Enteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic route

Abstract

An efficient targeting delivery technology is needed for functional oligonucleotides to exert their potential effect on the target gene without an adverse effect in vivo. Development of enteral delivery systems for nucleic acids is a major challenge because of their large molecular size and instability. Here, we describe a new enteral delivery technique that enables small interfering RNA (siRNA) selectively delivered to the liver to silence its target Apolipoprotein B gene expression. A nuclease-resistant synthetic siRNA was conjugated with α-tochopherol and administered as lipid nanoparticle to the large intestine of the mice in a postprandial state. The selective transport into the liver, effective gene silence, and consequently significant reduction in serum low density lipoprotein-cholesterol level, were demonstrated. The chylomicron-mediated pathway via the lymphatic route was suggested as major mechanism. This unique approach may provide a basis for developing oral and rectal delivery systems for nucleic acids targeting liver.

Improved systemic delivery of insulin by condensed drug loading in a dimpled suppository

“…On the other hand, this strategy not only applies to the rectal absorption of polypeptides but also can be expanded to other biomedicines such as oligonucleotides, which are poorly permeable across the mucosa and unstable against enzymes in the intestine. We demonstrated that our rectal siRNA delivery technique using lipid nanoparticles provided therapeutic gene silencing in the liver through its delivery via the lymphatic route (37,38). Feasibility of our dimple-type suppository to rectal oligonucleotide delivery is now under investigation.…”

Liposomal delivery systems for intestinal lymphatic drug transport

“…The lymphatic transport of halofantrine accounted for 1.3% and 54% of the administered dose after fasting and in a postprandial state, respectively, suggesting that a postprandial state is the main factor influencing lymphatic halofantrine transport. More recently, Murakami et al showed that, in a postprandial state, vitamin E–siRNA complex was administered by direct injection in a ligated loop of the large intestine and delivered delivered by the chylomicron-mediated lymphatic pathway [11]. Lipoprotein lipase changed the form from chylomicrons to chylomicron remnants, which finally accumulated in the liver.…”

Drug delivery system of therapeutic oligonucleotides

“…Intestinal infusion is another way to deliver Toc-siRNA to the liver. Toc-siRNA administered as a lipid nanoparticle to the mouse large intestine in a postprandial state at a dose of 30 mg/kg reduced ApoB mRNA level in the liver by approximately 40% compared to the unconjugated siRNA (27).…”