A Pt(iv)-mediated polymer architecture for facile and stimuli-responsive intracellular gene silencing with chemotherapy
| Autor: | Junseok Lee, Won Jong Kim, Hyori Lee, Jinhwan Kim, Swapan Pramanick, Sungjin Jung, Hyeongmok Park |
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| Rok vydání: | 2018 |
| Předmět: |
Static Electricity
Biomedical Engineering Mice Nude Polymer architecture Antineoplastic Agents Platinum Compounds 02 engineering and technology 010402 general chemistry 01 natural sciences chemistry.chemical_compound Mice In vivo Cell Line Tumor Gene silencing Animals Humans Polyethyleneimine General Materials Science Prodrugs Gene Silencing Polyethylenimine Mice Inbred BALB C Neoplasms Experimental Prodrug 021001 nanoscience & nanotechnology In vitro 0104 chemical sciences RNAi Therapeutics chemistry Proto-Oncogene Proteins c-bcl-2 Biophysics Nanoparticles Female Nanocarriers 0210 nano-technology Intracellular |
| Zdroj: | Biomaterials science. 6(12) |
| ISSN: | 2047-4849 |
| Popis: | Conventional chemotherapy has been impeded by the inherent characteristics of cancer including fast mutagenesis and drug resistance; thus a combination therapy consisting of multiple therapeutic strategies has attracted much attention. However, the loading processes of multiple therapeutic molecules affect each other; thus the development of a nanocarrier that enables independent 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 a cationic polymer (polyethylenimine, PEI) with a Pt(IV) prodrug. Therapeutic siRNA (anti-BCL2) was simply loaded by electrostatic interaction to form a stable nanocomplex. In the cellular study, the simultaneous release of both the active Pt(II) drug and siRNA was monitored under the intracellular reducing environment, driven by dissociation of the polymer architecture due to an inherent characteristic of the Pt(IV) crosslinker. Therefore, an enhanced gene silencing effect and an anticancer effect were observed. Furthermore, in the animal study, an improved therapeutic effect of the nanocomplex was observed, which can be explained by tumor targeting via the EPR effect, and enhanced drug and siRNA release at the intracellular environment simultaneously. Taken together, the overall results from in vitro and in vivo studies strongly suggest the therapeutic potential of our precisely designed Pt(IV)-mediated polymer architecture. |
| Databáze: | OpenAIRE |
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