Secure splenic delivery of plasmid DNA and its application to DNA vaccine.

In this experiment, we developed a novel safe and effective gene delivery vector coated with γ-polyglutamic acid (γ-PGA-coated complexes). The γ-PGA-coated complex was composed of chiseled spherical nano-particles with anionic charges. The plasmid DNA/polyethyleneimine complex (non-coated complex) showed high transgene efficiency in the spleen and lung after intravenous administration in mice, with high liver toxicity and lethality. On the other hand, γ-PGA-coated complex selectively showed high transgene efficiency in the spleen without such toxicity. Furthermore, the γ-PGA-coated complex highly accumulated and showed high gene expression in the marginal zone of the spleen. Those results strongly indicated that γ-PGA-coated complex was suitable as a DNA vaccine vector. We therefore applied γ-PGA-coated complex to melanoma DNA vaccine, pUb-M. The γ-PGA-coated complex containing pUb-M significantly inhibited the growth and metastasis of a melanoma cell line, B16-F10 cells. In conclusion, we developed a splenic gene vector, γ-PGA-coated complex, as a novel technology for clinical vaccination.

[1]  A. Fischer,et al.  Gene therapy for primary immunodeficiencies: Part 1. , 2012, Current opinion in immunology.

[2]  Hsueh-Hsiao Wang,et al.  Nonviral gene therapy targeting cardiovascular system. , 2012, American journal of physiology. Heart and circulatory physiology.

[3]  Nikos K. Karamanos,et al.  Vectors for Inhaled Gene Therapy in Lung Cancer. Application for Nano Oncology and Safety of Bio Nanotechnology , 2012, International journal of molecular sciences.

[4]  Leaf Huang,et al.  Cancer Immunotherapy and Nanomedicine , 2011, Pharmaceutical Research.

[5]  Azam Bolhassani,et al.  Improvement of different vaccine delivery systems for cancer therapy , 2011, Molecular Cancer.

[6]  S. Kawakami,et al.  Gamma-polyglutamic acid-coated vectors for effective and safe gene therapy. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[7]  Ying Cai,et al.  DNA vaccine manufacture: scale and quality , 2009, Expert review of vaccines.

[8]  S. Kawakami,et al.  The development of a gene vector electrostatically assembled with a polysaccharide capsule. , 2009, Biomaterials.

[9]  H. Sasaki,et al.  Ternary complexes of pDNA, polyethylenimine, and gamma-polyglutamic acid for gene delivery systems. , 2009, Biomaterials.

[10]  T. Kozel,et al.  Macrophage Uptake, Intracellular Localization, and Degradation of Poly-γ-d-Glutamic Acid, the Capsular Antigen of Bacillus anthracis , 2008, Infection and Immunity.

[11]  Michele A. Kutzler,et al.  DNA vaccines: ready for prime time? , 2008, Nature Reviews Genetics.

[12]  T. Kozel,et al.  In Vivo Fate and Distribution of Poly-γ-d-Glutamic Acid, the Capsular Antigen from Bacillus anthracis , 2008, Infection and Immunity.

[13]  M. Frank,et al.  Cancer stem cells and human malignant melanoma , 2007, Pigment Cell & Melanoma Research.

[14]  Barbara A Pockaj,et al.  Malignant melanoma in the 21st century, part 2: staging, prognosis, and treatment. , 2007, Mayo Clinic proceedings.

[15]  Xiang Gao,et al.  Nonviral gene delivery: What we know and what is next , 2007, The AAPS Journal.

[16]  Shubiao Zhang,et al.  Toxicity of cationic lipids and cationic polymers in gene delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[17]  M. Cesta.  Normal Structure, Function, and Histology of the Spleen , 2006, Toxicologic pathology.

[18]  F. Hodi,et al.  Well-Defined Melanoma Antigens as Progression Markers for Melanoma: Insights into Differential Expression and Host Response Based on Stage , 2006, Clinical Cancer Research.

[19]  Feng Liu,et al.  Non‐immunostimulatory nonviral vectors , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  M. Glennie,et al.  Multivalent conjugates of poly-gamma-D-glutamic acid from Bacillus licheniformis with antibody F(ab') and glycopeptide ligands. , 2003, Bioconjugate chemistry.

[21]  Cameron S. Osborne,et al.  LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1 , 2003, Science.

[22]  Y. Barenholz,et al.  Lipoplex-induced hemagglutination: potential involvement in intravenous gene delivery , 2002, Gene Therapy.

[23]  G. Parmiani.  Melanoma antigens and their recognition by T cells. , 2001, The Keio journal of medicine.

[24]  T. Chao,et al.  An autologous oral DNA vaccine protects against murine melanoma. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  E Marshall,et al.  Gene Therapy Death Prompts Review of Adenovirus Vector , 1999, Science.

[26]  R. Dellavalle,et al.  Melanoma chemoprevention. , 2006, Journal of the American Academy of Dermatology.

[27]  J. Coll,et al.  Side‐effects of a systemic injection of linear polyethylenimine–DNA complexes , 2002, The journal of gene medicine.

[28]  G. Kraal.  Cells in the marginal zone of the spleen. , 1992, International review of cytology.