyrins - pharmacology Microscopy, Fluorescence Nanoparticles - chemistry Oxygen - chemistry Oxygen - metabolism Spheroids, Cellular - drug effects Spheroids, Cellular - metabolism |
| Title | Live Microscopy of Multicellular Spheroids with the Multimodal Near-Infrared Nanoparticles Reveals Differences in Oxygenation Gradients |
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