Inhibiting Notch Activity in Breast Cancer Stem Cells by Glucose Functionalized Nanoparticles Carrying γ-secretase Inhibitors

• Published in: Molecular therapy Vol. 24; no. 5; pp. 926 - 936
• Main Authors: Mamaeva, Veronika, Niemi, Rasmus, Beck, Michaela, Özliseli, Ezgi, Desai, Diti, Landor, Sebastian, Gronroos, Tove, Kronqvist, Pauliina, Pettersen, Ina K N, McCormack, Emmet, Rosenholm, Jessica M, Linden, Mika, Sahlgren, Cecilia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2016; Nature Publishing Group
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Cell Line, Tumor; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Female; Glucose - metabolism; Humans; MCF-7 Cells; Medicin och hälsovetenskap; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Neoplastic Stem Cells - drug effects; Original; Receptors, Notch - metabolism; Signal Transduction - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1038/mt.2016.42

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.