International Journal of Oral Biology

The Korean Academy of Oral Biology (대한구강생물학회)
권호 표지
DOI QR코드

DOI QR Code

Cholesterol conjugated spermine as a delivery modality of antisense oligonucleotide

  • Im, Yoon Kyung (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chosun University) ;
  • Kim, Myung Su (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chosun University) ;
  • Yoo, Hoon (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chosun University)
  • Received : 2013.09.24
  • Accepted : 2013.12.10
  • Published : 2013.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

The major issue in the development of nucleic acid based therapeutics is the inefficient delivery of these agents into cells. We prepared cholesterol conjugated spermine and evaluated its usefulness as a delivery modality for antisense oligonucleotides in HeLa-Luc cells. A 2'-O-methyl antisense oligonucleotide sequence, designed to correct splicing at an aberrant intron inserted into a normal luciferase reporter gene, was used for complex formation with cholesterol conjugated spermine. Effective delivery of this antisense agent into nucleus would results in the expression of a luciferasereporter gene product. The cholesterol-spermine formed stable complexes with the antisense oligonucleotide and showed modest delivery activity. Furthermore, this delivery activity was maintained even in the presence of serum proteins, mimicking in vivo conditions. Cholesterol-spermine thus has potential as a delivery system for antisense oligonucleotides into cells.

Keywords

References

  1. Juliano RL, Akhtar S. Liposomes as a drug delivery system for antisense oligonucleotides. Antisense Res Dev 1992; 2:165-176. https://doi.org/10.1089/ard.1992.2.165
  2. Gao X, Huang L. Cationic liposome-mediated gene transfer. Gene Ther 1995;2:710-722.
  3. Gao X, Huang L. Potentiation of cationic liposome- mediated gene delivery by polycations. Biochemistry 1996;35: 1027-1036. https://doi.org/10.1021/bi952436a
  4. Alahari SK, DeLong R, Fisher MH, Dean NM, Viliet P, Juliano RL. Novel chemically modified oligonucleotides provide potent inhibition of P-glycoprotein expression. J Pharmacol Exp Ther 1998;286:419-428.
  5. Bennett CF, Chiang MY, Chan H, Shoemaker JE, Mirabelli CK. Cationic lipids enhance cellular uptake and activity of phosphorothioate antisense oligonucleotides. Mol Pharmacol 1992;41:1023-1033.
  6. Betts CA, Wood MJ. Cell penetrating Peptide delivery of splice directing oligonucleotides as a treatment for duchenne muscular dystrophy. Curr Pharm Des 2013;19:2948-2962. https://doi.org/10.2174/1381612811319160009
  7. Degols G, Leonetti JP, Lebleu B. Sequence-specific activity of antisense oligonucleotides conjugated to poly (L-lysine) carriers. Ann N Y Acad Sci 1992;660:331-333. https://doi.org/10.1111/j.1749-6632.1992.tb21104.x
  8. Yoo H, Juliano RL. Enhanced delivery of antisense oligonucleotides with fluorophore-conjugated PAMAM dendrimers. Nucleic Acids Res 2000;28:4225-4231. https://doi.org/10.1093/nar/28.21.4225
  9. Liang E, Hughes J. Characterization of a pH-sensitive surfactant, dodecyl-2-(1'-imidazolyl) propionate (DIP), and preliminary studies in liposome mediated gene transfer. Biochim Biophys Acta 1998;1369:39-50. https://doi.org/10.1016/S0005-2736(97)00172-7
  10. Alahari SK, Dean NM, Fisher MH, Delong R, Manoharan M, Tivel KL, et al. Inhibition of expression of the multidrug resistance-associated P-glycoprotein of by phosphorothioate and 5' cholesterol-conjugated phosphorothioate antisense oligonucleotides. Mol Pharmacol 1996;50:808-819.
  11. DeLong RK, Yoo H, Alahari SK, Fisher M, Short SM, Kang SH, et al. Novel cationic amphiphiles as delivery agents for antisense oligonucleotides. Nucleic Acids Res 1999; 27:3334-3341. https://doi.org/10.1093/nar/27.16.3334
  12. Rajur SB, Roth CM, Morgan JR, Yarmush ML. Covalent protein-oligonucleotide conjugates for efficient delivery of antisense molecules. Bioconjug Chem 1997;8:935-940. https://doi.org/10.1021/bc970172u
  13. Juliano R, Bauman J, Kang H, Ming X. Biological barriers to therapy with antisense and siRNA oligonucleotides. Mol Pharm 2009;6:686-695. https://doi.org/10.1021/mp900093r
  14. Zelphati O, Szoka FC, Jr. Mechanism of oligonucleotide release from cationic liposomes. Proc Natl Acad Sci U S A 1996;93:11493-11498. https://doi.org/10.1073/pnas.93.21.11493
  15. Juliano RL, Ming X, Nakagawa O. The chemistry and biology of oligonucleotide conjugates. Acc Chem Res 2012;45:1067-1076. https://doi.org/10.1021/ar2002123
  16. Wong FM, MacAdam SA, Kim A, Oja C, Ramsay EC, Bally MB. A lipid-based delivery system for antisense oligonucleotides derived from a hydrophobic complex. J Drug Target 2002;10:615-623. https://doi.org/10.1080/1061186021000066246
  17. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001; 411:494-498. https://doi.org/10.1038/35078107
  18. Huang L, Sullenger B, Juliano R. The role of carrier size in the pharmacodynamics of antisense and siRNA oligonucleotides. J Drug Target 2010;18:567-574. https://doi.org/10.3109/10611861003734019
  19. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev 2001;15:188-200. https://doi.org/10.1101/gad.862301
  20. Juliano RL, Ming X, Nakagawa O. Cellular uptake and intracellular trafficking of antisense and siRNA oligonucleotides. Bioconjug Chem 2012;23:147-157. https://doi.org/10.1021/bc200377d
  21. Meidan VM, Glezer J, Salomon S, Sidi Y, Barenholz Y, Cohen JS, et al. Specific lipoplex-mediated antisense against Bcl-2 in breast cancer cells: a comparison between different formulations. J Liposome Res 2006;16:27-43. https://doi.org/10.1080/08982100500528685
  22. Bahadur KCR, Thapa B, Xu P. Design of serum compatible tetrary complexes for gene delivery. Macromol Biosci 2012;12:637-646. https://doi.org/10.1002/mabi.201100464
  23. Duan SY, Ge XM, Lu N, Wu F, Yuan W, Jin T. Synthetic polyspermine imidazole-4, 5-amide as an efficient and cytotoxicity-free gene delivery system. Int J Nanomedicine 2012;7:3813-3822.
  24. Gagnon KT, Watts JK, Pendergraff HM, Montaillier C, Thai D, Potier P, et al. Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide- oligospermine conjugates. J Am Chem Soc 2011;133: 8404-8407. https://doi.org/10.1021/ja200312y
  25. Lacomino G, Picariello G, D'Agostino L. DNA and nuclear aggregates of polyamines. Biochim Biophys Acta 2012;1823:1745-1755. https://doi.org/10.1016/j.bbamcr.2012.05.033
  26. Maslov MA, Kabilova TO, Petukhov IA, Morozova NG, Serebrennikova GA, Vlassov VV, et al. Novel cholesterol spermine conjugates provide efficient cellular delivery of plasmid DNA and small interfering RNA. J Control Release 2012;160:182-193. https://doi.org/10.1016/j.jconrel.2011.11.023
  27. Kang SH, Cho MJ, Kole R. Up-regulation of luciferase gene expression with antisense oligonucleotides: implications and applications in functional assay development. Biochemistry 1998;37:6235-6239. https://doi.org/10.1021/bi980300h
  28. Yoo H, Sazani P, Juliano RL. PAMAM dendrimers as delivery agents for antisense oligonucleotides. Pharm Res 1999; 16:1799-1804. https://doi.org/10.1023/A:1018926605871
  29. Felber AE, Bayo-Puxan N, Deleavey GF, Castagner B, Damha MJ, Leroux JC. The interactions of amphiphilic antisense oligonucleotides with serum proteins and their effects on in vitro silencing activity. Biomaterials 2012;33:5955-5965. https://doi.org/10.1016/j.biomaterials.2012.05.019