Design and Synthesis of N 4,N 9-Disubstituted Spermines for Non-viral siRNA Delivery – Structure-Activity Relationship Studies of siFection Efficiency Versus Toxicity

Reference:

Soltan, M. K., Ghonaim, H. M., El Sadek, M., Abou Kull, M., El-Aziz, L. A. and Blagbrough, I. S., 2009. Design and Synthesis of N 4,N 9-Disubstituted Spermines for Non-viral siRNA Delivery – Structure-Activity Relationship Studies of siFection Efficiency Versus Toxicity. Pharmaceutical Research, 26 (2), pp. 286-295.

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Official URL:

http://dx.doi.org/10.1007/s11095-008-9731-z

Abstract

Purpose. To study the effect of sequentially changing the chain length, oxidation level, and charge distribution in N-4,N-9-diacyl and N-4,N-9-dialkyl spermines on siRNA formulation, and then to compare their lipoplex transfection efficiency in cell lines. Methods. Eight N-4,N-9-diacyl polyamines: N-4,N-9-[didecanoyl, dilauroyl, dimyristoyl, dimyristoleoyl, dipalmitoyl, distearoyl, dioleoyl and diretinoyl]-1,12-diamino-4,9-diazadodecane were synthesized. Their abilities to bind to siRNA and form nanoparticles were studied using a RiboGreen intercalation assay and particle sizing. Two diamides were also reduced to afford tetraamines N-4,N-9-distearyl- and N-4, N-9-dioleyl-1,12-diamino-4,9-diazadodecane. Delivery of fluorescein-labelled Label IT (R) RNAi Delivery Control was studied in FEK4 primary skin cells and in an immortalized cancer cell line (HtTA), and compared with TransIT-TKO. Results. The design, synthesis, and structure-activity relationship studies of a series of N-4,N-9-disubstituted spermines as efficient vectors for non-viral siRNA delivery to primary skin and cancer cell lines is reported. These non-liposomal cationic lipids are promising siRNA carriers based on the naturally occurring polyamine spermine showing that C-18 is a better chain length as shorter chains are more toxic. Conclusions. N-4,N-9-Distearoyl spermine and N-4,N-9-dioleoyl spermine are efficient siRNA formulation and delivery vectors, even in the presence of serum, comparable to TransIT-TKO. However, four positive charges distributed as in spermine was significantly more toxic.

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