Secure and effective gene vector of polyamidoamine dendrimer pharmaceutically modified with anionic polymer

• Published in: Journal of pharmaceutical sciences 2011-11, Vol.100 (11), p.4855-4863
• Main Authors: Kurosaki, Tomoaki, Yamashita, Yumi, Aki, Keisei, Harasawa, Hitomi, Nakagawa, Hiroo, Kodama, Yukinobu, Higuchi, Norihide, Nakamura, Tadahiro, Kitahara, Takashi, Sasaki, Hitoshi
• Format: Article
• Language: English
• Subjects: Agglutination; Animals; Anions; Biological and medical sciences; Cytotoxicity; dendrimers; Dendrimers - chemistry; Electrophoresis, Agar Gel; Electrostatic properties; gene delivery; Gene expression; General pharmacology; Genetic Vectors; Heparin; Lung; Medical sciences; Melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - pathology; Mice; Particle Size; Pharmaceutical Preparations; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; plasmid DNA; polyamidoamines; polymers; Polymers - chemistry; Spleen; Toxicity; Veins
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1002/jps.22701

The purpose of this study was to develop a new type of gene vector, polyamidoamine (PAMAM) dendriplex pharmaceutically modified, based on electrostatic interactions, by various anionic polymers. The γ‐polyglutamic acid (γ‐PGA)/PAMAM dendriplex and the α‐PGA/PAMAM dendriplex formed a stable complex, although α‐polyaspartic acid and heparin released pDNA from the complex. The addition of anionic polymer decreased the ζ‐potential, although it did not greatly affect the size of the complex. As a result of an in vitro gene expression study of mouse melanoma cells, we found that the γ‐PGA/PAMAM dendriplex showed high gene expression comparable to the PAMAM dendriplex, although the α‐PGA/PAMAM dendriplex showed lower gene expression. Tail vein injection of the γ‐PGA/PAMAM dendriplex into mice also led to high gene expression in the spleen and lung. The γ‐PGA/PAMAM dendriplex showed no cytotoxicity and no agglutination, although severe cytotoxicity and agglutination were observed in the PAMAM dendriplex. Thus, we discovered that complexes of pDNA, PAMAM dendrimers, and γ‐PGA showed higher gene expression in vitro and in vivo, and markedly lower toxicity. This complex is valuable and is expected to be a safe and effective gene vector. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4855–4863, 2011