14 Generation of χ-secretase inhibitor-loaded PLGA-FE3o4 magnetic nanoparticles

Stem cell derived myogenic progeny play important roles in the pathophysiological processes of various vascular disorders, such as arteriosclerosis, atherosclerosis, and in-stent restenosis. Targeting these cells is an attractive therapeutic strategy for treating vascular remodelling. However, while polymer-coated DES have significantly reduced the incident of in-stent restenosis, current DESs lack the fundamental capacity for (i) adjustment of the drug dose and release kinetics and the (ii) ability to replenish the stent with a new drug on depletion. This limitation can be overcome by a strategy combining magnetic targeting via a uniform field-induced magnetization effect and a biocompatible magnetic nanoparticle (MNP) formulation designed for efficient entrapment and delivery of specific drugs that target the resident vascular stem cell source of the SMC. Magnetic nanoparticles (MNP’s) containing magnetite (Fe3O4) were fabricated, polymer coated with poly (Dl-lactide-co-glycolide) polyvinyl alcohol [PLGA-PVA] and loaded with a χ-secretase inhibitor (GSI) of Notch signalling, DAPT using an oil in water emulsification technique. The free GSI’s and GSI-loaded MNP’s were assessed for drug release, the efficacy at controlling mesenchymal stem cell (MSC) growth (proliferation and apoptosis) and inhibiting myogenic differentiation under magnetic and non-magnetic conditions. The DAPT-loaded MNPs had an average hydrodynamic diameter of 351 d.nm Up to 40% of drug was released from MNPs within 48 hour rising to 65% after 1 week under magnetic conditions. The Notch ligand, Jagged1 increased Hey1 mRNA levels and promoted myogenic differentiation of MSCs in vitro by increasing SMC differentiation markers, myosin heavy chain 11 (Myh11) and calponin1 (CNN1) expression, respectively. This effect was significantly attenuated following treatment of cells with MNP’s loaded with DAPT when compared to unloaded MNP’s. Notch GSI -loaded magnetic nanoparticles are functional at targeting vascular stem cells in vitro.