Overcoming Therapeutic Failure in Osteosarcoma via Apatinib-Encapsulated Hydrophobic Poly (ester amide) Nanoparticles

Anti-angiogenesis tyrosine kinase inhibitors (TKIs) have been proved to be effective in prolonging progression-free survival in advanced osteosarcoma. However, osteosarcoma stem-like cells persist long term and ultimately cause disease recurrence and therapy resistance. Here, we reveal that inefficient accumulation of Apatinib, an anti-angiogenesis TKI, induces the expression of ribosome-associated genes in osteosarcoma, which confers apoptosis resistance. An engineered nanoscale delivery system based on hydrophobic poly (ester amide) has been established to effectively deliver Apatinib to improve the treatment. Notably, the considerable uptake by osteosarcoma cells enables this nanodrug to distribute increasingly inside the tumor. Furthermore, the delivered nano-Apatinib can suppress osteosarcoma stemness and enhance osteosarcoma stem-like cell apoptosis, which overcomes the crucial bottleneck of the unfavorable stem-like cell residue for TKI therapy. Importantly, nano-Apatinib significantly inhibits the osteosarcoma stem-like cells-derived tumor growth in contrast with free Apatinib, with minimal side effects. These results suggest that this Apatinib loaded nano delivery system may serve as a promising strategy to solve the issue of TKI therapeutic resistance existing in advanced osteosarcoma.