Prussian Blue nanoparticles: An FDA-approved substance that may quickly degrade at physiological pH

Prussian blue (PB) is a coordination polymer based on the Fe^2+…CN^…Fe³⁺ sequence. It is an FDA-approved drug, intended for oral use at the acidic pH of the stomach and of most of the intestine track. However, based on FDA approval, a huge number of papers proposed the use of PB nanoparticles (PBnp) under "physiological conditions", meaning pH buffered at 7.4 and high saline concentration. While most of these papers report that PBnp are stable at this pH, a small number of papers describes instead PBnp degradation at the same or similar pH values, i.e. in the 7-8 range. Here we give a definitively clear picture: PBnp are intrinsically unstable at pH ≥ 7, degrading with the fast disappearance of their 700 nm absorption band, due to the formation of OH^- complexes from the labile Fe³⁺ centers. However, we show also that the presence of a polymeric coating (PVP) can protect PBnp at pH 7.4 for over 24 h. Moreover, we demonstrate that when "physiological conditions" include serum, a protein corona is rapidly formed on PBnp, efficiently avoiding degradation. We also show that the viability of PBnp-treated EA.hy926, NCI-H1299, and A549 cells is not affected in a wide range of conditions that either prevent or promote PBnp degradation.