RSC Advances
Paper
using 7d, 7e, 7f and 7i. The oleyl group was found to be the best
choice for the transfection, and oleyl-contained lipids 7e and 7h
gave the best TEs. The linoleyl-contained 7f and 7i gave much
decreased TEs, which were even lower than the lipid with
saturated chains (7d). As many reported and some commer-
cially available transfection reagents also have oleyl moiety in
their structures, such results might be reasonable. The intro-
ducing of monounsaturated hydrophobic chain would facilitate
membrane disruption and DNA escape from endosome by
increasing the membrane uidity. Further increase of unsa-
turation degree may lead to difficulty of liposome forming and
subsequent DNA binding, which would hamper the transfection
process. The above structure–activity relationships may afford
us clues for further optimization of gemini lipid gene delivery
materials.
4 (a) Y. Su, R. Mani and M. Hong, J. Am. Chem. Soc., 2008, 130,
8856–8864; (b) Y. Su, S. Li and M. Hong, Amino Acids, 2013,
44, 821–833.
5 T. R. G. P. L. Felgner, M. Holm, R. Roman, H. W. Chan,
M. Wenz, J. P. Northrop, G. M. Ringold and M. Danielsen,
Proc. Natl. Acad. Sci. U. S. A., 1987, 84, 7413–7417.
6 S. Bhattacharya and A. Bajaj, Chem. Commun., 2009, 4632–
4656.
7 F. M. Menger and C. A. Littau, J. Am. Chem. Soc., 1993, 115,
10083–10090.
8 F. M. Menger, J. S. Keiper and V. Azov, Langmuir, 1999, 16,
2062–2067.
9 M. Kumar, K. Jinturkar, M. R. Yadav and A. Misra, Crit. Rev.
Ther. Drug Carrier Syst., 2010, 27, 237–278.
10 V. Floch, N. Legros, S. Loisel, C. Guillaume, J. Guilbot,
T. Benvegnu, V. Ferrieres, D. Plusquellec and C. Ferec,
Biochem. Biophys. Res. Commun., 1998, 251, 360–365.
15
4
. Conclusion
11 T. Zhou, A. Llizo, P. Li, C.-x. Wang, Y. Guo, M. Ao, L. Bai,
C. Wang, Y. Yang and G. Xu, J. Phys. Chem. C, 2013, 117,
In summary, a series of cyclen-based cationic gemini lipids with
two symmetrical head groups and two hydrophobic tails were
designed and synthesized. Cystine was used as backbone
between the two amphiphilic units. Liposomes could be
smoothly formed by these lipids and helper lipid DOPE. The
interaction between the liposome and plasmid DNA was
studied. Results reveal that these liposomes have strong DNA
binding ability, and full DNA condensation could be achieved at
the N/P ratio of 2–4. The lipoplexes have proper sizes and zeta-
potentials, which might be suitable for gene transfection. These
materials were applied as non-viral gene delivery vectors, and
their structure–activity relationship was investigated. Subtle
changes in the structure of the lipids would lead to large effect
on the TE. The oleyl amine derived lipid 7e gave the best TE,
which was close to the commercially available transfection
reagent lipofectamine 2000. Besides, these lipids have very low
cytotoxicity, suggesting their good biocompatibility. Further
modications and extended application of such type of gemini
lipids are currently underway.
26573–26581.
1
1
2 B. Kedika and S. V. Patri, Mol. Pharm., 2012, 9, 1146–1162.
3 D. Zhi, S. Zhang, S. Cui, Y. Zhao, Y. Wang and D. Zhao,
Bioconjugate Chem., 2013, 24, 487–519.
4 R. Koynova, B. Tenchov, L. Wang and R. C. MacDonald, Mol.
Pharm., 2009, 6, 951–958.
5 D. Zhi, S. Zhang, B. Wang, Y. Zhao, B. Yang and S. Yu,
Bioconjugate Chem., 2010, 21, 563–577.
6 B. Kedika and S. V. Patri, Bioconjugate Chem., 2011, 22, 2581–
1
1
1
1
1
2592.
7 M. Rajesh, J. Sen, M. Srujan, K. Mukherjee, B. Sreedhar and
A. Chaudhuri, J. Am. Chem. Soc., 2007, 129, 11408–11420.
8 R. Mukthavaram, S. Marepally, M. Y. Venkata, G. N. Vegi,
R. Sistla and A. Chaudhuri, Biomaterials, 2009, 30, 2369–
2384.
1
9 Q. Liu, Q.-Q. Jiang, W.-J. Yi, J. Zhang, X.-C. Zhang, M.-B. Wu,
Y.-M. Zhang, W. Zhu and X.-Q. Yu, Bioorg. Med. Chem., 2013,
21, 3105–3113.
2
2
2
2
2
2
2
2
2
0 B.-Q. Liu, W.-J. Yi, J. Zhang, Q. Liu, Y.-H. Liu, S.-D. Fan and
X.-Q. Yu, Org. Biomol. Chem., 2014, 12, 3484–3492.
1 Q.-D. Huang, G.-X. Zhong, Y. Zhang, J. Ren, Y. Fu, J. Zhang,
W. Zhu and X.-Q. Yu, PLoS One, 2011, 6, e23134.
2 R. M. Izatt, K. Pawlak, J. S. Bradshaw and R. L. Bruening,
Chem. Rev., 1991, 91, 1721–2085.
Acknowledgements
This work was nancially supported by the National Program on
Key Basic Research Project of China (973 Program,
2
2
012CB720603), the National Science Foundation of China (no.
1232005), and the Specialized Research Fund for the Doctoral
3 J. W. Jeon, S. J. Son, C. E. Yoo, I. S. Hong, J. B. Song and
J. Suh, Org. Lett., 2002, 4, 4155–4158.
Program of Higher Education (20120181130006) in China. J. Z.
thanks the Program for New Century Excellent Talents in
University (NCET-11-0354). We also thank Analytical & Testing
Center of Sichuan University for the TEM analysis.
4 C. Fong, D. Wells, I. Krodkiewska, P. G. Hartley and
C. J. Drummond, Chem. Mater., 2006, 18, 594–597.
5 M. Sodeoka, R. Sampe, S. Kojima, Y. Baba, T. Usui, K. Ueda
and H. Osada, J. Med. Chem., 2001, 44, 3216–3222.
6 Q. Liu, W.-J. Yi, Y.-M. Zhang, J. Zhang, L. Guo and X.-Q. Yu,
Chem. Biol. Drug Des., 2013, 82, 376–383.
References
7 K. Luo, C. Li, L. Li, W. She, G. Wang and Z. Gu, Biomaterials,
1
(a) G. M. Rubanyi, Mol. Aspects Med., 2001, 22, 113–142; (b)
A. El-Aneed, Eur. J. Pharmacol., 2004, 498, 1–8.
2012, 33, 4917–4927.
8 B. Wang, W.-J. Yi, J. Zhang, Q.-F. Zhang, M.-M. Xun and
X.-Q. Yu, Bioorg. Med. Chem. Lett., 2014, 24, 1771–1775.
2
3
A. El-Aneed, J. Controlled Release, 2004, 94, 1–14.
X. Guo and L. Huang, Acc. Chem. Res., 2011, 45, 971–979.
44268 | RSC Adv., 2014, 4, 44261–44268
This journal is © The Royal Society of Chemistry 2014