Octaarginine-modified multifunctional envelope-type nanoparticles for gene delivery

This study describes a multifunctional envelope-type nano device (MEND) that mimics an envelope-type virus based on a novel packaging strategy. MEND particles contain a DNA core packaged into a lipid envelope modified with an octaarginine peptide. The peptide mediates internalization via macropinocytosis, which avoids lysosomal degradation. MEND-mediated transfection of a luciferase expression plasmid achieved comparable efficiency to adenovirus-mediated transfection, with lower associated cytotoxicity. Furthermore, topical application of MEND particles containing constitutively active bone morphogenetic protein (BMP) type IA receptor (caBmpr1a) gene had a significant impact on hair growth in vivo. These data demonstrate that MEND is a promising non-viral gene delivery system that may provide superior results to existing non-viral gene delivery technologies.

[1]  R. Hoffman,et al.  Visualizing gene expression by whole-body fluorescence imaging. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Schmid,et al.  The emergence of clathrin-independent pinocytic pathways. , 1995, Current opinion in cell biology.

[3]  E. Cundari,et al.  Integrinα3β1 Is an Alternative Cellular Receptor for AdenovirusSerotype5 , 2003, Journal of Virology.

[4]  Steven F Dowdy,et al.  Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis , 2004, Nature Medicine.

[5]  G. Cotsarelis,et al.  Efficient delivery of transgenes to human hair follicle progenitor cells using topical lipoplex , 2000, Nature Biotechnology.

[6]  J. Behr,et al.  Gene delivery: a single nuclear localization signal peptide is sufficient to carry DNA to the cell nucleus. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Leaf Huang,et al.  Folate-targeted, Anionic Liposome-entrapped Polylysine-condensed DNA for Tumor Cell-specific Gene Transfer (*) , 1996, The Journal of Biological Chemistry.

[8]  H Akita,et al.  Quantitative three-dimensional analysis of the intracellular trafficking of plasmid DNA transfected by a nonviral gene delivery system using confocal laser scanning microscopy. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  H. Harashima,et al.  Intracellular trafficking and transgene expression of viral and non-viral gene vectors. , 2001, Advanced drug delivery reviews.

[10]  Meng Yang,et al.  High efficiency genetic modification of hair follicles and growing hair shafts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Hideyoshi Harashima,et al.  Pharmacokinetic and pharmacodynamic considerations in gene therapy. , 2003, Drug discovery today.

[12]  S. Itohara,et al.  BMPR1A signaling is necessary for hair follicle cycling and hair shaft differentiation in mice , 2004, Development.

[13]  I. Khalil,et al.  Pharmacokinetics of Gene Delivery in Cells , 2005 .

[14]  H Harashima,et al.  Mechanism of improved gene transfer by the N-terminal stearylation of octaarginine: enhanced cellular association by hydrophobic core formation , 2004, Gene Therapy.

[15]  H Harashima,et al.  Stearylated arginine-rich peptides: a new class of transfection systems. , 2001, Bioconjugate chemistry.

[16]  Shiroh Futaki,et al.  High Density of Octaarginine Stimulates Macropinocytosis Leading to Efficient Intracellular Trafficking for Gene Expression* , 2006, Journal of Biological Chemistry.

[17]  Jeremy C Simpson,et al.  Cellular uptake of arginine-rich peptides: roles for macropinocytosis and actin rearrangement. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[18]  R. Hoffman,et al.  The feasibility of targeted selective gene therapy of the hair follicle , 1995, Nature Medicine.

[19]  Joseph Zabner,et al.  Cellular and Molecular Barriers to Gene Transfer by a Cationic Lipid (*) , 1995, The Journal of Biological Chemistry.

[20]  S. Futaki,et al.  Arginine-rich Peptides , 2001, The Journal of Biological Chemistry.

[21]  H. Farhood,et al.  The role of dioleoyl phosphatidylethanolamine in cationic liposome mediated gene transfer. , 1995, Biochimica et biophysica acta.

[22]  Shiroh Futaki,et al.  A multifunctional envelope-type nano device for novel gene delivery of siRNA plasmids. , 2005, International journal of pharmaceutics.

[23]  I. Hafez,et al.  Cholesteryl hemisuccinate exhibits pH sensitive polymorphic phase behavior. , 2000, Biochimica et biophysica acta.

[24]  I. Khalil,et al.  Uptake Pathways and Subsequent Intracellular Trafficking in Nonviral Gene Delivery , 2006, Pharmacological Reviews.

[25]  Steven F Dowdy,et al.  Cationic TAT peptide transduction domain enters cells by macropinocytosis. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[26]  Hiroshi Ochiai,et al.  Intranuclear disposition of exogenous DNA in vivo: Silencing, methylation and fragmentation , 2006, FEBS letters.

[27]  K. Mechtler,et al.  Activation of the complement system by synthetic DNA complexes: a potential barrier for intravenous gene delivery. , 1996, Human gene therapy.

[28]  Wong,et al.  Biological barriers to cellular delivery of lipid-based DNA carriers. , 1999, Advanced drug delivery reviews.

[29]  Sarah E. Millar,et al.  Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development , 2004, Development.

[30]  Shiroh Futaki,et al.  Development of a non-viral multifunctional envelope-type nano device by a novel lipid film hydration method. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[31]  Kazuo Maruyama,et al.  Transferrin-modified liposomes equipped with a pH-sensitive fusogenic peptide: an artificial viral-like delivery system. , 2004, Biochemistry.

[32]  E. Fuchs,et al.  Defining BMP functions in the hair follicle by conditional ablation of BMP receptor IA , 2003, The Journal of cell biology.

[33]  T. Giorgio,et al.  Convective flow increases lipoplex delivery rate to in vitro cellular monolayers , 2005, Gene Therapy.

[34]  Takao Hayakawa,et al.  Quantitative comparison of intracellular trafficking and nuclear transcription between adenoviral and lipoplex systems. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[35]  S. Eichmüller,et al.  Alkaline phosphatase activity and localization during the murine hair cycle , 1994, The British journal of dermatology.