Abstract
A series of drug delivery systems based on a sodium alginate derivative were prepared by mixing glycyrrhetinic acid (GA) and doxorubicin (DOX) conjugates at different ratios. GA (a liver-targeting ligand) and DOX (an antitumor drug) were both conjugated to oligomeric glycol monomethyl ether-modified sodium alginate (ALG-mOEG) for prolonged duration of action. These NP-based delivery systems exhibited active cell uptake and cytotoxicity in vitro and liver-targeted distribution and anti-tumor activity in vivo. In addition, nanoparticles with a 1:1 (W:W) ratio of GA-ALG-mOEG and DOXALG-mOEG (NPs-3) showed the highest cellular uptake and cytotoxicity in vitro and liver-targeted distribution and antitumor activity in vivo. Specifically, when mixed nanoparticles defined as NPs-3 were injected in mice, liver DOX concentration reached 61.9 μg/g 3 h after injection, and AUC0-∞ and t 1/2 of DOX in liver reached 4744.9 μg·h/g and 49.5 h, respectively. In addition, mice receiving a single injection of NPs-3 exhibited much slower tumor growth (88.37% reduction in tumor weight) 16 days after injection compared with placebo. These results indicate that effective cancer treatment may be developed using mixed NP delivery systems with appropriate ratio of targeted ligand and drug.
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References
Miyata, K., Christie, R.J. and Kataoka, K., React. Funct. Polym., 2011, 71(3): 227
Zhang, L.Z., Zhang, Y.J., Wu, W. and Jiang, X.Q., Chinese J. Polym. Sci, 2013, 31(5): 778
She, W., Luo, K., Zhang, C., Wang, G., Geng, Y., Li, L., He, B. and Gu, Z.W., Biomaterials, 2013, 34(5): 1613
Zhang, Q., Ko, N.R. and Oh, J.K., Chem. Commun., 2012, 48(61): 7542
Xiong, X.B. and Lavasanifar, A., ACS Nano, 2011, 5(6): 5202
Zhang, J., Li C., Xue, Z.Y., Cheng, H.W., Huang, F.W., Zhuo, R.X. and Zhang, X.Z., Acta Biomater., 2011, 7(4): 1665
Zhang, C.N., Wang W., Liu, T., Wu, Y.K., Guo, H., Wang, P., Tian, Q., Wang, Y.M. and Yuan, Z., Biomaterials, 2012, 33(7): 2187
Zhao, B.X., Zhao, Y., Huang, Y., Luo, L.M., Song, P., Wang, X., Chen, S., Yu, K.F., Zhang, X. and Zhang, Q., Biomaterials, 2012, 33(8): 2508
Zhao, J., Mi, Y., Liu, Y. and Feng, S.S., Biomaterials, 2012, 33(6): 1948
Romberg, B., Hennink, W.E. and Storm, G., Pharm. Res., 2008, 25(1): 55
Shen, Y., Jin, E., Zhang, B., Murphy, C.J., Sui, M., Zhao, J., Wang, J., Tang, J., Fan, M. and Van, K.E., Murdoch, W.J., J. Am. Chem. Soc., 2010, 132(12): 4259
Wang, X.J., Wu, G.L., Lu, C.C., Zhao, W.P., Wang, Y.N., Fan, Y.G., Gao, H. and Ma, J.B., Eur. J. Pharm. Sci., 2012, 47(1): 256
Chen, C.C. and Borden, M.A., Biomaterials, 2011, 32(27): 6579
Guo, H., Yang, C.L., Hu, Z.P., Wang, W., Wu, Y.K., Lai, Q.Y. and Yuan, Z., J. Mater. Chem. B, 2013, 1(43): 5933
Takae, S., Akiyama, Y., Otsuka, H., Nakamura, T., Nagasaki, Y. and Kataoka, K.K., Biomacromolecules, 2005, 6(2): 818
Bae, Y., Nishiyama, N. and Kataoka, K.K., Bioconjugate Chem., 2007, 18(4): 1131
Moradi, E., Vllasaliu, D., Garnett, M., Falcone, F. and Stolnik, S., RSC Adv., 2012, 2(7): 3025.
Lamanna, G., Russier, J., Dumortier, H. and Bianco, A., Biomaterials, 2012, 33(22): 5610
Yoo, H.S. and Park, T.G., J. Control. Release, 2004, 96(2): 273
Bae, Y., Alani, A.W., Rockich, N.C., Lai, T.S. and Kwon, G.S., Pharm. Res., 2010, 27(11): 2421
Tsai, H.C., Chang, W.H., Lo, C.L., Tsai, C.H., Chang, C.H., Ou, T.W., Yen, T.C. and Hsiue, G.H., Biomaterials, 2010, 31(8): 2293
Wu, X.L., Kim, J.H., Koo, H., Bae, S.M., Shin, H., Kim, M.S., Lee, B.H., Park, R.W., Kim, I.S. and Choi, K., Bioconjugate Chem., 2010, 21(2): 208
Huang, W., Wang, W., Wang, P., Tian, Q., Zhang, C.N., Wang, C.H., Yuan, Z., Liu, M., Wan, H.Y. and Tang, H., Acta Biomater., 2010, 6(10): 3927
Tian, Q., Wang, X.H., Wang, W., Zhang, C.N., Liu, Y. and Yuan, Z., Int. J. Pharm., 2010, 400: 153
Tian, Q., Wang, X.H., Wang, W., Zhang, C.N., Wang, P. and Yuan, Z., Nanomed.-Nanotechnol. Biol. Med., 2012, 8(6): 870
Frederick, C.A., Williams, L.D., Ughetto, G., Marel, G.A., Boom, J.H., Rich, A. and Wang A.H., Biochemistry, 1990, 29(10): 2538
Zhao, L.L., Zhu, L.J., Liu, F.Y., Liu, C.Y., Shan, D., Wang, Q., Zhang, C.L., Li, J.L., Liu, J.G., Qu, X.Z. and Yang, Z.Z., Int. J. Pharm., 2011, 410: 83
Rastello, M., Leonard, M., Hubert, P., Marcha, l P., Stequert, A., Castel, C., Favre, E., Dellacherie, E., J. Colloid Interface Sci., 2004, 273(1): 131
Sheeja S.R., Mangalam N.A., Prathapachandra Kurup M.R., Sheena Mary Y., Raju K., Varghese H.T. and Panicker C.Y., J. Mol. Struct., 2010, 973: 36
Torchilin, V., Adv. Drug Deliv. Rev., 2011, 63(3): 131
Huang, K., Ma, H., Liu, J., Huo, S., Kumar, A., Wei, T., Zhang, X., Jin, S., Gan, Y. and Wang P.C., ACS Nano, 2012, 6(5): 4483
Fonge, H., Huang, H., Scollard, D., Reilly, R.M. and Allen, C., J. Control. Release, 2012, 157(3): 366
Yuan, H.Y. and Zhang, S.L., Appl. Phys. Lett., 2010, 96(3): 033704
Du, J.Z., Du, X.J., Mao, C.Q. and Wang, J., J. Am. Chem. Soc., 2011, 133(44): 17560
Guo, H., Lai, Q.Y., Wang W., Wu, Y.K., Zhang, C.N., Liu, Y. and Yuan, Z., Int. J. Pharm., 2013, 451: 1
Lu, D.X., Wen, X.T., Liang, J., Zhang, X.D., Gu, Z.W. and Fan, Y.J., Chinese J. Polym. Sci, 2008, 26(3): 369
Tian, Q., Zhang, C.N., Wang, X.H., Wang, W., Huang, W., Cha, R.T., Wang, C.H., Yuan, Z., Liu, M., Wang, H.Y. and Tang, H., Biomaterials, 2010, 31(17): 4748
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This work was financially supported by the National Natural Science Foundation of China (Nos. 51073080 and 51273095), Natural Science Foundation of Tianjin (No. 13JCYBJC25100) and PCSIRT (No. IRT1257).
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Guo, H., Yang, Cl., Wang, W. et al. Studies on antineoplastic effect by adjusting ratios of targeted-ligand and antitumor drug. Chin J Polym Sci 32, 540–550 (2014). https://doi.org/10.1007/s10118-014-1432-y
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DOI: https://doi.org/10.1007/s10118-014-1432-y