Physicochemical properties of low molecular weight alkylated chitosans: a new class of potential nonviral vectors for gene delivery.
Low molecular weight chitosans grafted with N-/2(3)-(dodec-2-enyl)succinoyl groups (HM-LMW-chitosans) with a mean molecular mass of 5 kDa, a degree of acetylation of 3% and a degree of tetradecenoyl substitution (TDC) of 3-18 mol% have been synthesized. These molecules are monodisperse and soluble in water at neutral pH. Using tensiometry and Nile Red fluorescence, the HM-LMW-chitosans were found to form micelles through hydrophobic interactions involving their tetradecenoyl chains and nonprotonated glucosamine monomers. Their critical micelle concentration decreases with increasing TDC values but varies little with pH and salt. Interaction with large unilamellar vesicles taken as model membranes indicated that HM-LMW-chitosans interact mainly with vesicles mimicking the inner leaflet of biomembranes both through electrostatic and hydrophobic interactions. This preferential interaction may destabilize endosomal membranes and favor the DNA release into the cytoplasm in gene delivery applications. Moreover, since this interaction significantly decreased the membrane fluidity of these vesicles, the HM-LMC-chitosans are thought to exhibit limited lateral mobility and flip-flop ability, and thus, limited cytotoxicity. These properties suggest that the HM-LMW-chitosans may constitute a promising new class of nonviral vectors for gene therapy.
Ercelen
Sebnem
S
Département de Pharmacologie & Physicochimie, Equipe Photophysique des Interactions Biomoléculaires, Institut Gilbert Laustriat, UMR 7175-LC1, Faculté de Pharmacie, Université Louis Pasteur, B.P. 60024, 67401 Illkirch Cedex, France.
Zhang
Xin
X
Duportail
Guy
G
Grandfils
Christian
C
Desbrières
Jacques
J
Karaeva
Svetlana
S
Tikhonov
Vladimir
V
Mély
Yves
Y
Babak
Valery
V
D000478:Alkylation; D049109:Cell Proliferation / Q000187:drug effects*; D048271:Chitosan / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008823:Micelles; D008970:Molecular Weight
D008823:Micelles; D048271:Chitosan