MDM2-Targeting Reassembly Peptide (TRAP) Nanoparticles for p53-Based Cancer Therapy

Adv Mater. 2023 Nov;35(45):e2305164. doi: 10.1002/adma.202305164. Epub 2023 Oct 11.

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. The results reveal that the expression of the MDM2 inhibitor ARF is inhibited in p53-wild-type tumors, indicating that the restoration of ARF could be a potential oncotherapy strategy for p53-wild-type tumors. Therefore, ARF-mimetic MDM2-targeting reassembly peptide nanoparticles (MtrapNPs) for p53-based tumor therapy is developed. The results elucidated that the MtrapNPs respond to and form a nanofiber structure with MDM2. By trapping MDM2, the MtrapNPs stabilize and activate 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 are used to load and deliver arsenic trioxide, a p53 mutation rescuer, for p53-mutated tumor treatment in both orthotopic and metastatic models, and they exhibit significant therapeutic effects. Therefore, the study provides evidence supporting a link between decreased ARF expression and tumor development in patients with p53-wild-type tumors. Thus, the MDM2-trap strategy, which addresses both the inhibition and mutations of p53, is an efficient strategy for the treatment of p53-mutated tumors.

Keywords: ARF; MDM2 trap; arsenic trioxide; cancer therapy; mutant p53; peptides; wild-type p53.

MeSH terms

  • Humans
  • Neoplasms* / drug therapy
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Peptides / metabolism
  • Peptides / pharmacology
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Tumor Suppressor Protein p53
  • Nuclear Proteins
  • Tumor Suppressor Protein p14ARF
  • Proto-Oncogene Proteins c-mdm2
  • Peptides
  • MDM2 protein, human