TY - JOUR
T1 - Structural advantage of dendritic poly(l-lysine) for gene delivery into cells
AU - Yamagata, Masato
AU - Kawano, Takahito
AU - Shiba, Kouhei
AU - Mori, Takeshi
AU - Katayama, Yoshiki
AU - Niidome, Takuro
N1 - Funding Information:
This research was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (No. 16790106) and a Grant-in-Aid for Scientific Research in the Priority Area ‘Molecular Nano Dynamics’ (No. 17034049) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
PY - 2007/1/1
Y1 - 2007/1/1
N2 - This study aimed to investigate the relationships between structures of gene carrier molecules and their activities for gene delivery into cells. We compared 2 types of poly(l-lysine) as carriers, that is, dendritic poly(l-lysine) (KG6) and linear poly(l-lysine) (PLL). KG6 formed a neutral DNA complex, and its DNA compaction level was weaker than that of PLL. The amount of DNA binding and uptake into cells mediated by PLL was 4-fold higher than that with KG6. However, KG6-mediated gene expression was 100-fold higher than that by PLL. Since pKa values of terminal amines of KG6 were lowered even though small amounts of DNA were internalized into cells, sufficient DNA amounts for effective gene expression escaped to the cytosol due to the proton sponge effect in the endosome. In addition, weakly compacted DNA with KG6 was advantageous in accessing RNA polymerase in the cell nucleus. On the other hand, PLL did not show the proton sponge effect in the endosome and resulted in strong compaction of DNA. Even though large DNA amounts were internalized into cells, most of the DNA would not take part in gene expression systems in the nucleus. Amount of induced cytokine production after intravenous injection of DNA complexes with KG6 and PLL was low, and was similar to the case when DNA was injected alone. Therefore, no significant difference in effects on cytokine production was observed between KG6 and PLL.
AB - This study aimed to investigate the relationships between structures of gene carrier molecules and their activities for gene delivery into cells. We compared 2 types of poly(l-lysine) as carriers, that is, dendritic poly(l-lysine) (KG6) and linear poly(l-lysine) (PLL). KG6 formed a neutral DNA complex, and its DNA compaction level was weaker than that of PLL. The amount of DNA binding and uptake into cells mediated by PLL was 4-fold higher than that with KG6. However, KG6-mediated gene expression was 100-fold higher than that by PLL. Since pKa values of terminal amines of KG6 were lowered even though small amounts of DNA were internalized into cells, sufficient DNA amounts for effective gene expression escaped to the cytosol due to the proton sponge effect in the endosome. In addition, weakly compacted DNA with KG6 was advantageous in accessing RNA polymerase in the cell nucleus. On the other hand, PLL did not show the proton sponge effect in the endosome and resulted in strong compaction of DNA. Even though large DNA amounts were internalized into cells, most of the DNA would not take part in gene expression systems in the nucleus. Amount of induced cytokine production after intravenous injection of DNA complexes with KG6 and PLL was low, and was similar to the case when DNA was injected alone. Therefore, no significant difference in effects on cytokine production was observed between KG6 and PLL.
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U2 - 10.1016/j.bmc.2006.09.033
DO - 10.1016/j.bmc.2006.09.033
M3 - Article
C2 - 17035030
AN - SCOPUS:33750932907
VL - 15
SP - 526
EP - 532
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 1
ER -