Reverse Microemulsion-Based Synthesis of (Bis)phosphonate–Metal Materials with Controllable Physical Properties: An Example Using Zoledronic Acid–Calcium Complexes

The development of phosphonate-metal materials is tightly related to the advancement in their synthesis methods. Herein, using zoledronic acid (Zol), a bisphosphonate (bioacitve phosphonate with a "P-C-P" structure), and calcium as model molecules, we applied the reverse microemulsion (RM) method to synthesize a series of Zol-Ca complexes. We comprehensively (i) studied the relationship between RM conditions, including the component ratio of RM, cosurfactants, reaction time, reactant concentration, reaction temperature, and the presence of a phospholipid, 1, 2-dioleoyl-sn-glycero-3-phosphate acid (DOPA), and the physical properties of the complexes synthesized (i.e., shape, size, uniformity, monodispersity, and hydrophilicity/hydrophobicity) and (ii) explored the underlying mechanisms. To evaluate the biomedical application potential of the Zol-Ca complexes synthesized, one type of hydrophobic, DOPA-coated spherical Zol-Ca complexes (denoted as Zol-Ca@DOPA) was formulated into a PEGylated lipid-based nanoparticle formulation (i.e., Zol-Ca@bilipid NPs, ∼24 nm in diameter). In a mouse model with orthotopic mammary tumors, the Zol-Ca@bilipid NPs significantly enhanced the distribution of Zol in tumors, as compared to free Zol. It is expected that the RM-based synthesis of (bis)phosphonate-metal materials with controllable physical properties will help expand their applications.