Nanoparticle-Mediated Rescue of p53 Through Targeted Degradation of MDM2
Abstract
The interaction between mdm2 and p53 is a viable therapeutic target, as overexpression of mdm2 can lead to excessive p53 degradation, suppressing a cell's ability to cope with cellular insult. The goal of this research is to use recent advances in nanotechnology to develop a specific nanoparticle antagonist to disrupt the mdm2:p53 interaction. Inhibiting the interaction between p53 and mdm2 allows wild-type p53 concentrations to rise to functional levels, effectively killing proliferating tumor cells. By incorporating traditional peptide inhibitors of mdm2 with mixed monolayer protected gold cluster nanoparticles, we hope to effect mdm2 denaturation on the nanoparticle surface, increase peptide stability, and facilitate intracellular peptide delivery. Nanoparticle characteristics, such as size, surface chemistry and biocompatibility, may be controlled and modified for these specific applications. In the first year of the research grant, nanoparticles featuring mdm2-specific peptides have been synthesized and characterized by transmission electron microscopy, gel electrophoresis, UV-Vis absorbance, and fluorescence spectrometry. The nanoparticles are water soluble, stable for months at room temperature, and successfully inhibit the binding of mdm2 top 53. Current work is focused on optimizing peptide loading on the nanoparticle, determining changes in mdm2 conformation upon nanoparticle binding, and preparing for experiments on cultured cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2004
- Accession Number
- ADA430001
Entities
People
- Nicholas Fischer
- Vincent Rotello
Organizations
- University of Massachusetts Amherst