TY - JOUR A1 - Sheikhi Mehrabadi, Fatemeh A1 - Zeng, Hanxiang A1 - Johnson, Mark A1 - Schlesener, Cathleen A1 - Guan, Zhibin A1 - Haag, Rainer T1 - Multivalent dendritic polyglycerolamine with arginine and histidine end groups for efficient siRNA transfection JF - Beilstein Journal of Organic Chemistry PY - 2015/// VL - 11 SP - 763 EP - 772 SN - 1860-5397 DO - 10.3762/bjoc.11.86 PB - Beilstein-Institut JA - Beilstein J. Org. Chem. UR - https://doi.org/10.3762/bjoc.11.86 KW - arginine KW - dendritic polyglycerolamine KW - histidine KW - multivalent vector KW - siRNA delivery N2 - The success of siRNA-based therapeutics highly depends on a safe and efficient delivery of siRNA into the cytosol. In this study, we post-modified the primary amines on dendritic polyglycerolamine (dPG-NH2) with different ratios of two relevant amino acids, namely, arginine (Arg) and histidine (His). To investigate the effects from introducing Arg and His to dPG, the resulting polyplexes of amino acid functionalized dPG-NH2s (AAdPGs)/siRNA were evaluated regarding cytotoxicity, transfection efficiency, and cellular uptake. Among AAdPGs, an optimal vector with (1:3) Arg to His ratio, showed efficient siRNA transfection with minimal cytotoxicity (cell viability ≥ 90%) in NIH 3T3 cells line. We also demonstrated that the cytotoxicity of dPG-NH2 decreased as a result of amino acid functionalization. While the incorporation of both cationic (Arg) and pH-responsive residues (His) are important for safe and efficient siRNA transfection, this study indicates that AAdPGs containing higher degrees of His display lower cytotoxicity and more efficient endosomal escape. ER -