title: Biodegradable PAMAM ester for enhanced transfection efficiency with low cytotoxicity.
abstract: We synthesized biodegradable polycationic PAMAM (polyamidoamine) esters (e-PAM-R, e-PAM-K) that contain arginines or lysines at the peripheral ends of PAMAM-OH dendrimer through ester bond linkages. The PAMAM esters were readily degradable under physiological conditions (pH 7.4, 37 degrees C), with more than 50% of the grafted amino acids hydrolyzed within 5h. However, polyplexes were very stable and were hardly degraded in the endosomal pH range. Moreover, these amino-acid-modified polymers showed excellent buffering capacities between pH 5.1 and 7.4, facilitating endosomal escape of polyplexes. While the lysine-grafted PAMAM ester did not display significant improvement in transfection efficiency, the arginine-conjugated PAMAM ester-mediated transfection of a luciferase gene showed better transfection efficiency than the branched 25 kDa PEI (polyethylenimine) and PAM-R (peptide bond), and lower cytotoxicity, especially with primary cells such as HUVECs (human umbilical vein endothelial cells) and SMCs (primary rat aorta vascular smooth muscle cells). Furthermore, after DNA release, free e-PAM-R degraded completely into nontoxic PAMAM-OH and arginines by hydrolysis, which resulted in lower cytotoxicity in contrast to the poorly degradable arginine-modified PAMAM with amide bonds. These findings demonstrated that the arginine-grafted biodegradable PAMAM dendrimer, e-PAM-R, is a potential candidate as a safe and efficient gene delivery carrier for gene therapy.
authors.affiliation: School of Chemistry and Molecular Engineering, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-747, Republic of Korea.
authors.forename: Hye Yeong
authors.initials: HY
authors.lastname: Nam
authors.forename: Kihoon
authors.initials: K
authors.lastname: Nam
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Hahn
authors.forename: Bo Hye
authors.initials: BH
authors.lastname: Kim
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lim
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Joon Sig
authors.initials: JS
authors.lastname: Choi
authors.forename: Jong-Sang
authors.initials: JS
authors.lastname: Park
mesh_terms: D000818:Animals; D001120:Arginine; D002021:Buffers; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D050091:Dendrimers; D004587:Electrophoresis, Agar Gel; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008239:Lysine; D018613:Microscopy, Confocal; D010957:Plasmids / Q000378:metabolism; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011108:Polymers; D051381:Rats; D017186:Titrimetry; D014162:Transfection
chemical_list: D002021:Buffers; D050091:Dendrimers; D004952:Esters; C104700:PAMAM Starburst; D011073:Polyamines; D011108:Polymers; D001120:Arginine; D008239:Lysine