title: Inhibition of Gene Expression and Cancer Cell Migration by CD44v3/6-Targeted Polyion Complexes.
abstract: In recent years, siRNA technology has emerged as a promising strategy for gene silencing in cancer therapy. We have designed novel CD44-targeted polyion complexes (PICs) composed of poly(ethylene glycol)-block-polyethylenimine (PEG-b-PEI) and laminin-derived peptides (mA5G27D or mA5G27F) for in vivo siRNA delivery and gene silencing in tumors. The full-length A5G27 peptide (RLVSYNGIIFFLK), from which mA5G27D and mA5G27F are derived, binds to CD44v3 and CD44v6 and inhibits tumor cell migration, invasion, and angiogenesis. Thus, when attached to the surface of PICs, A5G27-based peptides can serve both as targeting ligands to navigate siRNA molecules directly to CD44-overexpressing tumors, and as anti-migratory agents to inhibit tumor progression. The mA5G27D- or mA5G27F-harboring PEG-b-PEI copolymers strongly condensed siRNA molecules into nanosized PICs presenting positive surface charges, low in vitro cytotoxicity, and high serum stability. mA5G27D- or mA5G27F-bearing PICs demonstrated high efficacy and selectivity in delivering siRAC1 into CD44-overexpressing cells, thereby silencing RAC1 mRNA and protein levels in such cells. These PICs presented substantial anti-migratory features in vitro and accumulated significantly in SK-OV-3 tumor-bearing mice, following 3 sequential intraperitoneal (i.p.) injections. Treatment of mice with 8 or 9 sequential parenteral (intravenous, (i.v.) or i.p.) injections of mA5G27F-PEG-b-PEI/siRNA efficiently inhibited tumor growth in two different CD44-overexpressing tumor mouse models (A549 and SK-OV-3), regardless of the type of siRNA (siPLK1 or siLUC) used. The results thus reveal the potential utility of this system for targeted delivery of siRNA molecules into solid tumors to prolong the survival time of mice, while at the same time reducing potential toxicity.
authors.forename: Moran
authors.initials: M
authors.lastname: Golan
authors.forename: Valeria
authors.initials: V
authors.lastname: Feinshtein
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University , Tel Aviv 6997801, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Polyak
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University , Tel Aviv 6997801, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Scomparin
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University , Tel Aviv 6997801, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
authors.forename: Ayelet
authors.initials: A
authors.lastname: David
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D009842:Oligopeptides