Optimization of siRNA Delivery Method into the Liver by Sequential Injection of Polyglutamic Acid and Cationic Lipoplex

Kumi  Kawano; Yoko  Machida; Ryou  Okamoto; Megumi  Hamada; Takuto  Kikuchi; Shohei  Arai; Yoshiyuki  Hattori

doi:10.4236/pp.2015.67032

Yoshiyuki Hattori^*, Shohei Arai, Takuto Kikuchi, Megumi Hamada, Ryou Okamoto, Yoko Machida, Kumi Kawano

Abstract: Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of poly-L-glutamic acid (PGA) and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined the effects of the charge ratio (+/-) of cationic liposome/siRNA, molecular weight of PGA and cationic lipid of cationic liposome on the biodistribution of siRNA after sequential injection of PGA plus cationic lipoplex. When 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (Chol) lipoplex was intravenously injected into mice, the accumulation of siRNA was mainly observed in the lungs. In contrast, when DOTAP/Chol lipoplex was intravenously injected at 1 min after intravenous injection of PGA, siRNA was largely accumulated in the liver. The charge ratio (+/-) of DOTAP/Chol liposome/siRNA did not affect the biodistribution of siRNA after sequential injection. As regards the molecular weight of PGA, the accumulation of siRNA was observed mainly in the liver after the sequential injection of PGA of 20.5, 38, 64 or 200 kDa plus DOTAP/Chol lipoplex. Furthermore, to examine the effect of cationic lipid of cationic liposome on the biodistribution of siRNA, we prepared other cationic liposomes composed of 1,2-di-O-octadecenyl-3-trimethylammonium propane chloride (DOTMA)/Chol, dimethyldioctade-cylammonium bromide (DDAB)/Chol and O,O’-ditetradecanoyl-N-(α-trimethylammonioacetyl)di-ethanolamine chloride (DC-6-14)/Chol. For the cationic liposomes, the accumulation of siRNA was observed mainly in the liver when their cationic lipoplexes were sequentially injected after injection of PGA into mice. From these findings, sequential injection of PGA plus cationic lipoplex could deliver siRNA efficiently into the liver regardless of the charge ratio (+/-) of lipoplex, lengths of PGA and cationic lipid of liposome.

Keywords: Cationic Liposome, siRNA Delivery, Polyglutamic Acid, Liver Targeting, Sequential Injection

Cite this paper: Hattori, Y. , Arai, S. , Kikuchi, T. , Hamada, M. , Okamoto, R. , Machida, Y. and Kawano, K. (2015) Optimization of siRNA Delivery Method into the Liver by Sequential Injection of Polyglutamic Acid and Cationic Lipoplex. Pharmacology & Pharmacy, 6, 302-310. doi: 10.4236/pp.2015.67032.

References

[1] Kubowicz, P., Zelaszczyk, D. and Pekala, E. (2013) RNAi in Clinical Studies. Current Medicinal Chemistry, 20, 1801-1816.
http://dx.doi.org/10.2174/09298673113209990118

[2] Zhang, S.B., Zhi, D.F. and Huang, L. (2012) Lipid-Based Vectors for siRNA Delivery. Journal of Drug Targeting, 20, 724-735.
http://dx.doi.org/10.3109/1061186X.2012.719232

[3] Zhou, J.H., Shum, K.T., Burnett, J.C. and Rossi, J.J. (2013) Nanoparticle-Based Delivery of RNAi Therapeutics: Progress and Challenges. Pharmaceuticals, 6, 85-107.
http://dx.doi.org/10.3390/ph6010085

[4] de Fougerolles, A.R. (2008) Delivery Vehicles for Small Interfering RNA in Vivo. Human Gene Therapy, 19, 125-132.
http://dx.doi.org/10.1089/hum.2008.928

[5] Eliyahu, H., Servel, N., Domb, A.J. and Barenholz, Y. (2002) Lipoplex-Induced Hemagglutination: Potential Involvement in Intravenous Gene Delivery. Gene Therapy, 9, 850-858.

[6] Simberg, D., Weisman, S., Talmon, Y., Faerman, A., Shoshani, T. and Barenholz, Y. (2003) The Role of Organ Vascularization and Lipoplex-Serum Initial Contact in Intravenous Murine Lipofection. The Journal of Biological Chemistry, 278, 39858-39865.
http://dx.doi.org/10.1074/jbc.M302232200

[7] Hattori, Y., Nakamura, A., Arai, S., Nishigaki, M., Ohkura, H., Kawano, K., Maitani, Y. and Yonemochi, E. (2014) In Vivo siRNA Delivery System for Targeting to the Liver by Poly-L-Glutamic Acid-Coated Lipoplex. Results in Pharma Sciences, 4, 1-7.
http://dx.doi.org/10.1016/j.rinphs.2014.01.001

[8] Hattori, Y., Arai, S., Okamoto, R., Hamada, M., Kawano, K. and Yonemochi, E. (2014) Sequential Intravenous Injection of Anionic Polymer and Cationic Lipoplex of siRNA Could Effectively Deliver siRNA to the Liver. International Journal of Pharmaceutics, 476, 289-298.
http://dx.doi.org/10.1016/j.ijpharm.2014.09.059

[9] Song, Y.K., Liu, F., Chu, S.Y. and Liu, D.X. (1997) Characterization of Cationic Liposome-Mediated Gene Transfer in Vivo by Intravenous Administration. Human Gene Therapy, 8, 1585-1594.
http://dx.doi.org/10.1089/hum.1997.8.13-1585

[10] Templeton, N.S., Lasic, D.D., Frederik, P.M., Strey, H.H., Roberts, D.D. and Pavlakis, G.N. (1997) Improved DNA: Liposome Complexes for Increased Systemic Delivery and Gene Expression. Nature Biotechnology, 15, 647-652.
http://dx.doi.org/10.1038/nbt0797-647

[11] Lu, C., Stewart, D.J., Lee, J.J., Ji, L., Ramesh, R., Jayachandran, G., Nunez, M.I., Wistuba, I.I., Erasmus, J.J., Hicks, M.E., Grimm, E.A., Reuben, J.M., Baladandayuthapani, V., Templeton, N.S., McMannis, J.D. and Roth, J.A. (2012) Phase I Clinical Trial of Systemically Administered TUSC2(FUS1)-Nanoparticles Mediating Functional Gene Transfer in Humans. PloS ONE, 7, e34833.
http://dx.doi.org/10.1371/journal.pone.0034833

[12] Tan, Y., Liu, F., Li, Z., Li, S. and Huang, L. (2001) Sequential Injection of Cationic Liposome and Plasmid DNA Effectively Transfects the Lung with Minimal Inflammatory Toxicity. Molecular Therapy, 3, 673-682.
http://dx.doi.org/10.1006/mthe.2001.0311

[13] Tagami, T., Suzuki, T., Matsunaga, M., Nakamura, K., Moriyoshi, N., Ishida, T. and Kiwada, H. (2012) Anti-Angiogenic Therapy via Cationic Liposome-Mediated Systemic siRNA Delivery. International Journal of Pharmaceutics, 422, 280-289.
http://dx.doi.org/10.1016/j.ijpharm.2011.10.059

[14] Wollenberg, B., Kastenbauer, H.M., Schaumberg, J., Mayer, A., Andratschke, M., Lang, S., Pauli, C., Zeidler, R., Ihrler, S., Lohrs, K.N. and Rollston, R. (1999) Gene Therapy—Phase I Trial for Primary Untreated Head and Neck Squamous Cell Cancer (HNSCC) UICC Stage II-IV with a Single Intratumoral Injection of hIL-2 Plasmids Formulated in DOTMA/Chol. Human Gene Therapy, 10, 141-147.
http://dx.doi.org/10.1089/10430349950019273

[15] Jin, Y., Wang, S., Tong, L. and Du, L. (2015) Rational Design of Didodecyldimethylammonium Bromide-Based Nano-assemblies for Gene Delivery. Colloids and Surfaces B: Biointerfaces, 126, 257-264.
http://dx.doi.org/10.1016/j.colsurfb.2014.12.032

[16] Kurosaki, T., Kitahara, T., Fumoto, S., Nishida, K., Yamamoto, K., Nakagawa, H., Kodama, Y., Higuchi, N., Nakamura, T. and Sasaki, H. (2010) Chondroitin Sulfate Capsule System for Efficient and Secure Gene Delivery. Journal of Pharmacy & Pharmaceutical Sciences, 13, 351-361.

[17] Kurosaki, T., Kitahara, T., Kawakami, S., Higuchi, Y., Yamaguchi, A., Nakagawa, H., Kodama, Y., Hamamoto, T., Hashida, M. and Sasaki, H. (2010) Gamma-Polyglutamic Acid-Coated Vectors for Effective and Safe Gene Therapy. Journal of Controlled Release, 142, 404-410.
http://dx.doi.org/10.1016/j.jconrel.2009.11.010

[18] Moghimi, S.M. and Hunter, A.C. (2001) Recognition by Macrophages and Liver Cells of Opsonized Phospholipid Vesicles and Phospholipid Headgroups. Pharmaceutical Research, 18, 1-8.
http://dx.doi.org/10.1023/A:1011054123304

[19] Hattori, Y., Yamashita, J., Sakaida, C., Kawano, K. and Yonemochi, E. (2015) Evaluation of Antitumor Effect of Zoledronic Acid Entrapped in Folate-Linked Liposome for Targeting to Tumor-Associated Macrophages. Journal of Liposome Research, in Press.

[20] Lorenz, C., Hadwiger, P., John, M., Vornlocher, H.P. and Unverzagt, C. (2004) Steroid and Lipid Conjugates of siRNAs to Enhance Cellular Uptake and Gene Silencing in Liver Cells. Bioorganic & Medicinal Chemistry Letters, 14, 4975-4977.
http://dx.doi.org/10.1016/j.bmcl.2004.07.018

[21] Nair, J.K., Willoughby, J.L., Chan, A., Charisse, K., Alam, M.R., Wang, Q., Hoekstra, M., Kandasamy, P., Kel’in, A.V., Milstein, S., Taneja, N., O’Shea, J., Shaikh, S., Zhang, L., van der Sluis, R.J., Jung, M.E., Akinc, A., Hutabarat, R., Kuchimanchi, S., Fitzgerald, K., Zimmermann, T., van Berkel, T.J., Maier, M.A., Rajeev, K.G. and Manoharan, M. (2014) Multivalent N-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing. Journal of the American Chemical Society, 136, 16958-16961.
http://dx.doi.org/10.1021/ja505986a