Conclusion
This study suggests that the AS1411-SL1 chimeras could be promising c-MET degraders for targeted therapy of OS.
Methods
We select the ssDNA c-MET aptamer SL1 as the c-MET ligand to design dual aptamer-functionalized PROTACs, as SL1 can be easily conjugated to AS1411 through base-pair complementarity using a nucleic acid linker. Four AS1411-SL1 chimeras are generated by linking AS1411 to either the 5' or 3' terminus of SL1 via two different lengths of nucleic acid linkers. The therapeutic efficacy of these PROTACs is evaluated through both in vitro and in vivo experiments.
Results
The PROTACs enable the ubiquitination and degradation of c-MET. The PROTACs effectively inhibit growth, enhance apoptosis, and overcome drug resistance of OS cells in vitro. The PROTACs demonstrate in vivo tumor-targeting ability and facilitate the OS treatment with no detectable toxicity.