title: Inhibiting Notch Activity in Breast Cancer Stem Cells by Glucose Functionalized Nanoparticles Carrying γ-secretase Inhibitors.
abstract: Cancer stem cells (CSCs) are a challenge in cancer treatment due to their therapy resistance. We demonstrated that enhanced Notch signaling in breast cancer promotes self-renewal of CSCs that display high glycolytic activity and aggressive hormone-independent tumor growth in vivo. We took advantage of the glycolytic phenotype and the dependence on Notch activity of the CSCs and designed nanoparticles to target the CSCs. Mesoporous silica nanoparticles were functionalized with glucose moieties and loaded with a γ-secretase inhibitor, a potent interceptor of Notch signaling. Cancer cells and CSCs in vitro and in vivo efficiently internalized these particles, and particle uptake correlated with the glycolytic profile of the cells. Nanoparticle treatment of breast cancer transplants on chick embryo chorioallantoic membranes efficiently reduced the cancer stem cell population of the tumor. Our data reveal that specific CSC characteristics can be utilized in nanoparticle design to improve CSC-targeted drug delivery and therapy.
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Veronika
authors.initials: V
authors.lastname: Mamaeva
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Niemi
authors.affiliation: Inorganic Chemistry II, Ulm University, Ulm, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Beck
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
authors.forename: Ezgi
authors.initials: E
authors.lastname: Özliseli
authors.affiliation: Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
authors.forename: Diti
authors.initials: D
authors.lastname: Desai
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Landor
authors.affiliation: Turku PET Centre, University of Turku, Turku, Finland.|Medicity Research Laboratories, University of Turku, Turku, Finland.
authors.forename: Tove
authors.initials: T
authors.lastname: Gronroos
authors.affiliation: Department of Pathology, University of Turku, Turku, Finland.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Kronqvist
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Ina K N
authors.initials: IK
authors.lastname: Pettersen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Medicine, Haematology Section, Haukeland University Hospital, Bergen, Norway.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.affiliation: Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Rosenholm
authors.affiliation: Inorganic Chemistry II, Ulm University, Ulm, Germany.
authors.forename: Mika
authors.initials: M
authors.lastname: Linden
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.|Department of Biomedical Engineering, Technical University of Eindhoven, Institute for Complex Molecular Systems, Eindhoven, the Netherlands.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sahlgren
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D005947:Glucose