期刊
MOLECULAR THERAPY
卷 19, 期 8, 页码 1538-1546出版社
CELL PRESS
DOI: 10.1038/mt.2011.105
关键词
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资金
- Academy of Finland [128477, 131034, 126161]
- Finnish Cancer Organizations
- Sigrid Juselius foundations
- European Union
- Tor, Joe, and and Pentti Borg foundation
- Abo Akademi cancer funds
- Academy of Finland (AKA) [126161, 128477, 131034, 126161, 128477, 131034] Funding Source: Academy of Finland (AKA)
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.-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.
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