Abstract
Spatiotemporal control of drug delivery is important for a number of medical applications and may be achieved using polymersome nanoparticles (PMs). Wnt signalling is a molecular pathway activated in various physiological processes, including bone repair, that requires precise control of activation. Here, we hypothesise that PMs can be stably loaded with a small molecule Wnt agonist, 6-bromoindirubin-3′-oxime (BIO), and activate Wnt signalling promoting the osteogenic differentiation in human primary bone marrow stromal cells (BMSCs). We showed that BIO-PMs induced a 40% increase in Wnt signaling activation in reporter cell lines without cytotoxicity induced by free BIO. BMSCs incubated with BIO-PMs showed a significant up-regulation of the Wnt target gene AXIN2 (14 ± 4 fold increase, P < 0.001) and a prolonged activation of the osteogenic gene RUNX2. We conclude that BIO-PMs could represent an innovative approach for the controlled activation of Wnt signaling for promoting bone regeneration after fracture.
Highlights
Controlled, spatiotemporal delivery of therapeutic molecules is a major goal in medicine that may be achieved by the use of nanosized carriers.[1]
We found a dose-dependent decrease in cell viability in response to free BIO (57 ± 10% of cell survival at an extracellular concentration of 5 μM), but no decrease in cell viability in response to BIO-polymersome nanoparticles (PMs), even at concentrations that induced a decline in pathway activation (Figure 5, B and C)
We have demonstrated that; (i) PMs can carry high concentrations of a relatively water-insoluble activator of Wnt signalling, (ii) PMs are taken up by cells important in the bone reparative process, and (iii) that activation of canonical Wnt signalling and osteogenic differentiation can be achieved while avoiding the toxicity that BIO causes when delivered with no carrier
Summary
Controlled, spatiotemporal delivery of therapeutic molecules is a major goal in medicine that may be achieved by the use of nanosized carriers.[1]. BIO-PMs induce Wnt signalling in a dose-dependent manner To determine whether PM-delivered BIO was able to induce Wnt signalling we incubated reporter cells with PBS-, DMF-dissolved PMs or free BIO for 24 hours and measured the level of Wnt activation by luciferase production (Figure 4, A).
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call