title: Mesoporous silica nanoparticles as drug delivery systems for targeted inhibition of Notch signaling in cancer.
abstract: Notch signaling, a key regulator of stem cells, is frequently overactivated in cancer. It is often linked to aggressive forms of cancer, evading standard treatment highlighting Notch as an exciting therapeutic target. Notch is in principle "druggable" by γ-secretase inhibitors (GSIs), inhibitory peptides and antibodies, but clinical use of Notch inhibitors is restricted by severe side effects and there is a demand for alternative cancer-targeted therapy. Here, we present a novel approach, using imagable mesoporous silica nanoparticles (MSNPs) as vehicles for targeted delivery of GSIs to block Notch signaling. Drug-loaded particles conjugated to targeting ligands induced cell-specific inhibition of Notch activity in vitro and exhibited enhanced tumor retainment with significantly improved Notch inhibition and therapeutic outcome in vivo. Oral administration of GSI-MSNPs controlled Notch activity in intestinal stem cells further supporting the in vivo applicability of MSNPs for GSI delivery. MSNPs showed tumor accumulation and targeting after systemic administration. MSNPs were biocompatible, and particles not retained within the tumors, were degraded and eliminated mainly by renal excretion. The data highlights MSNPs as an attractive platform for targeted drug delivery of anticancer drugs with otherwise restricted clinical application, and as interesting constituents in the quest for more refined Notch therapies.
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors.forename: Veronika
authors.initials: V
authors.lastname: Mamaeva
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Rosenholm
authors.forename: Laurel Tabe
authors.initials: LT
authors.lastname: Bate-Eya
authors.forename: Lotta
authors.initials: L
authors.lastname: Bergman
authors.forename: Emilia
authors.initials: E
authors.lastname: Peuhu
authors.forename: Alain
authors.initials: A
authors.lastname: Duchanoy
authors.forename: Lina E
authors.initials: LE
authors.lastname: Fortelius
authors.forename: Sebastian
authors.initials: S
authors.lastname: Landor
authors.forename: Diana M
authors.initials: DM
authors.lastname: Toivola
authors.forename: Mika
authors.initials: M
authors.lastname: Lindén
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sahlgren
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use*; D016062:Porosity; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D051880:Receptors, Notch; D012822:Silicon Dioxide; D053829:Amyloid Precursor Protein Secretases