title: Tumor Selective Silencing Using an RNAi-Conjugated Polymeric Nanopharmaceutical.
abstract: Small interfering RNA (siRNA) therapeutics have potential advantages over traditional small molecule drugs such as high specificity and the ability to inhibit otherwise "undruggable" targets. However, siRNAs have short plasma half-lives in vivo, can induce a cytokine response, and show poor cellular uptake. Formulating siRNA into nanoparticles offers two advantages: enhanced siRNA stability against nuclease degradation beyond what chemical modification alone can provide; and improved site-specific delivery that takes advantage of the enhanced permeability and retention (EPR) effect. Existing delivery systems generally suffer from poor delivery to tumors. Here we describe the formation and biological activity of polymeric nanopharmaceuticals (PNPs) based on biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) conjugated to siRNA via an intracellular cleavable disulfide linker (PLGA-siRNA). Additionally, these PNPs contain (1) PLGA conjugated to polyethylene glycol (PEG) for enhanced pharmacokinetics of the nanocarrier; (2) a cation for complexation of siRNA and charge compensation to avoid high negative zeta potential; and (3) neutral poly(vinyl alcohol) (PVA) to stabilize the PNPs and support the PEG shell to prevent particle aggregation and protein adsorption. The biological data demonstrate that these PNPs achieve prolonged circulation, tumor accumulation that is uniform throughout the tumor, and prolonged tumor-specific knockdown. PNPs employed in this study had no effect on body weight, blood cell count, serum chemistry, or cytokine response at doses >10 times the effective dose. PNPs, therefore, constitute a promising solution for achieving durable siRNA delivery and gene silencing in tumors.
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Sonke
authors.initials: S
authors.lastname: Svenson
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Roy I
authors.initials: RI
authors.lastname: Case
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Roderick O
authors.initials: RO
authors.lastname: Cole
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Jungyeon
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Sujan R
authors.initials: SR
authors.lastname: Kabir
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Lazarus
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lim Soo
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Pei-Sze
authors.initials: PS
authors.lastname: Ng
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Peters
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Pochi
authors.initials: P
authors.lastname: Shum
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Beata
authors.initials: B
authors.lastname: Sweryda-Krawiec
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Snehlata
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: van der Poll
authors.affiliation: Cerulean Pharma Inc. , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Eliasof
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D049452:Green Fluorescent Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000235:genetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C515652:AHSA1 protein, human; D018832:Molecular Chaperones; D011108:Polymers; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: PLGA; PLK1; cancer therapy; drug conjugation; polymeric nanoparticles; siRNA delivery