siRNA delivery to lung-metastasized tumor by systemic injection with cationic liposomes

Abstract

<div><p></p><p><i>Context</i>: Cationic liposomes can efficiently deliver siRNA to the lung by intravenous injection of cationic liposome/siRNA complexes (lipoplexes).</p><p><i>Objective:</i> The aim of this study was to examine a formulation of cationic liposomes for siRNA delivery to lung metastasis of breast tumor.</p><p><i>Materials and methods</i>: For the preparation of cationic liposomes, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or dimethyldioctadecylammonium bromide (DDAB) as a cationic lipid and cholesterol (Chol) or 1,2-dioleoyl-l-α-glycero-3-phosphatidylethanolamine (DOPE) as a neutral lipid were used. <i>In vitro</i> and <i>in vivo</i> gene silencing effects by cationic lipoplexes were evaluated after transfection into stably luciferase-expressing human breast tumor MCF-7-Luc cells and after intravenous injection into mice with lung MCF-7-Luc metastasis, respectively. Intracellular localization of siRNA after transfection into MCF-7 cells by cationic lipoplexes and biodistribution of siRNA after intravenous injection of cationic lipoplexes into the mice with lung metastasis were examined by confocal and fluorescent microscopy analyses, respectively.</p><p><i>Results</i>: In <i>in vitro</i> transfection, DOTAP/DOPE and DDAB/DOPE lipoplexes of luciferase siRNA strongly suppressed luciferase activity in MCF-7-Luc cells, but DOTAP/Chol and DDAB/Chol lipoplexes did not, although DOTAP/Chol and DDAB/Chol lipoplexes exhibited higher cellular uptake than DOTAP/DOPE and DDAB/DOPE lipoplexes. When their cationic lipoplexes were intravenously injected into mice with lung MCF-7-Luc metastasis, siRNAs were mainly accumulated in the lungs; however, the reduced luciferase activities in the lung-metastasized tumors were observed only by injections of DOTAP/Chol and DOTAP/DOPE lipoplexes, but not by DDAB/Chol and DDAB/DOPE lipoplexes.</p><p><i>Conclusions</i>: DOTAP-based liposomes might be useful as an <i>in vivo</i> siRNA delivery carrier that can induce gene silencing in lung-metastasized tumors.</p></div