title: Delivery of antisense oligonucleotides using poly(alkylene oxide)-poly(propylacrylic acid) graft copolymers in conjunction with cationic liposomes.
abstract: The clinical application of gene silencing is hindered by poor stability and low delivery efficiency of naked oligonucleotides. Here, we present the in vitro and in vivo behaviors of a rationally designed, ternary, self-assembled nanoparticle complex, consisting of an anionic copolymer, cationic DOTAP liposome, and antisense oligonucleotide (AON). The multifunctional copolymers are based on backbone poly(propylacrylic acid) (PPAA), a pH-sensitive hydrophobic polymer, with grafted poly(alkylene oxides) (PAOs) varying in extent of grafting and PAO chemistry. The nanoparticle complexes with PPAA-g-PAO copolymers enhance antisense gene silencing effects in A2780 human ovarian cancer cells. A greater amount of AON is delivered to ovarian tumor xenografts using the ternary copolymer-stabilized delivery system, compared to a binary DOTAP/AON complex, following intraperitoneal injection in mice. Further, intratumoral injection of the nanoparticle complexes containing 1 mol% grafted PAO reduced tumoral bcl-2 expression by up to 60%. The data for complexes across the set of PAO polymers support a strong role for the hydrophilic-lipophilic balance of the graft copolymer in achieving serum stability and cellular uptake. Based upon these results, we anticipate that this novel nanoparticle delivery system can be extended to the delivery of plasmid DNA, siRNA, or aptamers for preclinical and clinical development.
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, USA.
authors.forename: Lavanya Y
authors.initials: LY
authors.lastname: Peddada
authors.affiliation: Department of Pharmaceutics, Rutgers University, Piscataway, USA.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Garbuzenko
authors.affiliation: U.S. Army Institute of Surgical Research, Fort Sam Houston, 78234, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Devore
authors.affiliation: Department of Pharmaceutics, Rutgers University, Piscataway, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Minko
authors.affiliation: Department of Biomedical Engineering, Rutgers University, Piscataway, USA; Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, USA. Electronic address: cmroth@rutgers.edu.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Roth
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000178:Acrylamides; D000180:Acrylic Resins / Q000737:chemistry*; D000818:Animals; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009369:Neoplasms / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000180:Acrylic Resins; D002412:Cations; D004337:Drug Carriers; D008081:Liposomes; D016376:Oligonucleotides, Antisense; C512582:poly(N-isopropylacrylamide-co-propylacrylic acid); D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols
keywords: Antisense; Drug delivery; Gene silencing; Nanoparticle; Self assembly; Tumor