Angiogenic and Osteogenic Coupling Effects of Deferoxamine-Loaded Poly(lactide-co-glycolide)-Poly(ethylene glycol)-Poly(lactide-co-glycolide) Nanoparticles

Angiogenesis and osteogenesis coupling processes are essential for bone regeneration, and human bone marrow stromal cells (hBMSCs) along with endothelial cells (ECs) are crucial participants. Deferoxamine (DFO), a hypoxia-mimetic agent, could activate the hypoxia-inducible factor (HIF)-1α signaling pathway and trigger angiogenic and osteogenic effects in these cells. However, the lifetime of DFO is very short, thus a suitable delivery system is urgently needed. In this study, we encapsulated DFO in Poly(lactide-co-glycolide)-Poly(ethylene glycol)-Poly(lactide-co-glycolide) (PLGA-PEG-PLGA) nanoparticles (DFO-loaded NPs) to realize its long-term angiogenic and osteogenic bioactivities. Surface morphology, size, size distribution of DFO-loaded NPs as well as DFO loading content (LC), encapsulation efficiency (EE) and release profile were systematically evaluated. When hBMSCs were exposed to the vehicle with DFO concentration of 100 μM, cells showed good viability, increased HIF-1α expression and enhanced vascular endothelial growth factor (VEGF) secretion. The transcriptional levels of the angiogenic and osteogenic genes were also upregulated. Moreover, promoted alkaline phosphatase (ALP) activity further confirmed better osteogenic differentiation. Similarly, angiogenic activity of human umbilical vein endothelial cells (HUVECs) were enhanced after the addition of DFO-loaded NPs, evidenced by increased angiogenic genes expressions and tube formation. Taken together, DFO-loaded NPs could provide a sustained supply of DFO, with its angiogenic and osteogenic coupling effects preserved, which extends the potential of this system for bone defect repair.