Effect of cationic lipid in cationic liposomes on siRNA delivery into the lung by intravenous injection of cationic lipoplex

Abstract

Cationic liposomes composed of dialkyl cationic lipid such as 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) can efficiently deliver siRNA to the lungs following the intravenous injection of cationic liposome/siRNA complexes (lipoplexes). In this study, we examined the effect of cationic lipid of cationic liposomes on siRNA delivery to the lungs after intravenous injection. We used six kinds of cationic cholesterol derivatives and 11 kinds of dialkyl or trialkyl cationic lipids as cationic lipids, and prepared 17 kinds of cationic liposomes composed of a cationic lipid and 1,2-dioleoyl-L-α-glycero-3-phosphatidylethanolamine (DOPE) for evaluation of siRNA biodistribution and in vivo gene silencing effects. Among cationic liposomes, those composed of N-hexadecyl-N,N-dimethylhexadecan-1-aminium bromide (DC-1-16), N,N-dimethyl-N-octadecyloctadecan-1-aminium bromide (DC-1-18), 2-((1,5-bis(octadecyloxy)-1,5-dioxopentan-2-yl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride (DC-3-18D), 11-((1,3-bis(dodecanoyloxy)-2-((dodecanoyloxy)methyl)propan-2-yl)amino)-N,N,N-trimethyl-11-oxoundecan-1-aminium bromide (TC-1-12), or cholesteryl (3-((2-hydroxyethyl)amino)propyl)carbamate hydroiodide (HAPC-Chol) with DOPE exhibited high accumulation of siRNA in the lung and significant suppression of Tie2 mRNA expression after the intravenous injection of cationic lipoplexes with Tie2 siRNA. Furthermore, DC-1-16/DOPE and DC-1-18/DOPE lipoplexes with protein kinase N3 (PKN3) siRNA could suppress the tumour growth when intravenously injected into mice with lung LLC metastasis. These findings indicate that the siRNA biodistribution and in vivo knockdown efficiency after the intravenous injection of cationic lipoplexes were strongly affected by the type of cationic lipid of cationic liposomes.

Effect of pre‑freezing and saccharide types in freeze‑drying of siRNA lipoplexes on gene‑silencing effects in the cells by reverse transfection

“…The sizes of the cationic liposomes prepared in this study were approximately 80-100 nm with a monodisperse distribution, and the ζ-potentials were approximately 41-56 mV (12). in the preparation of sirna lipoplexes, we reported previously that the optimal charge ratios (+:-) were 7:1 for cationic liposomes composed of cationic cholesterol derivatives and 4:1 for cationic liposomes composed of dialkyl or trialkyl cationic lipids (16,19); therefore, in subsequent experiments, we used sirna lipoplexes formed at charge ratios (+:-) of 7:1 for lP-oH, lP-oH-c, and lP-HaPc and 4:1 for lP-doTaP, lP-ddaB, and lP-Tc-1-12, respectively. The sizes of sirna lipoplexes were approximately 150-190 nm, and the ζ-potentials were approximately 34-47 mV (12).…”

“…To prepare cationic liposome/sirna complexes (sirna lipoplexes), each liposome preparation was added to 50 pmol sirna at a charge ratio (+:-) of 7:1 for cationic liposomes composed of cationic cholesterol derivatives and doPe (14,16) or 4:1 for cationic liposomes composed of dialkyl or trialkyl cationic lipids and doPe (16,17) with vortex-mixing for 10 sec and left at room temperature for 15 min. The charge ratio (+:-) of liposomes:sirna is expressed as the molar ratio of cationic lipid to sirna phosphate.…”

Barriers and Strategies of Cationic Liposomes for Cancer Gene Therapy

“…The efficiency of CLs in gene delivery is affected by many factors in vivo and may not closely correspond to the studies in vitro . 9 , 10 First, CLs can elicit opsonization after intravenous administration. 11 CLs pick up plasma protein such as serum albumin, complements, immunoglobulins (Igs), and apolipoproteins to form a corona layer on their surface, providing them with a totally new biological identity that will dramatically alter their fates in vivo .…”

Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases

“…propyl} carbamate hydroiodide (HAPC-Chol) showed increased buildup of siRNA in lungs and decreased the expression of Tie2 mRNA [29].…”