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Resurrecting a p53 peptide activator - An enabling nanoengineering strategy for peptide therapeutics
- Source :
- Journal of Controlled Release. 325:293-303
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Many high-affinity peptide antagonists of MDM2 and MDMX have been reported as activators of the tumor suppressor protein p53 with therapeutic potential. Unfortunately, peptide activators of p53 generally suffer poor proteolytic stability and low membrane permeability, posing a major pharmacological challenge to anticancer peptide drug development. We previously obtained several potent dodecameric peptide antagonists of MDM2 and MDMX termed PMIs, one of which, TSFAEYWALLSP, bound to MDM2 and MDMX at respective affinities of 0.49 and 2.4 nM. Here we report the development of gold nanoparticles (Np) as a membrane-traversing delivery vehicle to carry PMI for anticancer therapy. Np-PMI was substantially more active in vitro than Nutlin-3 in killing tumor cells bearing wild-type p53, and effectively inhibited tumor growth in metastasis in a mouse homograft mode of melanoma and a patient-derived xenograft model of colon cancer with a favorable safety profile. This clinically viable drug delivery strategy can be applied not only to peptide activators of p53 for cancer therapy, but also to peptide therapeutics in general aimed at targeting intracellular protein-protein interactions for disease intervention.
- Subjects :
- MDMX
Membrane permeability
Metal Nanoparticles
Pharmaceutical Science
Cell Cycle Proteins
Peptide
02 engineering and technology
Mice
03 medical and health sciences
medicine
Animals
Amino Acid Sequence
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
biology
Activator (genetics)
Chemistry
Melanoma
Proto-Oncogene Proteins c-mdm2
021001 nanoscience & nanotechnology
medicine.disease
Drug development
Drug delivery
Cancer research
biology.protein
Mdm2
Gold
Tumor Suppressor Protein p53
Peptides
0210 nano-technology
Subjects
Details
- ISSN :
- 01683659
- Volume :
- 325
- Database :
- OpenAIRE
- Journal :
- Journal of Controlled Release
- Accession number :
- edsair.doi.dedup.....a4ce6cfe2e6c9c9afa5981e146e21f2a