title: Incorporation of histone derived recombinant protein for enhanced disassembly of core-membrane structured liposomal nanoparticles for efficient siRNA delivery.
abstract: A novel recombinant protein tetra-H2A (TH) derived from histone H2A has been developed to replace protamine as a conditionally reversible, nucleic acid condensing agent. The novel protein will address the insufficient release of nucleic acid therapeutics, which is captured by protamine for siRNA delivery. TH is composed of 4 tandem repeats of the histone H2A N-terminal sequence, intervened by the cathepsin D cleavage site. The repeating H2A sequence enhances the binding affinity to anionic nucleic acids, forming more stable condensates, as demonstrated by the binding affinity assay. The TH/siRNA condensates are formulated into a core-membrane structured liposomal nanoparticle (NP). The endosomes of cancer cells are rich in cathepsin D, allowing on-site degradation of TH and facilitating the intracellular release of siRNA. The NPs assembled with TH produced a higher silencing efficiency of target genes in vitro and in vivo than the NPs assembled with protamine as the nucleic acid condensing agent. The exploitation of TH in the NP formulation exhibited a biocompatibility profile similar to that of protamine, with minimal immunostimulating and systemic toxicity observed after repeated administration.
authors: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, USA. Electronic address: alwang@email.unc.edu.
authors: Yuhua
authors: Y
authors: Wang
authors: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, USA.
authors: Lu
authors: L
authors: Zhang
authors: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, USA.
authors: Shutao
authors: S
authors: Guo
authors: Department of Pharmaceutics, Ernest Mario School of Pharmacy, University of Rutgers, Piscataway, USA.
authors: Arash
authors: A
authors: Hatefi
authors: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, USA.
authors: Leaf
authors: L
authors: Huang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D005260:Female; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012756:Sheep
chemical_list: D006657:Histones; D008081:Liposomes; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D011092:Polyethylene Glycols
keywords: 1,2-dioctadecanoyl-sn-glycero-3-phosphoethanolamine; 1,2-dioleoyl-3-trimethylammonium-propane; DOTAP; DSPE; Liposome; Nanoparticle; RNAi; Recombinant protein; TH; TH/ΔCathD; TH/ΔGALA; TH/ΔGALA/ΔCathD; Tumor targeted delivery; tetra-H2A polypeptide; tetra-H2A polypeptide without GALA; tetra-H2A polypeptide without GALA or cathepsin D cleavage site; tetra-H2A polypeptide without cathepsin D cleavage site
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