Biodistribution and Genotoxicity of Transferrin-Conjugated Liposomes/DNA Complexes in Mice

Sang Mi Lee; Jin-Seok Kim; Yu-Kyoung Oh; Yong-Bok Lee; Hongkee Sah

Macromolecular Research, Vol.13, No.3, 218-222, June, 2005

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Biodistribution and Genotoxicity of Transferrin-Conjugated Liposomes/DNA Complexes in Mice

Sang Mi Lee, Jin-Seok Kim^†, Yu-Kyoung Oh¹, Yong-Bok Lee², and Hongkee Sah³

College of Pharmacy, Sookmyung Women’s University, Seoul 140-724, Korea
¹Pocheon CHA University, Pocheon, Korea
²College of Pharmacy, Chonnam National University, Gwangju 500-757, Korea
³College of Pharmacy, Catholic University of Daegu, Daegu, Korea

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Transferrin-conjugated liposomes (Tf-liposomes) were made and formulated with pCMVluc DNA to form a lipoplex. Among the various formulations studied, the Tf-liposome: pCMVluc DNA complex at a ratio of 5:1 (wt/wt) showed the highest transfection efficiency, which was twice that of LipofectinTM on HeLa cells. The maximum tolerated dose (MTD) of this lipoplex formulation from a single intravenous injection was over 10 mg/kg in healthy ICR mice. The RT-PCR results showed that the highest level of luciferase mRNA was detected in the lungs, followed by the liver, spleen, heart and kidneys, after an intravenous injection into mice. Two weeks after the injection, the levels of luciferase mRNA decreased gradually in the liver, spleen, heart, and kidney, but not in the lungs. The micro-array study showed that the cancer-related genes, including the bcl 6 gene, were highly up-regulated by the treatment with Tf-liposome/ pCMVluc DNA complex on HeLa cells, indicating that there were possible interactions between the host chromosomal DNA and the Tf-liposome within the cells. The results obtained from this study are expected to be useful for designing a safe and efficient gene delivery system using transferrin-conjugated liposomes.

Keywords:gene delivery;Tf-liposome;biodistribution;microarray;MTD

[References]

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Oh EJ, Shim JY, Kim JS, Macromol. Res., 11(1), 19 (2003)
Son S, Chae SY, Choi C, Kim MY, Ngugen VG, Jang MK, Nah JW, Macromol. Res., 12(6), 573 (2004)
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Mahato RI, Rolland A, Tomlinson E, Pharm. Res., 14, 853 (1997)
Cheng P, Hum. Gene Ther., 7, 275 (1996)
Wagner E, Curiel D, Cotton M, Adv. Drug Deliv. Rev., 14, 113 (1994)
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Lee S, Kim JS, Arch. Pharm. Res., 28, 93 (2005)
Szoka F, Papadjopoulos D, Proc. Natl. Acad. Sci. U.S.A., 75, 4194 (1978)
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Ponka P, Lok CN, Int. J. Biochem. Cell Biol., 31, 1111 (1999)
Kirchesis R, Wightman L, Schreiber A, Wagner E, Gene Ther., 8, 28 (2001)

[Referenced By]

[1] Wu GY, Wu CH, J. Biol. Chem., 262, 4429 (1987)

[2] Oh EJ, Shim JY, Kim JS, Macromol. Res., 11(1), 19 (2003)

[3] Son S, Chae SY, Choi C, Kim MY, Ngugen VG, Jang MK, Nah JW, Macromol. Res., 12(6), 573 (2004)

[4] Gao X, Huang L, Gene Ther., 2, 710 (1995)

[5] Mahato RI, Rolland A, Tomlinson E, Pharm. Res., 14, 853 (1997)

[6] Cheng P, Hum. Gene Ther., 7, 275 (1996)

[7] Wagner E, Curiel D, Cotton M, Adv. Drug Deliv. Rev., 14, 113 (1994)

[8] Thorstensen K, Romslo I, J. Clin. Lab. Invest. Suppl., 215, 113 (1993)

[9] Lee S, Kim JS, Arch. Pharm. Res., 28, 93 (2005)

[10] Szoka F, Papadjopoulos D, Proc. Natl. Acad. Sci. U.S.A., 75, 4194 (1978)

[11] Carlsson J, Devin H, Axon R, Biochem. J., 173, 723 (1978)

[12] Martin F, Heath T, New R, in Liposomes: A Practical Approach, R. New, Ed., IRL Press, Oxford, 1990, pp 163-182

[13] Ponka P, Lok CN, Int. J. Biochem. Cell Biol., 31, 1111 (1999)

[14] Kirchesis R, Wightman L, Schreiber A, Wagner E, Gene Ther., 8, 28 (2001)