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

Abstract

AbstractGene 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