Synthesis and Antitumor Activity of Phthalimide-Based Polymers Containing Camptothecin

Neung-Ju Lee; Emmanuel A. Theodorakis

Macromolecular Research, Vol.11, No.1, 47-52, February, 2003

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Synthesis and Antitumor Activity of Phthalimide-Based Polymers Containing Camptothecin

Neung-Ju Lee^†, and Emmanuel A. Theodorakis¹

Department of Premedical Sciences, College of Medicine, Kosin University, Pusan 602-703, Korea
¹Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive,La Jolla, California 92093-0358, USA

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The objective of this study was to develop a polymeric drug delivery system for camptothecin (CPT), capable of improving its therapeutic index and reducing its side effects. A monomeric conjugate, 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidoethanoylcamptothecin (ETECPT) between CPT and 3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidoethanoic acid was synthesized. Its homo- and copolymer with acrylic acid (AA) were prepared by photopolymerization using 2,2-dimethoxy-2-phenylacetophenone (DMP) as a photoinitiator. The monomer and its polymers were characterized by IR, 1H- and 13C-NMR spectra. The ETECPT content in poly(ETECPT-co-AA) obtained by elemental analysis was 82 wt%. The number-average molecular weights of the polymers determined by gel permeation chromatography were as follows: Mn = 11,400 for poly(ETECPT), Mn = 17,900 for poly(ETECPT-co-AA). The IC50 values of ETECPT and its polymers against cancer cells were much larger than that of CPT. Our results from the in vivo antitumor activity indicated that all polymers show high antitumor activity than CPT at a dose of 100 mg/kg.

Keywords:3,6-endo-methylene-1,2,3,6-tetrahydrophthalimidoethanoylcamptothecin;camptothecin;photopolymerization;in vitro cytotoxicity;in vivo antitumor activity

[References]

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Liu Z, Rimmer S, J. Control. Release, 81, 91 (2002)
Thomson AH, Vasey PA, Murry LS, Cassidy J, Fraier D, Frigerio E, Twelves C, Br. J. Cancer, 81, 99 (1999)
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[1] Khang G, Lee JH, Lee JW, Cho JC, Lee HB, Korea Polym. J., 8(2), 80 (2000)

[2] Khang G, Choi HS, Rhee JM, Yoon SC, Cho JC, Lee HB, Korea Polym. J., 8(6), 253 (2000)

[3] Khang G, Seo SA, Choi HS, Rhee JM, Lee HB, Macromol. Res., 10(5), 246 (2002)

[4] Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM, Chem. Rev., 99(11), 3181 (1999)

[5] Choi WM, Jung ID, Lee NJ, Kim SH, Ha CS, Cho WJ, Polym. Adv. Technol., 8, 701 (1997)

[6] Liu Z, Rimmer S, J. Control. Release, 81, 91 (2002)

[7] Thomson AH, Vasey PA, Murry LS, Cassidy J, Fraier D, Frigerio E, Twelves C, Br. J. Cancer, 81, 99 (1999)

[8] Vasey PA, Kaye SB, Morrison R, Twelve C, Wilson P, Duncan R, Thomson AH, Murray LS, Hilditch TE, Murray T, Burtles S, Fraier D, Frigerio E, Cassidy J, Clin. Cancer Res., 5, 83 (1999)

[9] Pendri A, Conover CD, Greenwald RB, Anti-Cancer Drug Design, 13, 387 (1998)

[10] Terwogt JMM, Huinink WWB, Schellens JHM, Schot M, Mandjes IAM, Zurlo MG, Rocchetti M, Rosing H, Koopman FJ, Beijnen JH, Anti-Cancer Drugs, 12, 315 (2001)

[11] Maeda H, Med. Res. Rev., 6, 181 (1991)

[12] Greenwald RB, Conover CD, Pendri A, Choe YH, Martinez A, Wu D, Guan S, Yao Z, Shum KL, J. Control. Release, 61, 281 (1999)

[13] Greenwald RB, Pendri A, Conover CD, Lee C, Choe YH, Gilbert C, Martinez A, Xia J, Wu D, Hsue M, Bioorg. Med. Chem., 6, 551 (1998)

[14] Fraier D, Frigerio E, Brianceschi G, Casati M, Benecchi A, James C, J. Pharm. Biom. Anal., 22, 505 (2000)

[15] Conover CD, Greenwald RB, Pendri A, Gilbert CW, Shurn KL, Cancer Chemotherm. Pharmacol., 42, 407 (1998)

[16] Caiolfa VR, Zamai M, Fiorino A, Frigerio E, Pellizzoni C, d'Argy R, Ghiglieri A, Castelli MG, FaraoM, Pesenti E, Gigli M, Angelucci F, Suarato A, J. Control. Release, 65, 105 (2000)

[17] Giovanella B, Hinz H, Kozielski A, Stehlin J, Silber R, Potmesil M, Cancer Res., 51, 3052 (1991)

[18] Hsiang YH, Liu LF, Wall ME, Wani MC, Nicholas AW, Manikumar G, Kirschenbaum S, Silber R, Potmesil M, Cancer Res., 49, 4385 (1989)

[19] Hertzberg RP, Caranfa MJ, Hecht SM, Biochemistry, 28, 4629 (1989)

[20] Pantazis P, Clin. Cancer Res., 1, 1235 (1995)

[21] Park JG, Choi WM, Lee NJ, Ha CS, Cho WJ, J. Polym. Sci. A: Polym. Chem., 36(10), 1625 (1998)

[22] Choi WM, Chung ID, Lee NJ, Lee YW, Ha CS, Cho WJ, J. Polym. Sci. A: Polym. Chem., 36(13), 2177 (1998)

[23] Jung EY, Chung ID, Lee NJ, Park JS, Ha CS, Cho WJ, J. Polym. Sci. A: Polym. Chem., 38(8), 1247 (2000)

[24] Lee NJ, Kim KH, Rhew HY, Choi WM, Chung ID, Cho WJ, Polym. Int., 49, 1702 (2000)

[25] Lee NJ, Koo JC, Ju SS, Moon SB, Cho WJ, Jeong IC, Lee SJ, Cho MY, Theodorakis EA, Polym. Int., 51, 569 (2002)

[26] Mosmann T, J. Immunol. Methods, 65, 55 (1983)