Effect of Bond Linkage on In vitro Drug Release and Anti-HIV Activity of Chitosan-Stavudine Conjugates

Rong Zeng; Zehu Wang; Hongran Wang; Liqiang Chen; Lin Yang; Renzhong Qiao; Liming Hu; Zelin Li

Macromolecular Research, Vol.20, No.4, 358-365, April, 2012

DOI10.1007/s13233-012-0022-5 Export Citation

Effect of Bond Linkage on In vitro Drug Release and Anti-HIV Activity of Chitosan-Stavudine Conjugates

Rong Zeng^†, Zehu Wang, Hongran Wang¹, Liqiang Chen¹, Lin Yang¹, Renzhong Qiao^{1, †}, Liming Hu², and Zelin Li²

Department of Materials Science and Engineering, College of Science and Engineering, Jinan University, Guangzhou, 510632, P. R. China, Korea
¹State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, Beijing, 100029, P. R. China
²College of Life Science and Bioengineering, Beijing University of Technology, Beijing, 100022, P. R. China

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Two kinds of chitosan-stavudine (d4T) conjugates, chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate (Cs-P-d4T) with a phosphoramide linkage and chitosan-5'-O-succinyl-d4T conjugate (Cs-S-d4T) with a succinic spacer, were synthesized using an Atherton-Todd reaction and carbodiimide coupling reaction, respectively, and then structurally characterized. Their in vitro drug release behaviors and anti-human immunodeficiency virus (HIV) activity were investigated and compared. Both of the chitosan-d4T conjugates more strongly prefer to release corresponding d4T derivatives rather than free d4T in a prolonged manner but have different hydrolysis routes. The anti-HIV activity and cytotoxicity evaluated in the MT4 cell line revealed that the anti-HIV selectivity index was in the following order: Cs-P-d4T > d4T >> Cs-S-d4T since the released d4T-5'-(O-isopropyl) monophosphate from Cs-P-d4T can bypass the rate-limiting bottleneck of nucleoside phosphorylation, while the released 5'-O-succinyl-d4T from Cs-Sd4T has to be hydrolyzed to d4T and then successively phosphorylated to its active form to exert antiviral activity. The results suggested that constructing a chitosan-nucleoside reverse transcriptase inhibitor (NRTI) conjugate with a phosphoramide linkage may be an efficient approach for improving NRTI therapy efficacy in antiretroviral treatment.

Keywords:chitosan;stavudine;polymeric conjugate;drug release;anti-HIV activity.

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[2] Khandare J, Minko T, Prog. Polym. Sci., 31, 359 (2006)

[3] Pasut G, Veronese FM, Prog. Polym. Sci., 32, 933 (2007)

[4] Garnett MC, Adv. Drug Deliv. Rev., 53, 171 (2001)

[5] D’souza AJM, Topp EM, J. Pharm. Sci., 93, 1962 (2004)

[6] Shiose Y, Kuga H, Ohki H, Ikeda M, Yamashita F, Hashida M, Bioconjug. Chem., 20, 60 (2009)

[7] Zhang ZS, Zhang QB, Wang J, Shi XL, Zhang JJ, Song HF, Carbohydr. Polym., 79, 628 (2010)

[8] Kumar MNVR, Muzzarelli RAA, Muzzarelli C, Sashiwa H, Domb AJ, Chem. Rev., 104(12), 6017 (2004)

[9] Vinsova J, Vavrikova E, Curr. Pharm. Des., 14, 1311 (2008)

[10] Park JH, Saravanakumar G, Kim K, Kwon IC, Adv.Drug Deliv. Rev., 62, 28 (2010)

[11] Ouchi T, Banba T, Fujimoto M, Hamamoto S, Macromol.Chem. Phys., 190, 1817 (1989)

[12] Lee E, Kim H, Lee IH, Jon S, J. Control. Release., 140, 79 (2009)

[13] Riddler SA, Anderson RE, Mellors JW, Antiviral Res., 27, 189 (1995)

[14] Wiebe LI, Knaus EE, Adv. Drug Deliv. Rev., 39, 63 (1999)

[15] Martina JC, Hitchcock MJM, Clercq ED, Prusoff WH, Antiviral Res., 85, 34 (2010)

[16] Giammona G, Cavallaro G, Fontana G, Pitarresi G, Carlisi B, J. Control. Release., 54, 321 (1998)

[17] Chimalakonda KC, Agarwal HK, Kumar A, Parang K, Mehvar R, Bioconjug. Chem., 18, 2097 (2007)

[18] Yang L, Chen LQ, Zeng R, Li C, Qiao RZ, Hu LM, Li ZL, Bioorg. Med. Chem., 18, 117 (2010)

[19] Sun XB, Kang JX, Zhao YF, Chem. Commun., 20, 2414 (2002)

[20] Nishimura S, Kohgo O, Kurita K, Kuzuhara H, Macromolecules., 24, 4745 (1991)