Alendronate Pt^IV Prodrug Amphiphile for Enhanced Chemotherapy Targeting and Bone Destruction Inhibition in Osteosarcoma

Abstract Chemotherapy remains the primary treatment method for osteosarcoma after surgery. However, the lack of selectivity of chemotherapy for osteosarcoma leads to unpredictable therapeutic effects, undesirable side effects, and drug resistance. A platinum(IV) (Pt^IV) prodrug amphiphile (ALN‐Pt^IV‐Lipo) covalently bound to alendronate (ALN) and a lipid tail is designed to overcome these limitations. ALN‐Pt^IV‐Lipo can self‐assemble into Pt^IV lipid nanoparticles (APt^IV) for osteosarcoma targeting chemotherapy and bone destruction inhibition. It is demonstrated that APt^IV achieved an eightfold increase in the eradication of osteosarcoma cells compared to cisplatin and threefold selective inhibition of osteosarcoma cells over breast cancer cells via APt^IV in vitro. After intravenous injection, APt^IV effectively accumulates at the osteosarcoma site in vivo, resulting in significantly suppressed primary osteosarcoma growth, and alleviation of bone destruction. Therefore, APt^IV delivers a promising solution for enhanced chemotherapy targeting and bone destruction inhibition in osteosarcoma.