Mdm2 Targeting Reassembly Peptide (Trap) Nanoparticles For P53 Based Cancer Therapy.

Abstract

Gene mutations and functional inhibition are the major obstacles for p53-mediated oncotherapy. For p53-wild type tumors, the underlying mechanisms of functional inhibition of p53 during oncogenesis are unknown. Our results revealed that the expression of the MDM2 inhibitor ARF was inhibited in p53-wild type tumors, indicating that the restoration of ARF could be a potential oncotherapy strategy for p53-wild type tumors. Therefore, we developed ARF-mimetic MDM2-targeting reassembly peptide nanoparticles (MtrapNPs) for p53-based tumor therapy. Our results elucidated that the MtrapNPs responded to and formed a nanofiber structure with MDM2. By trapping MDM2, the MtrapNPs stabilized and activated p53 for the inhibition of p53-wild type tumors. In most cases, reactivated mutant p53 is inhibited and degraded by MDM2. In the present study, MtrapNPs were used to load and deliver arsenic trioxide, a p53 mutation rescuer, for p53-mutated tumor treatment in both orthotopic and metastatic models, and they exhibited significant therapeutic effects. Therefore, our study provides evidence supporting a link between decreased ARF expression and tumor development in patients with p53-wild type tumors. Thus, the novel MDM2-trap strategy, which addresses both the inhibition and mutations of p53, is an efficient strategy for the treatment of p53-mutated tumors. This article is protected by copyright. All rights reserved.