Poly(ethylenimine-co-L-lactamide-co-succinamide): a biodegradable polyethylenimine derivative with an advantageous pH-dependent hydrolytic degradation for gene delivery.
A biodegradable gene transfer vector has been synthesized by linking several low molecular weight (MW) polyethylenimine (PEI, 1200 Da) blocks using an oligo(L-lactic acid-co-succinic acid) (OLSA, 1000 Da). The resulting copolymer P(EI-co-LSA) (8 kDa) is soluble in water and degrades via base-catalyzed hydrolytic cleavage of amide bonds. With regard to its application as a gene transfer agent, the polymer showed an interesting pH dependency of degradation. At pH 5, when DNases are highly active, the degradation proceeds at a slower rate than at a physiological pH of 7.4. PEI and P(EI-co-LSA) spontaneously formed complexes with plasmid DNA. Whereas the complexes formed with PEI were not stable and aggregated, forming particles of up to 1 microm hydrodynamic diameter, P(EI-co-LSA) formed complexes, which were about 150 nm in size and of narrow size distribution. The latter complexes were stable, due to their high surface charge (zeta-potential + 18 mV). Similar to low MW PEI, the copolymer exhibited a low toxicity profile. At the same time, the copolymer showed a significant enhancement of transfection activity in comparison to the low MW PEI. This makes P(EI-co-LSA) a promising candidate for long-term gene therapy where biocompatibility and biodegradability become increasingly important.
Petersen
Holger
H
Department of Pharmaceutics and Biopharmacy, Philipps-University of Marburg, Ketzerbach 63, D-35032 Marburg, Germany.
Merdan
Thomas
T
Kunath
Klaus
K
Fischer
Dagmar
D
Kissel
Thomas
T
D000818:Animals; D001673:Biodegradation, Environmental; D002460:Cell Line; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D051379:Mice; D010316:Particle Size; D010957:Plasmids / Q000737:chemistry; D011073:Polyamines / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D011094:Polyethyleneimine / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D014162:Transfection / Q000379:methods* / Q000592:standards
D011073:Polyamines; C476044:poly(ethyleneimine-co-lactamide-co-succinamide); D011094:Polyethyleneimine