Efficient delivery of sticky siRNA and potent gene silencing in a prostate cancer model using a generation 5 triethanolamine-core PAMAM dendrimer.

Abstract

Successful achievement of RNA interference in therapeutic applications requires safe and efficient vectors for siRNA delivery. In the present study, we demonstrate that a triethanolamine (TEA)-core PAMAM dendrimer of generation 5 (G(5)) is able to deliver sticky siRNAs bearing complementary A(n)/T(n) 3'-overhangs effectively to a prostate cancer model in vitro and in vivo and produce potent gene silencing of the heat shock protein 27, leading to a notable anticancer effect. The complementary A(n)/T(n) (n = 5 or 7) overhangs characteristic of these sticky siRNA molecules help the siRNA molecules self-assemble into "gene-like" longer double-stranded RNAs thus endowing a low generation dendrimer such as G(5) with greater delivery capacity. In addition, the A(n)/T(n) (n = 5 or 7) overhangs act as protruding molecular arms that allow the siRNA molecule to enwrap the dendrimer and promote a better interaction and stronger binding, ultimately contributing toward the improved delivery activity of G(5). Consequently, the low generation dendrimer G(5) in combination with sticky siRNA therapeutics may constitute a promising gene silencing-based approach for combating castration-resistant prostate tumors or other cancers and diseases, for which no effective treatment currently exists.

• Authors: Xiaoxuan Liu, Cheng Liu, Erik Laurini, Paola Posocco, Sabrina Pricl, Fanqi Qu, Palma Rocchi, Ling Peng
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 9 Issue 3 Pg. 470-81 (Mar 05 2012) ISSN: 1543-8392 [Electronic] United States
• PMID: 22208617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dendrimers
• Ethanolamines
• PAMAM Starburst
• RNA, Small Interfering
• triethanolamine

Topics

• Animals
• Apoptosis (genetics, physiology)
• Blotting, Western
• Cell Line, Tumor
• Dendrimers (administration & dosage, chemistry)
• Ethanolamines (chemistry)
• Flow Cytometry
• Gene Silencing (physiology)
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Nude
• Microscopy, Confocal
• Prostatic Neoplasms (genetics, therapy)
• RNA, Small Interfering (administration & dosage, genetics)
• Real-Time Polymerase Chain Reaction
• Xenograft Model Antitumor Assays