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lüll Zoledronic Acid-containing Nanoparticles With Minimum Premature Release Show Enhanced Activity Against Extraskeletal Tumor Li X; Valdes SA; Alzhrani RF; Hufnagel S; Hursting SD; Cui ZACS Appl Mater Interfaces 2019[Feb]; 11 (7): 7311-7319Bisphosphonates 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 macrophages. In a mouse model with orthotopically transplanted mammary tumors, Zol-NPs significantly reduced the distribution of Zol in bones, but increased its distribution in tumors. Importantly, Zol-NPs also significantly inhibited tumor growth, whereas the equivalent dose of free Zol did not. This platform technology may be exploited to treat extraskeletal tumors with bisphosphonates.|*Antineoplastic Agents/chemistry/pharmacokinetics/pharmacology[MESH]|*Mammary Neoplasms, Experimental/drug therapy/genetics/metabolism/pathology[MESH]|*Nanoparticles/chemistry/therapeutic use[MESH]|*Zoledronic Acid/chemistry/pharmacokinetics/pharmacology[MESH]|Animals[MESH]|Cell Line, Tumor[MESH]|Delayed-Action Preparations/chemistry/pharmacokinetics/pharmacology[MESH]|Female[MESH]|Mice[MESH]|Mice, Transgenic[MESH]|Tissue Distribution[MESH] |