Efficient suppression of secretory clusterin levels by polymer-siRNA nanocomplexes enhances ionizing radiation lethality in human MCF-7 breast cancer cells in vitro*
Autor: | Konstantin Leskov, Xintao Shuai, Damon Sutton, Jinming Gao, João Trindade Marques, David A. Boothman, Bryan R.G. Williams, Saejeong Kim |
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Jazyk: | angličtina |
Rok vydání: | 2006 |
Předmět: |
Small interfering RNA
siRNA delivery Materials science secretory clusterin Cell Survival Infrared Rays Polymers Biophysics Pharmaceutical Science Bioengineering Breast Neoplasms Biomaterials 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cell Line Tumor Drug Discovery Gene silencing cancer radiotherapy Humans Gene Silencing RNA Small Interfering 030304 developmental biology Original Research 0303 health sciences Gene knockdown Polyethylenimine Drug Carriers Clusterin biology Organic Chemistry RNA General Medicine Molecular biology nanomedicine 3. Good health Cell biology polyethylenimine Nanostructures MCF-7 chemistry 030220 oncology & carcinogenesis biology.protein |
Zdroj: | International Journal of Nanomedicine |
ISSN: | 1178-2013 1176-9114 |
Popis: | Small interfering RNA molecules (siRNA) hold great promise to specifically target cytoprotective factors to enhance cancer therapy. Like antisense RNA strategies, however, the use of siRNA is limited because of in vivo instability. As a first step to overcome delivery issues, a series of graft copolymers of polyethylene glycol and polyethylenimine (PEI-g-PEG) were synthesized and investigated as nontoxic carriers for delivery of siRNA targeting the signaling peptide of secretory clusterin (sCLU), a prosurvival factor that protects cells from ionizing radiation (IR) injury, as well as chemotherapeutic agents. Three copolymers with different PEG grafting densities were tested for their abilities to bind and form nanocomplexes with siRNA. A copolymer composed of 10 PEG grafts (2 kDa each) per PEI polymer (2k10 copolymer) gave the highest binding affinity to siRNA by ethidium bromide exclusion assays, and had the smallest nanocomplex size (115 +/- 13 nm diameter). In human breast cancer MCF-7 cells, 2k10-siRNA-sCLU nanocomplexes suppressed both basal as well as IR-induced sCLU protein expression, which led to an over 3-fold increase in IR-induced lethality over 2k10-siRNA scrambled controls. In summary, this study demonstrates the proof-of-principle in using nanoparticle-mediated delivery of specific siRNAs to enhance the lethality of IR exposure in vitro, opening the door for siRNA-mediated knockdown of specific cytoprotective factors, such as DNA repair, anti-apoptotic, free radical scavenging, and many other proteins. |
Databáze: | OpenAIRE |
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