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.

Targeting cancer stem cells by using the nanoparticles

“…109,110 They demonstrate that these drug-conjugated MSNPs have significantly enhanced cytotoxicity by selective targeting the Notch signaling in various cancer cell types, such as cervical and breast cancer cells. 111 In addition, Steg et al have developed Jagged1 (Notch ligand) siRNAs-loaded chitosan NPs, which selectively inhibit ovarian cancer both in vitro and in vivo by selectively targeting Notch ligand Jagged1. 112 Despite the number of in vitro studies' evidences for the therapeutic efficiency and selectivity of drug-conjugated NPs targeting Notch signaling, valid in vivo models are still largely lacking.…”

Targeted modulation of cell differentiation in distinct regions of the gastrointestinal tract via oral administration of differently PEG-PEI functionalized mesoporous silica nanoparticles

“…30,31 We also evaluated the effect on small intestinal stem cell differentiation by oral delivery of γ-secretase inhibitorloaded FA-PEI-MSNs and demonstrated enhanced cell fate switching as compared to free drug. 30 However, the effect of different surface functionalizations, the interaction of the MSNs with the intestinal epithelium, and the effect in different GI regions were not evaluated.…”

“…30,31 We also evaluated the effect on small intestinal stem cell differentiation by oral delivery of γ-secretase inhibitorloaded FA-PEI-MSNs and demonstrated enhanced cell fate switching as compared to free drug. 30 However, the effect of different surface functionalizations, the interaction of the MSNs with the intestinal epithelium, and the effect in different GI regions were not evaluated. In this study, we took advantage of the same model system to evaluate the potential of a series of functionalized MSNs as drug carriers for celltargeted drug delivery through the oral route, with focus on the effect of the different combinations of PEI, PEG, and FA surface modifications on intestinal targeting.…”

Poly-l-lysine Functionalized Large Pore Cubic Mesostructured Silica Nanoparticles as Biocompatible Carriers for Gene Delivery

“…Polymer-and liposome-based nanoparticles are nowadays among the most commonly used materials for gene delivery. 1,3,4 Recently, however, silica-based materials have emerged as new candidates for targeted drug delivery applications, 5,6 which can offer distinct advantages over other materials. Silica is usually less toxic compared to polycations.…”