Splenic Delivery System of pDNA through Complexes Electrostatically Constructed with Protamine and Chondroitin Sulfate

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  • Kodama Yukinobu
    Department of Hospital Pharmacy, Nagasaki University Hospital
  • Nishigaki Waka
    Department of Hospital Pharmacy, Nagasaki University Hospital
  • Nakamura Tadahiro
    Department of Hospital Pharmacy, Nagasaki University Hospital
  • Fumoto Shintaro
    Department of Pharmaceutics, Graduate School of Biomedical Sciences, Nagasaki University
  • Nishida Koyo
    Department of Pharmaceutics, Graduate School of Biomedical Sciences, Nagasaki University
  • Kurosaki Tomoaki
    Department of Hospital Pharmacy, Nagasaki University Hospital
  • Nakagawa Hiroo
    Department of Hospital Pharmacy, Nagasaki University Hospital
  • Kitahara Takashi
    Department of Hospital Pharmacy, Nagasaki University Hospital
  • Muro Takahiro
    Department of Hospital Pharmacy, Nagasaki University Hospital
  • Sasaki Hitoshi
    Department of Hospital Pharmacy, Nagasaki University Hospital

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Abstract

<p>We developed and optimized a novel gene delivery vector constructed electrostatically with an anionic biological component and a cationic biological component. Cationic binary complexes of plasmid DNA (pDNA) with novo-protamine sulfate as a medical product (PRT complexes) demonstrated high gene expression with minimal cytotoxicity, likely related with its total cationic charge. Subsequently, anionic compounds were added to the PRT complexes to form ternary complexes with neutral or anionic charges. Among the anionic compounds examined, chondroitin sulfate sodium (CS) as a medical product encapsulated the PRT complexes to produce stable ternary complexes (CS complexes) at charge ratios of ≥4 with pDNA. CS complexes exhibited high gene expression without cytotoxicity in mouse melanoma cell line, B16-F10 cells, in vitro. An inhibition study with endocytosis inhibitors suggested that PRT complexes were mainly taken up by caveolae-mediated endocytosis, and CS complexes were mainly taken up by clathrin-mediated endocytosis in B16-F10 cells. We found that CS complexes including pDNA encoding Oplophorus gracilirostris luciferase induced selective gene expression in the spleen after intravenous administration into ddY male mice. Thus, we successfully constructed useful gene vectors with biological components as medical products.</p>

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