Characterization and molecular mechanism of therapeutic peptide functionalized gold nanoparticle inhibiting p53-HDM2 interaction in retinoblastoma

Publication date: Available online 20 October 2017
Source:Molecular Therapy - Nucleic Acids
Author(s): Sushma Kalmodia, Sowmya Parameswaran, Kalaivani Ganapathy, Wenrong Yang, Colin J. Barrow, Jagat Kanwar, Kislay Roy, Madavan Vasudevan, Kirti Kulkarni, Sailaja V. Elchuri, Subramanian Krishnakumar
Inhibition of p53-HDM2 interactions is an effective therapeutic strategy in cancers such as retinoblastoma (RB) that harbor a wild-type p53 protein. Nanoparticle based delivery of therapeutic molecules has been shown to be advantageous in localized delivery, including to the eye, by overcoming the ocular barriers. In this study, we utilized biocompatible gold nanoparticles (GNP), to deliver anti-HDM2 peptide to RB cells. Characterization studies suggested that GNP-HDM2 was stable in biologically relevant solvents and had optimal cellular internalization capability, the primary requirement of any therapeutic molecule. GNP-HDM2 treatment in RB cells in vitro suggested that they function by arresting RB cells at the G2M phase of the cell cycle and initiating apoptosis. Analysis of molecular changes in the GNP-HDM2 treated cells by quantitative reverse transcription PCR and western blotting revealed that the p53 protein was upregulated; however, trans-activation of its downstream targets was minimal, except for the PUMA-BCl2 and Bax axis. Global gene expression and in silico bioinformatic analysis of the GNP-HDM2 treated cells suggested that upregulation of p53 might mediate apoptosis presumptively, through the induction of p53 inducible miRNAs.



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