Design and synthesis of N 4,N 9-disubstituted spermines for non-viral siRNA delivery – structure-activity relationship studies of siFection efficiency versus toxicity

Moustafa K. Soltan, Hassan M. Ghonaim, Mohamed El Sadek, M. Abou Kull, Lubna Abd El-aziz, Ian S. Blagbrough

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)286-295
Number of pages10
JournalPharmaceutical Research
Volume26
Issue number2
DOIs
Publication statusPublished - Feb 2009

Fingerprint

Spermine
Structure-Activity Relationship
Small Interfering RNA
Toxicity
Poisons
Cells
Polyamines
Chain length
Cell Line
Skin
Diamide
Charge distribution
Skin Neoplasms
Intercalation
RNA Interference
Fluorescein
Nanoparticles
Transfection
Labels
Assays

Keywords

  • NVGT
  • siRNA delivery
  • N-4
  • N-9-dioleoyl spermine
  • Lipopolyamines
  • Primary skin cells

Cite this

Design and synthesis of N 4,N 9-disubstituted spermines for non-viral siRNA delivery – structure-activity relationship studies of siFection efficiency versus toxicity. / Soltan, Moustafa K.; Ghonaim, Hassan M.; El Sadek, Mohamed; Abou Kull, M.; El-aziz, Lubna Abd; Blagbrough, Ian S.

In: Pharmaceutical Research, Vol. 26, No. 2, 02.2009, p. 286-295.

Research output: Contribution to journalArticle

Soltan, Moustafa K. ; Ghonaim, Hassan M. ; El Sadek, Mohamed ; Abou Kull, M. ; El-aziz, Lubna Abd ; Blagbrough, Ian S. / Design and synthesis of N 4,N 9-disubstituted spermines for non-viral siRNA delivery – structure-activity relationship studies of siFection efficiency versus toxicity. In: Pharmaceutical Research. 2009 ; Vol. 26, No. 2. pp. 286-295.
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T1 - Design and synthesis of N 4,N 9-disubstituted spermines for non-viral siRNA delivery – structure-activity relationship studies of siFection efficiency versus toxicity

AU - Soltan, Moustafa K.

AU - Ghonaim, Hassan M.

AU - El Sadek, Mohamed

AU - Abou Kull, M.

AU - El-aziz, Lubna Abd

AU - Blagbrough, Ian S.

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N2 - 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.

AB - 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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