title: Cellular environment-responsive nanomaterials for use in gene and siRNA delivery: molecular design for biomembrane destabilization and intracellular collapse.
abstract: The development of gene and nucleic acid-based medication is one of the ultimate strategies in the research field of personalized medicine. For the desired function of a gene or siRNA, these molecules need to be delivered to the appropriate organelle (i.e. nucleus and cytoplasm, respectively).
  
  
  
  The topics covered herein are rational design in order to control the pharmacokinetics, intracellular trafficking and release (decondensation or decapsulation) of the intended material. Since the endosome and cytoplasm are acidic (endosome) and reducing (cytoplasm) environments, respectively, a large variety of the materials have been developed that induce destabilization of endosome via its protonation, or are spontaneously collapsed in the cytoplasm. Finally, we propose materials (SS-cleavable and pH-activated lipid-like materials: ssPalm) that mount these sensing motifs, i.e., a positive charging unit in response to the acid environment (tertiary amines) and a cleavage unit (disulfide bonding) that is responsive to an reducing environment, respectively.
  
  
  
  Currently, the main target of the nanocarrier-mediated siRNA delivery systems is liver. The targeting of non-hepatic tissue is the next challenge. In this case, the design of neutral particle with well-organized intracellular trafficking, as well as an identification of the promising ligand is needed.
authors.affiliation: a Faculty of Pharmaceutical Sciences , Hokkaido University , Sapporo , Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: a Faculty of Pharmaceutical Sciences , Hokkaido University , Sapporo , Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: a Faculty of Pharmaceutical Sciences , Hokkaido University , Sapporo , Japan.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.affiliation: a Faculty of Pharmaceutical Sciences , Hokkaido University , Sapporo , Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
mesh_terms: D011992:Endosomes; D006801:Humans; D008055:Lipids; D053758:Nanoparticles; D049329:Nanostructures; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering
keywords: DNA; SS-cleavable pH-activated lipid-like material; intracellular trafficking; pH; siRNA; ssPalm