Effective co-delivery of nutlin-3a and p53 genes: Via core-shell microparticles for disruption of MDM2-p53 interaction and reactivation of p53 in hepatocellular carcinoma

Davoodi, P, Madapusi, S and Wang, C 2017, 'Effective co-delivery of nutlin-3a and p53 genes: Via core-shell microparticles for disruption of MDM2-p53 interaction and reactivation of p53 in hepatocellular carcinoma', Journal of Materials Chemistry B, vol. 5, no. 29, pp. 5816-5834.


Document type: Journal Article
Collection: Journal Articles

Title Effective co-delivery of nutlin-3a and p53 genes: Via core-shell microparticles for disruption of MDM2-p53 interaction and reactivation of p53 in hepatocellular carcinoma
Author(s) Davoodi, P
Madapusi, S
Wang, C
Year 2017
Journal name Journal of Materials Chemistry B
Volume number 5
Issue number 29
Start page 5816
End page 5834
Total pages 19
Publisher Royal Society of Chemistry
Abstract The tumor suppressor protein p53 is the most frequently inactivated, mutated, or deleted transcriptional factor in tumor cells. Recent studies have shown that the negative regulation of p53 by the murine double minute 2 (MDM2) protein in human cells interrupts the p53 apoptotic pathway and causes tumorigenesis. Therefore, the disruption of the MDM2-p53 complex by small molecules such as nutlin-3a and the administration of the active p53 protein can effectively restore the apoptotic activity of the p53 protein in tumor cells. This study aims to introduce a unique combined p53-based gene and chemotherapy approach using core-shell polymeric microparticles for the localized treatment of cancers. Core-shell microparticles were successfully fabricated in a single step using a modified electrohydrodynamic atomization (EHDA) technique, where the core and shell layers were loaded with nutlin-3a and β-cyclodextrin-g-chitosan/p53 nanoparticles, respectively. The grafting of β-cyclodextrin (β-CD) onto chitosan chains demonstrated remarkable cellular uptake (∼5-fold) compared to pure chitosan at N/P = 6, attributed to a strong interaction and temporary disruption of the lipid bilayer in the cell membrane by the synthesized copolymer. The therapeutic efficiencies of single- and dual-agent loaded microparticle formulations were also evaluated and compared against free-drug treatment in terms of cell viability and intracellular expression of p53, caspase 3, and MDM2 proteins via an MTS assay, an enzyme-linked immunosorbent assay, and an immunostaining assay. The results revealed that the controlled and sustained release of both agents from the microparticles synergistically enhanced the anti-proliferative efficacy of the agents via the continuous overexpression of p53 and caspase 3 proteins over 5 days. However, MDM2 protein expression remained at the basal level over that period. The findings also indicated that nu
Subject Nanobiotechnology
DOI - identifier 10.1039/c7tb00481h
Copyright notice © 2017 The Royal Society of Chemistry.
ISSN 2050-7518
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