Targeted siRNA Delivery Using a Lipo-Oligoaminoamide Nanocore with an Influenza Peptide and Transferrin Shell.
Developing RNA-interference-based therapeutic approaches with efficient and targeted cytosolic delivery of small interfering RNA (siRNA) is remaining a critical challenge since two decades. Herein, a multifunctional transferrin receptor (TfR)-targeted siRNA delivery system (Tf&INF7) is designed based on siRNA complexes formed with the cationic lipo-oligoamino amide 454, sequentially surface-modified with polyethylene glycol-linked transferrin (Tf) for receptor targeting and the endosomolytic peptide INF7 for efficient cytosolic release of the siRNA. Effective Tf&INF7 polyplex internalization and target gene silencing are demonstrated for the TfR overexpressing tumor cell lines (K562, D145, and N2a). Treatment with antitumoral EG5 siRNA results in a block of tumor cell growth and triggered apoptosis. Tf-modified polyplexes are far more effective than the corresponding albumin- (Alb) or nonmodified 454 polyplexes. Competition experiments with excess of Tf demonstrate TfR target specificity. As alternative to the ligand Tf, an anti-murine TfR antibody is incorporated into the polyplexes for specific targeting and gene silencing in the murine N2a cell line. In vivo distribution studies not only demonstrate an enhanced tumor residence of siRNA in N2a tumor-bearing mice with the Tf&INF7 as compared to the 454 polyplex group but also a reduced siRNA nanoparticle stability limiting the in vivo performance.
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.
Wei
W
Zhang
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.
Katharina
K
Müller
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.|Nanosystems Initiative Munich, Schellingstrasse 4, D-80799, Munich, Germany.
Eva
E
Kessel
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.
Sören
S
Reinhard
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.|Nanosystems Initiative Munich, Schellingstrasse 4, D-80799, Munich, Germany.
Dongsheng
D
He
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.
Philipp M
PM
Klein
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.
Miriam
M
Höhn
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.
Wolfgang
W
Rödl
Department of Physics, Ludwig-Maximilians-Universität München, Geschwister-Scholl-Platz 1, 80539, Munich, Germany.
Susanne
S
Kempter
Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München (LMU), Butenandtstrasse 5-13, D-81377, Munich, Germany.|Nanosystems Initiative Munich, Schellingstrasse 4, D-80799, Munich, Germany.
Ernst
E
Wagner
D000818:Animals; D018014:Gene Transfer Techniques; D006801:Humans; D020014:K562 Cells; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D014168:Transferrin / Q000737:chemistry / Q000494:pharmacology
D034741:RNA, Small Interfering; D014168:Transferrin
endosomal escape; lipo-oligoamino amide; siRNA delivery; target; transferrin