3D-printing magnesium-polycaprolactone loaded with melatonin inhibits the development of osteosarcoma by regulating cell-in-cell structures.

Melatonin has been proposed as a potent anticarcinogen presents a short half-life for osteosarcoma (OS). Cell-in-cell (CIC) structures play a role in the development of malignant tumors by changing the tumor cell energy metabolism. This study developed a melatonin-loaded 3D printed magnesium-polycaprolactone (Mg-PCL) scaffold and investigated its effect and molecular mechanism on CIC in OS. Mg-PCL scaffold was prepared by 3D-printing and its characteristic was determined. The effect and molecular mechanism of Mg-PCL scaffold as well as melatonin-loaded Mg-PCL on OS growth and progression were investigated in vivo and in vitro. We found that melatonin receptor 1 (MT1) and CIC expressions were increased in OS tissues and cells. Melatonin treatment inhibit the key CIC pathway, Rho/ROCK, through the cAMP/PKA signaling pathway, interfering with the mitochondrial physiology of OS cells, and thus playing an anti-invasion and anti-metastasis role in OS. The Mg-PCL-MT could significantly inhibit distant organ metastasis of OS in the in vivo model. Our results showed that melatonin-loaded Mg-PCL scaffolds inhibited the proliferation, invasion and metastasis of OS cells through the CIC pathway. The Mg-PCL-MT could be a potential therapeutics for OS.