Magnetic-Driven Hydrogel Microrobots Selectively Enhance Synthetic Lethality in MTAP-Deleted Osteosarcoma

Background: Drugs based on synthetic lethality have advantages such as inhibiting tumor growth and affecting normal tissue in vivo . However, specific targets for osteosarcoma have not been acknowledged yet. In this study, a non-targeted but controllable drug delivery system has been applied to selectively enhance synthetic lethality in osteosarcoma in vitro , using the magnetic-driven hydrogel microrobots. Methods: In this study, EPZ015666, a PRMT5 inhibitor, was selected as the synthetic lethality drug. Then, the drug was carried by hydrogel microrobots containing Fe 3 O 4 . Morphological characteristics of the microrobots were detected using electron microscopy. In vitro drug effect was detected by the CCK-8 assay kit, Western blotting, etc. Swimming of microrobots was observed by a timing microscope. Selective inhibition was verified by cultured tumors in an increasing magnetic field. Results: Genomic mutation of MTAP deletion occurred commonly in pan-cancer in the TCGA database (nearly 10.00%) and in osteosarcoma in the TARGET database (23.86%). HOS and its derivatives, 143B and HOS/MNNG, were detected by MTAP deletion according to the CCLE database and RT-PCR. EPZ015666, the PRMT5 inhibitor, could reduce the SDMA modification and inhibition of tumor growth of 143B and HOS/MNNG. The hydrogel microrobot drug delivery system was synthesized, and the drug was stained by rhodamine. The microrobots were powered actively by a magnetic field. A simulation of the selected inhibition of microrobots was performed and lower cell viability of tumor cells was detected by adding a high dose of microrobots. Conclusion: Our magnetic-driven drug delivery system could carry synthetic lethality drugs. Meanwhile, the selective inhibition of this system could be easily controlled by programming the strength of the magnetic field.