Design of naturally inspired jellyfish-shaped cyclo-polylactides to manage osteosarcoma cancer stem cells fate.

We report the synthesis, characterization and biological profile of new bis-triazoled cyclopolylactides (c-PLA, c-PLA-FA, c-PLA-Rhod) obtained by an optimized combination of ROP and click chemistry reactions. Cyclo-PLAhaving a number average molecular weight of 6000 g mol-1 and a polydispersity index of 1.52 was synthetizedby click ring-closure of well-defined ?,?-heterodifunctional linear precursors, followed by quaternarization ofN3-triazole nodes, and subsequent CuAAC with azido-folate and azido-rhodamine yielding jellyfish-shaped c-PLA-FA and c-PLA-Rhod. Salinomycin (Sal) was loaded into jellyfish-shaped c-PLA-FA and c-PLA-Rhod nanoparticles(NPs) by nanoprecipitation, with a good encapsulation efficiency (79% and 84%, respectively) andloading content (7.1% and 7.6%, respectively). The biological studies focused on their antiproliferative effectson osteosarcoma bulk MG63 and cancer stem cells (CSCs). The cycloPLA-based NPs, with a size ranging between125 and 385 nm, killed CSCs and MG63, with a higher efficacy on CSCs; they (unloaded or Sal-loaded) evoked onCSCs a cellular response similar to the payload, with a higher effect than the free Sal. Internalization studiesindicated a fast cellular uptake (within 2 h) and sarcospheres remained fluorescent till 72 h. To the best of ourknowledge, this is the first study reporting anti-CSCs properties of cycloPLA with jellyfish architecture and webelieve could contribute to the development of effective strategies for osteosarcoma targeting.