Novel degradable oligoethylenimine acrylate ester-based pseudodendrimers for in vitro and in vivo gene transfer.
A novel class of cationic hyperbranched polymers, containing branched oligoethylenimine (OEI 800 Da) as core, diacrylate esters as linkers and oligoamines as surface modification, was synthesized and evaluated regarding their structure-activity relationship as gene carriers. We show that pseudodendritic core characteristics as well as different surface modifications on the core influence DNA-binding ability, cytotoxicity and transfection efficiency. As most promising gene carrier, the pseudodendrimer HD O, that is, the OEI 800 Da core modified with hexane-1,6-diol diacrylate and surface-modified with OEI 800 Da, was identified. HD O exhibits efficient DNA-condensing ability to nanosized polyplexes (100-200 nm), low cytotoxicity, a degradation half-life of 3 days at 37 degrees C at physiological pH and in vitro reporter gene-expression levels similar to high molecular weight linear and branched polyethylenimines (PEIs) (LPEI and BPEI). In vivo studies in mice reveal that HD O/DNA polyplexes upon i.v. tail-vein injection have the potential for transfection of tumor tissue at levels comparable to that obtained with LPEI. Importantly, HD O was better tolerated than LPEI, while transgene expression was more tumor-specific and much lower in all other investigated organs, especially in the lung (15,000-fold lower compared with LPEI).
Russ
V
V
Department of Pharmacy, Center of Drug Research, Pharmaceutical Biology-Biotechnology, Ludwig-Maximilians University, Munich, Germany.
Elfberg
H
H
Thoma
C
C
Kloeckner
J
J
Ogris
M
M
Wagner
E
E
D000179:Acrylates; D000818:Animals; D001388:Aziridines; D002478:Cells, Cultured; D050091:Dendrimers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004952:Esters; D005260:Female; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D008099:Liver / Q000201:enzymology; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000201:enzymology / Q000628:therapy*; D011108:Polymers; D014162:Transfection / Q000379:methods*
D000179:Acrylates; D001388:Aziridines; D050091:Dendrimers; D004952:Esters; D011108:Polymers; D008156:Luciferases