873fe2e49536e3b3ca1b49f5e5c14bba pmc_34944987.pdf 3c3c518ae59d55e3580fc3b146b26a3ff73f5e85 pmc_34944987.pdf f6c7193cbc3fa1ce95d01894dab9525a2818e07f7ca4bcf0f17e21def5b953cc pmc_34944987.pdf Title: Cobaltabis(dicarbollide) ([o-COSAN]-) as Multifunctional Chemotherapeutics: A Prospective Application in Boron Neutron Capture Therapy (BNCT) for Glioblastoma Subject: Purpose: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8'-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. Methods: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. Results: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8'-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. Conclusions: These small molecules, particularly [8,8'-I2-o-COSAN]-, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma. Keywords: boron clusters; metallacarboranes; small molecules; COSAN; boron neutron capture therapy (BNCT); glioblastoma; 3D cell models; in vitro BNCT effect; C. elegans Author: Miquel Nuez-Martinez, Catarina I. G. Pinto, Joana F. Guerreiro, Filipa Mendes, Fernanda Marques, Amanda Muñoz-Juan, Jewel Ann Maria Xavier, Anna Laromaine, Valeria Bitonto, Nicoletta Protti, Simonetta Geninatti Crich, Francesc Teixidor and Clara Viñas Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Dec 21 03:49:39 2021 CET ModDate: Wed Dec 22 08:26:54 2021 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 22 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 6709946 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WSGKXC+VnURWPalladioL Type 1 Custom yes yes no 10 0 LTTEZH+EURM10 Type 1 Builtin yes yes no 15 0 MDEVGO+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 SMLUZN+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 CNQSBF+URWPalladioL-BoldItal Type 1 Custom yes yes no 28 0 HYYHEA+CMBSY10 Type 1 Builtin yes yes no 32 0 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Objects: 984 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Materials Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Instrumentation and Measurements Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Cell Lines Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Metallabis (Dicarbollides) Solutions Preparation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Cell Viability of Monolayer Cultures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: 3-D Spheroid Cultures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Cell Viability of Spheroid Cultures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: In Vivo Studies in C. elegans Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Uptake Experiments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Inductively Coupled Plasma Mass Spectrometry (ICP-MS) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Neutron Irradiation Experiments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Results and Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Children: Item: Title: Physical-Chemical Properties of the Sodium Salts of [o-COSAN]- and [8,8'-I2-o-COSAN]- Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Children: Item: Title: Solubility and Lipophilicity of Na[o-COSAN] and Na[8,8'-I2-o-COSAN] Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Dynamic Light Scattering and Transmission Electron Microscopy Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Infrared and NMR Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Cell Viability Assays Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Effect of Cobaltallabis (Dicarbollides) in GBM Spheroids’ Viability Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: In Vivo Tests with Caenorhabditis elegans (C. elegans) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Cell Uptake Experiments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: BNCT Studies in Glioblastoma Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Info: Title: Cobaltabis(dicarbollide) ([o-COSAN]-) as Multifunctional Chemotherapeutics: A Prospective Application in Boron Neutron Capture Therapy (BNCT) for Glioblastoma Author: Miquel Nuez-Martinez, Catarina I. G. Pinto, Joana F. Guerreiro, Filipa Mendes, Fernanda Marques, Amanda Muñoz-Juan, Jewel Ann Maria Xavier, Anna Laromaine, Valeria Bitonto, Nicoletta Protti, Simonetta Geninatti Crich, Francesc Teixidor and Clara Viñas Subject: Purpose: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8'-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. Methods: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. Results: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8'-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. Conclusions: These small molecules, particularly [8,8'-I2-o-COSAN]-, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma. Keywords: boron clusters; metallacarboranes; small molecules; COSAN; boron neutron capture therapy (BNCT); glioblastoma; 3D cell models; in vitro BNCT effect; C. elegans Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Dec 21 03:49:39 CET 2021 ModDate: Wed Dec 22 08:26:54 CET 2021 ID: 0x45015f9f8f5217bf14f223e85915f924, 0x45015f9f8f5217bf14f223e85915f924 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: HYYHEA+CMBSY10 FontSubset: true FirstChar: 0 LastChar: 0 FontDescriptor: FontName: HYYHEA+CMBSY10 Flags: Symbolic FontBBox: -26, -940, 1332, 825 FontFile: true Font: BaseFont: MDEVGO+URWPalladioL-Ital FontSubset: true FirstChar: 39 LastChar: 121 FontDescriptor: FontName: MDEVGO+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NUFNBZ+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: NUFNBZ+URWPalladioL-Roma Flags: Symbolic 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