A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA Inhibits Tumor Growth In vivo

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-08, Vol.69 (16), p.6531-6538
• Main Authors: YAGI, Nobuhiro, MANABE, Ichiro, KATO, Yasuki, YAMAUCHI, Masahiro, NAGAI, Ryozo, TOTTORI, Tsuneaki, ISHIHARA, Atsushi, OGATA, Fusa, JONG HEON KIM, NISHIMURA, Satoshi, FUJIU, Katsuhito, OISHI, Yumiko, ITAKA, Keiji
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Carbocyanines - administration & dosage; Cell Proliferation - drug effects; Drug Delivery Systems - methods; Gene Transfer Techniques; Half-Life; Humans; Kruppel-Like Transcription Factors - antagonists & inhibitors; Kruppel-Like Transcription Factors - genetics; Male; Medical sciences; Mice; Mice, Inbred C57BL; Models, Biological; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Neoplasms - diagnosis; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Pharmacology. Drug treatments; RNA Stability; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Tumor Cells, Cultured; Tumors; Whole Body Imaging - methods
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3945

Use of short interfering RNA (siRNA) is a promising new approach thought to have a strong potential to lead to rapid development of gene-oriented therapies. Here, we describe a newly developed, systemically injectable siRNA vehicle, the "wrapsome" (WS), which contains siRNA and a cationic lipofection complex in a core that is fully enveloped by a neutral lipid bilayer and hydrophilic polymers. WS protected siRNA from enzymatic digestion, providing a long half-life in the systemic circulation. Moreover, siRNA/WS leaked from blood vessels within tumors into the tumor tissue, where it accumulated and was subsequently transfected into the tumor cells. Because the transcription factor KLF5 is known to play a role in tumor angiogenesis, we designed KLF5-siRNA to test the antitumor activity of siRNA/WS. KLF5-siRNA/WS exhibited significant antitumor activity, although neither WS containing control scrambled-siRNA nor saline containing KLF5-siRNA affected tumor growth. KLF5-siRNA/WS inhibited Klf5 expression within tumors at both mRNA and protein levels, significantly reducing angiogenesis, and we detected no significant acute or long-term toxicity. Our findings support the idea that siRNA/WS can be used to knock down specific genes within tumors and thereby exert therapeutic effects against cancers.