Hybrid Self-Assembling Nanoparticles Encapsulating Zoledronic Acid: A Strategy for Fostering Their Clinical Use

Self-assembling nanoparticles (SANPs) promise an effective delivery of bisphosphonates ormicroRNAs in the treatment of glioblastoma (GBM) and are obtained through the sequential mixingof four components immediately before use. The self-assembling approach facilitates technologytransfer, but the complexity of the SANP preparation protocol raises significant concerns in the clinicalsetting due to the high risk of human errors during the procedure. In this work, it was hypothesizedthat the SANP preparation protocol could be simplified by using freeze-dried formulations. Anin-depth thermodynamic study was conducted on solutions of different cryoprotectants, namelysucrose, mannitol and trehalose, to test their ability to stabilize the produced SANPs. In addition,the ability of SANPs to deliver drugs after lyophilization was assessed on selected formulationsencapsulating zoledronic acid in vitro in the T98G GBM cell line and in vivo in an orthotopic mousemodel. Results showed that, after lyophilization optimization, freeze-dried SANPs encapsulatingzoledronic acid could retain their delivery ability, showing a significant inhibition of T98G cellgrowth both in vitro and in vivo. Overall, these results suggest that freeze-drying may help boost theindustrial development of SANPs for the delivery of drugs to the brain.