Nanoparticle-directed and ionically forced polyphosphate coacervation: a versatile and reversible core-shell system for drug delivery

Abstract

A drug encapsulation/delivery system using a novel principle is described that is based on an intra-particle migration of calcium ions between a central Ca²⁺-enriched nanoparticle core and the surrounding shell compartment. The supply of Ca²⁺ is needed for the formation of a coacervate shell around the nanoparticles, acting as the core of drug-loadable core-shell particles, using the physiological inorganic polymer polyphosphate (polyP). This polyanion has the unique property to form, at an alkaline pH and in the presence of a stoichiometric surplus of calcium ions, water-insoluble and stabile amorphous nanoparticles. At neutral pH a coacervate, the biologically active form of the polymer, is obtained that is composed of polyP and Ca²⁺. The drug-loaded core-shell particles, built from the Ca-polyP core and the surrounding Ca-polyP shell, were fabricated in two successive steps. First, the formation of the nanoparticle core at pH 10 and a superstoichiometric 2:1 molar ratio between CaCl₂ and Na-polyP into which dexamethasone, as a phosphate derivative, was incorporated. Second, the preparation of the coacervate shell, loaded with ascorbic acid, by exposure of the Ca-polyP core to soluble Na-polyP and L-ascorbate (calcium salt). EDX analysis revealed that during this step the Ca²⁺ ions required for coacervate formation migrate from the Ca-polyP core (with a high Ca:P ratio) to the shell. Electron microscopy of the particles show an electron-dense 150-200 nm sized core surrounded by a less sharply delimited electron-sparse shell. The core-shell particles exhibited strong osteogenic activity in vitro, based on the combined action of polyP and of dexamethasone and ascorbic acid, which reversibly bind to the anionic polyP via ionic Ca²⁺ bonds. Drug release from the particles occurs after contact with a peptide/protein-containing serum, a process which is almost complete after 10 days and accompanied by the conversion of the nanoparticles into a coacervate. Human osteosarcoma SaOS-2 cells cultivated onto or within an alginate hydrogel matrix showed increased growth/viability and mineralization when the hybrid particles containing dexamethasone and ascorbic acid were embedded in the matrix. The polyP-based core-shell particles have the potential to become a suitable, pH-responsive drug encapsulation/release system, especially for bone, cartilage and wound healing.