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Pt(IV)-mediated Polymer Architecture for Facile and Stimuli-Responsive Intracellular Gene Silencing with Chemotherapy

Abstract

Conventional chemotherapy has been impeded by inherent nature of cancer including fast mutagenesis and drug resistance, thus a combination therapy consisting of multiple therapeutic strategies has attracted much attention. However, the loading process of multiple therapeutic molecules affects each other, thus development of a nanocarrier which enables independently loading of the cargo molecules has been demanded. Herein, we report an ingeniously designed Pt(IV)-mediated polymeric architecture (Pt-PA) for combinatorial gene and chemotherapy to address the issue, prepared by crosslinking cationic polymer (polyethyleneimine, PEI) with Pt(IV) prodrug. Therapeutic siRNA (anti-BCL2) was simply loaded by electrostatic interaction to form a stable nanocomplex. In cellular study, simultaneous release of both active Pt(II) drug and siRNA was monitored under intracellular reducing environment, driven by dissociation of polymer architecture due to an inherent characteristic of the Pt(IV) crosslinker. Therefore, an enhanced gene silencing effect and anticancer effect was observed. Furthermore, in animal study, an improved therapeutic effect of the naocomplex was observed, which can be explained by tumor targeting via EPR effect, enhanced drug and siRNA release at intracellular environment simultaneously. Taken together, overall results from in vitro and in vivo studies strongly manifest the therapeutic potential of our precisely designed Pt(IV)-mediated polymer architecture

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Publication details

The article was received on 23 Aug 2018, accepted on 05 Oct 2018 and first published on 08 Oct 2018


Article type: Paper
DOI: 10.1039/C8BM01019F
Citation: Biomater. Sci., 2018, Accepted Manuscript
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    Pt(IV)-mediated Polymer Architecture for Facile and Stimuli-Responsive Intracellular Gene Silencing with Chemotherapy

    S. Jung, J. Kim, S. Pramanick, H. Park, H. Lee, J. Lee and W. J. Kim, Biomater. Sci., 2018, Accepted Manuscript , DOI: 10.1039/C8BM01019F

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