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In Vitro and In Vivo Studies of Different Liposomes Containing Topotecan

Hao, Yan-Li    (Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University   ); Deng, Ying-Jie    (Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University   ); Chen, Yan    (Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University   ); Wang, Xiu-Min    (Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University   ); Zhong, Hai-Jun    (Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University   ); Suo, Xu-Bin    (Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University  );
  • 초록

    Liposome as a carrier of topotecan (TPT), a promising anticancer drug, has been reported in attempt to improve the stability and antitumor activity of TPT. However, the biodistr ibution pattern of TPT liposome in vivo and PEG-modified liposome containing TPT have not been studied systemically. In this paper, the in vitro stability and in vivo biodistribution behavior of several liposomes containing TPT with different lipid compositions and PEG-modification were studied. Compared with the 'fluid' liposome (S-Lip) composed of soybean phosphatidylcholine (SPC), the 'solid' liposome (H-Lip) composed of hydrogenated soybean phosphatidylcholine HSPC decreased the leaking efficiency of TPT from liposome and enhanced the stability of liposome in fetal bovine serum (FBS) or human blood plasma (HBP). The results of biodistribution studies in S $_{180}$ tumor-bearing mice showed that liposomal encapsulation increased the concentrations of total TPT and the ratio of lactone form in plasma. Compared with free TPT, S-Lip and H-Lip resulted in 5- and 19- fold increase in the area under the curve (AUC $_{0\rightarrow\propto}$ ), respectively. PEG- modified H-Lip (H-PEG) showed 3.7-fold increase in AUC $_{0\rightarrow\propto}$ compared with H-Lip, but there was no significant increase in t $_{1/2}$ and AUC $_{0\rightarrow\propto}$ for PEG-modified S-Lip (S-PEG) compared with S-Lip. Moreover, the liposomal encapsulation changed the biodistribution behavior, and H-Lip and H-PEG dramatically increased the accumulation of TPT in tumor, and the relative tumor uptake ratios were 3.4 and 4.3 compared with free drug, respectively. There was also a marked increase in the distribution of TPT in lung when the drug was encapsulated into H-Lip and H-PEG. Moreover, H-PEG decreased the accumulation of TPT in bore marrow compared with unmodified H-Lip. All these results indicated that the membrane fluidity of liposome has an important effect on in vitro stability and in vivo biodistribution pattern of liposomes containing TPT, and PEG-modified 'solid' liposome may be an efficient carrier of TPT.


  • 주제어

    Topotecan .   'Fluid' liposome .   'Solid' liposome .   PEG-modified liposome .   Biodistribution.  

  • 참고문헌 (38)

    1. Allen, T. M., A study of phospholipid interactions between highdensity lipoproteins and small unilamellar vesicles. Biochim. Biophys. Acta, 640(2), 385-397 (1981) 
    2. Allen, T. M. and Hansen, C. B., Pharmacokinetics of steath versus conventional liposomes:effect of dose. Biochim. Biophys. Acta,1068, 133-141 (1991) 
    3. Burke, T. G., Liposomal stabilization of camptothecin's lactone ring. J. Am. Chem. Soc., 114, 8318-8319 (1990) 
    4. Damen, J., Regts, J., and Scherphof, G., Transfer and exchange of phospholipid between small unilamellar liposomes and rat plasma high density lipoproteins. Dependence on cholesterol content and phospholipid composition. Biochim. Biophys. Acta, 665(3), 538-45 (1981) 
    5. Fassberg, J. and Stella, V. J., A kinetic and mechanistic study of the hydrolysis of camptothecin and some analogues. J. Pharm. Sci., 81, 676-684 (1992) 
    6. Gabilzon, A., Goren, D., Horowitz, A. T., Tzemach, D., Lossos, A., and Siegal, T., Long-circulating lipsomes for drug delivery in cancer therapy:a review of biodistribution studies in tumorbearing animals. Adv. Drug Del. Rev., 24, 337-344 (1997) 
    7. Haran, G., Cohen, R., Bar, L. K., and Barenholz, Y., Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim. Biophys. Acta, 1151, 201-215 (1993) 
    8. Jaxel, C. and Kohn, K. W., Structure activity study of the actions of camptothecin derivatives on mammalian topoisomerase I. Cancer Res., 49, 5077-5082 (1989) 
    9. Subbarao, N. K. and MacDonald, R. C., Lipid unstauration influences melittin-induced leakage of vesicles. Biochim. Biophys. Acta, 1189, 101-107 (1994) 
    10. Subramanian, D. and Muller, M. T., Liposomal encapsulation increases the activity of the topoisomerase I inhibitor topotecan. Oncol. Res., 7, 461-469 (1995) 
    11. Tardi, P., Choice, E., Masin, D., Redelmeier, T., Bally, M., and Madden, T. D., Liposomal encapsulation of topotecan enhances anticancer efficacy in murine and human xenograft models. Cancer Res., 60, 3389-3393 (2000) 
    12. Burke, T. G. and Gao, X., Stability of topotacen in low pH liposome composed of disteroylphosphatidylcholine. J. Pharm. Sci., 83, 967-969 (1994) 
    13. Munn, M. W. and Parce, J. W., Antibody-dependent phagocytosis of haptenated liposomes by human neutrophils dependent on the physical state of the liposomal membrane. Biochim. Biophys. Acta, 692, 101-108 (1982) 
    14. Storm, G., Belliot, S. O., Daemen, T., and Lasic, D., Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system. Adv. Drug Del. Rev., 17, 31- 48 (1995) 
    15. Woodle, M. C., Sterically stabilized liposome therapeutics. Adv. Drug Del. Rev., 16, 249-265 
    16. Wu, N. Z., Da, D., Rudoll, T. L., Needham, D., Whorton, A. R., and Dewhirst, M. W. (1993) Increased microvascular permeability contributes to preferential accumulation of Steath liposomes in tumor tissue. Cancer Res., 53, 3765- 3770 (1995) 
    17. Senior, J. and Gregoriadis, G., Is half-life of circulating liposomes determined by changes in their permeability? FEBS Lett., 145, 109-114 (1982) 
    18. Giovanella, B. C. and Cheng, H. R., Complete growth inhibition of human cancer xenografts in nude mice by treatment with 20-S-camptothecin. Cancer Res., 51, 3052-3055 (1991) 
    19. Patel, H. M., Tuzel, N. S., and Ryman, B. E., Inhibitory effect of cholesterol on the uptake of liposomes by liver and spleen. Biochim. Biophys. Acta, 761, 142-151 (1983) 
    20. Allen, T. M., Hansen, C. B., and Lopes de Menezes, D. E., Pharmacokinetics of long-corculating liposomes. Adv. Drug Del. Rev., 16, 267-284 (1995) 
    21. Liu, J., Hong, R. L., Cheng, W. F., Hong, K., Chang, F. H., and Tseng, Y. L., Simple and efficient liposomal encapsulation of topotecan by ammonium sulfate gradient: stability, pharmacokinetic and therapeutic evaluation. Anti-caner Drugs, 13, 709-717 (2002) 
    22. Kingsbury, W. D., Boehm, J. C., Jakas, D. R., Holden, K. G., Hecht, S. M., Gallagher, G., Caranfa, M. J., McCabe, F. L., Faucette, L. F., and Johnson, R. K., Synthesis of watersoluble (aminoalkyl)-camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J. Med. Chem., 34, 98-107 (1991) 
    23. Torchilin, V. P., How do polymers prolonged circulation time of liposomes? J. Liposome Res., 6, 99-116 (1996) 
    24. Creemers, G. J., Bolis, G., Gore, M., Scarfone, G., Lacave, A. J., Guastalla, J. P., Despax, R., Favalli, G., Kreinberg, R., Van Belle, S., Hudson, I., Verweij, J., and Ten Bokkel Huinink, W. W., Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large Eurpean phase study. J. Clin. Oncol., 14, 3056-3061 (1996) 
    25. Papisov, M. I., Theroretical considerations of RES-avoiding lipsomes: Molecular mechancis and Chemistry of liposome interactions. Adv. Drug Del. Rev., 32, 119-138 (1998) 
    26. Mayer, L. D., Tai, L. C., Bally, M. B., Mitilenes, G. N., Ginsberg, R. S., and Cullis, P. R., Characterization of liposomal systems containing doxorubicin entrapped in response to pH gradients. Biochim. Biophys. Acta, 1025, 143-151 (1990) 
    27. Osaka, S., Tsuji, H., and Krwada. H., Uptake of liposomes surface-modified with glycyrrhizin by primary cultured rat hepatocytes. Biol. Pharm. Bull., 17, 940-943 (1994) 
    28. Creemers, G. J., Gerrits, C. J., Schellens, J. H., Planting, A. S., van der Burg, M. E., van Beurden, V. M., de Boer-Dennert, M., Harteveld, M., Loos, W., Hudson, I., Stoter, G., and Verweij, J., Phase and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer. J. Clin. Oncol., 14, 2540-2545 (1996) 
    29. Hara, T., Ishihara, H., Aramaki, Y., and Tsuchiya, S., Specific uptake of asialofetuin-labeled liposomes by isolated hepatocytes. Int. J. Pharm., 42, 69-75 (1988) 
    30. Gabizon, A. and Papahadjopoulos, D., Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc. Natl. Acad. Sci. U.S.A., 85, 6949-6953 (1988) 
    31. Wall, M. E., Wani, M. C., and Cook, C. E., Plant AntitumorAgents: The Isolation and Structure of Camptothecin, a Novel Alkaloid Leukemia and Tumor Inhibitor from Camptotheca acuminata. J .Am. Chem. Soc., 88, 3888-3890 (1966) 
    32. Senior, J., Crawley, J. C., and Gregoriadis. G., Tissue distribution of liposomes exhibiting long half-lifes in the circulation after intrvenous injection. Biochim. Biophys. Acta, 839, 1-8 (1985) 
    33. Burke, T. G., Mishra, A. K., Wani, M. C., and Wall, M. E., Lipid bilyer partitioning and stability of camptothecin drugs. Biochemistry, 32, 5352-5364 (1993) 
    34. Gabizon, A., Liposome circulation time and tumor targeting: implications for cancer chemotherapy. Adv. Drug Del. Rev., 16, 285-294 (1995) 
    35. Senior, J. and Alving, C. R., Fate and behavior of liposomes in vivo: a review of controlling factors. Crit. Rev. Ther. Drug Carrier Sys., 3, 123-193 (1987) 
    36. Hsiang, Y. and Liu, L. F., Identification of mammalian DNA topoisomeraseas an intracellular target of the anticancer drug camptothecin. Cancer Res., 48, 1722-1726 (1988) 
    37. Sugarman, S. M., Lipid-complexed camptothecin: formulation and initial biodistribution and antitumor activity studies. Cancer Chemother. Pharmacol., 37, 531-538 (1996) 
    38. Warner, D. L. and Burke, T. G., Simple and versatile high-performance liquid chromatographic method for the simultaneous quantitation of the lactone and carboxylate forms of camptothecin anticancer drugs. J. Chromatogr. B, 691, 161- 171 (1997) 

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