Penetration and efficacy of VEGF siRNA using polyelectrolyte complex micelles in a human solid tumor model in-vitro

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A polyelectrolyte complex(PEC) micelle-based siRNAdelivery system has been developed for vascular endothelial growth factor (VEGF),and its antitumor efficacy has been demonstrated using in-vivo animal models. Penetration and distribution through the avascular regions of human solid tumors after extravasation are important issues for antitumor efficacy especially for macromolecules such as VECF siRNA PEC micelles. Using an in-vitro solid tumor model, multicellular layers(MCL) culture of human colorectal cancer cells, we evaluated the penetration kinetics and efficacy of VEGF siRNA PEC micelles(PEC-siRNA) in comparison to unmodified siRNA(N-siRNA). The PEC-siRNA showed full penetration (15-17 layers of cells) with a unique punctuated distribution pattern at 48 h following initial accumulation in the top layers and a significant suppression of mRNA and protein expression in a dose-dependent manner after 72 h exposure. Although the initial penetration of N-siRNA was faster than that of PK-siRNA, N-siRNA showed complete loss of activity due to its instability within 24 h. Our data support the idea that PEC micelle formulation may provide stable penetration tool through the multilayers of cancer cells and ensure the gene silencing effect of VEGF. This study also demonstrated that MCL could serve as a useful in-vitro model to evaluate the dose- and time-dependent profiles of penetration and efficacy of macromolecular delivery systems in human solid tumor avascular regions. (C) 2009 Elsevier B.V. All rights reserved.
Publisher
Elsevier Science Bv
Issue Date
2009-07
Language
English
Article Type
Article
Keywords

ENDOTHELIAL GROWTH-FACTOR; SHORT INTERFERING RNAS; ENHANCED PERMEABILITY; SYSTEMIC DELIVERY; GENE-THERAPY; CANCER CELLS; EXPRESSION; THERAPEUTICS; CULTURE; VIVO

Citation

JOURNAL OF CONTROLLED RELEASE, v.137, no.2, pp.130 - 135

ISSN
0168-3659
DOI
10.1016/j.jconrel.2009.03.009
URI
http://hdl.handle.net/10203/174241
Appears in Collection
BS-Journal Papers(저널논문)
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