Zoledronic Acid-containing Nanoparticles With Minimum Premature Release Show Enhanced Activity Against Extraskeletal Tumor

Bisphosphonates are generally used to treat bone diseases, such as bone metastasis from cancer. There is evidence that, through the modification of the pharmacokinetics and biodistribution of bisphosphonates by formulating them into nanoparticles, they may be able to treat extraskeletal tumors. However, many previously reported bisphosphonate nanoparticle formulations show extensive premature release of bisphosphonates. Herein, using zoledronate (Zol), a third-generation bisphosphonate, we developed a new Zol nanoparticle formulation (denoted as Zol-NPs) by encapsulating anionic lipid-coated Zol-calcium nanocomplexes into poly(lactic-co-glycolic) acid nanoparticles emulsified with octadecanoic acid-hydrazone-polyethylene glycol (2000), an acid-sensitive cleavable emulsifying agent. The resultant Zol-NPs, about 180 nm in hydrodynamic diameter, show very limited premature release of Zol (i.e., <5% in 48 h in a simulated physiological condition) and enhanced cytotoxicity to both murine cancer cells and macro...