Abstract
In this study, a cleavable PEG-lipid (methoxypolyethyleneglycol 2000-cholesteryl hemisuccinate, PEG2000-CHEMS) linked via ester bond and galactosylated lipid ((5-cholesten-3β-yl) 4-oxo-4-[2-(lactobionyl amido) ethylamido] butanoate, CHS-ED-LA) were used to modify doxorubicin (DOX) liposome. DOX was encapsulated into conventional liposomes (CL), galactosylated liposomes (modified with CHS-ED-LA, GalL), pegylated liposomes (modified with PEG2000-CHEMS, PEG-CL), and pegylated galactosylated liposomes (modified with CHS-ED-LA and PEG2000-CHEMS, PEG-GalL) using an ammonium sulfate gradient loading method and then intravenously injected to normal mice. Both PEG-GalL DOX and GalL DOX gave relatively high overall drug targeting efficiencies to liver ((T e)liver) and were mainly taken up by hepatocyte. However, PEG-GalL DOX showed unique “sustained targeting” characterized by slowed transfer of DOX to liver and reduced peak concentrations in the liver. The biodistribution and antitumor efficacy of various DOX preparations were studied in hepatocarcinoma 22 (H22) tumor-bearing mice. The inhibitory rate of PEG-GalL DOX to H22 tumors was up to 94%, significantly higher than that of PEG-CL DOX, GalL DOX, CL DOX, and free DOX, although the tumor distribution of DOX revealed no difference between PEG-GalL DOX and PEG-CL DOX. Meanwhile, the gradual increase in the liver DOX concentration due to the sustained uptake of PEG-GalL DOX formulations resulted in lower damage to liver. In conclusion, the present investigation indicated that double modification of liposomes with PEG2000-CHEMS, and CHS-ED-LA represents a potentially advantageous strategy in the therapy of liver cancers or other liver diseases.
Similar content being viewed by others
References
Ashwell G, Harford J. Carbohydrate-specific receptors of the liver. Annu Rev Biochem. 1982;51:531–54.
Wu J, Nantz MH, Zern MA. Targeting hepatocytes for drug and gene delivery: emerging novel approaches and application. Front Biosci. 2002;7:d717–25.
Mandal AK, Das S, Basu MK, Chakrabarti RN, Das N. Hepatoprotective activity of liposomal flavonoid against arsenite-induced liver fibrosis. Pharmacol Exp Ther. 2007;320:994–1001.
Sato A, Takagi M, Shimamoto A, Kawakami S, Hashida M. Small interfering RNA delivery to the liver by intravenous administration of galactosylated cationic liposomes in mice. Biomaterials. 2007;28:1434–42.
Managit C, Kawakami S, Yamashita F, Hashida M. Effect of galactose density on asialoglycoprotein receptor-mediated uptake of galactosylated liposomes. J Pharm Sci. 2005;94:2266–75.
Murao A, Nishikawa M, Managit C, Wong J, Kawakami S, Yamashita F, et al. Targeting efficiency of galactosylated liposomes to hepatocytes in vivo: effect of lipid composition. Pharm Res. 2002;19:1808–14.
Wang SN, Deng YH, Xu H, Wu HB, Qiu YK, Chen DW. Synthesis of a novel galactosylated lipid and its application to the hepatocyte-selective targeting of liposomal doxorubicin. Eur J Pharm Biopharm. 2006;62:32–8.
Levy G. Targeted drug delivery—some pharmacokinetic considerations. Pharm Res. 1987;4:3–4.
Takino T, Koreeda N, Nomura T, Sakaeda T, Yamashita F, Takakura Y, et al. Control of plasma cholesterol-lowering action of probucol with various lipid carrier systems. Biol Pharm Bull. 1998;21:492–7.
Torchilin VP, Omelyanenko VG, Papisov MI, Bogdanov Jr AA, Trubetskoy VS, Herron JN, et al. Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity. Biochim Biophys Acta. 1994;1195:11–20.
Woodle MC, Lasic DD. Sterically stabilized liposomes. Biochim Biophys Acta. 1992;1113:171–99.
Maruyama K. PEG-immunoliposome. Biosci Rep. 2002;22:251–6.
Gosselin MA, Lee RJ. Folate receptor-targeted liposomes as vectors for therapeutic agents. Biotechnol Annu Rev. 2002;8:103–31.
Cattel L, Ceruti M, Dosio F. From conventional to stealth liposomes: a new frontier in cancer chemotherapy. Tumori. 2003;89:237–49.
Shimada K, Kamps JA, Regts J, Ikeda K, Shiozawa T, Hirota S, et al. Biodistribution of liposomes containing synthetic galactose-terminated diacylglyceryl-poly(ethyleneglycol)s. Biochim Biophys Acta. 1997;1326:329–41.
Gabizon A, Shmeeda H, Horowitz AT, Zalipsky S. Tumor cell targeting of liposome-entrapped drugs with phospholipid-anchored folic acid-PEG conjugates. Adv Drug Deliv Rev. 2004;56:1177–92.
Terada T, Iwai M, Kawakami S, Yamashita F, Hashida M. Novel PEG-matrix metalloproteinase-2 cleavable peptide-lipid containing galactosylated liposomes for hepatocellular carcinoma-selective targeting. J Control Release. 2006;111:333–42.
Xu H, Deng Y, Chen D, Hong W, Lu Y, Dong X. Esterase-catalyzed dePEGylation of pH-sensitive vesicles modified with cleavable PEG-lipid derivatives. J Control Release. 2008;130:238–45.
Lasic DD, Frederick PM, Stuart MCA, Barenholz Y, McIntosh TJ. Gelation of liposome interior: a novel method for drug encapsulation. FEBS Lett. 1992;312:255–8.
Mayer LD, Tai LC, Ko DS, Masin D, Ginsberg RS, Cullis PR, et al. Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res. 1989;49:5922–30.
Gupta PK, Hung CT. Quantitative evaluation of targeted drug delivery systems. Int J Pharm. 1989;56:217–26.
Valle JW, Dangoor A, Beech J, Sherlock DJ, Lee SM, Scarffe JH, et al. Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin (PLD): results of a phase II study. Br J Cancer. 2005;92:628–30.
Lind PA, Naucler G, Holm A, Gubanski M, Svensson C. Efficacy of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma. Acta Oncol. 2007;46:230–3.
Hopewel JW, Duncan R, Wilding D, Chakrabarti K. Preclinical evaluation of the cardiotoxicity of PK2: a novel HPMA copolymer-doxorubicin-galactosamine conjugate antitumour agent. Hum Exp Toxicol. 2001;20:461–70.
Fiume L, Baglioni M, Bolondi L, Farina C, Di Stefano G. Doxorubicin coupled to lactosaminated human albumin: a hepatocellular carcinoma targeted drug. Drug Discov Today. 2008;13:1002–9.
Managit C, Kawakami S, Nishikawa M, Yamashita F, Hashida M. Targeted and sustained drug delivery using PEGylated galactosylated liposomes. Int J Pharm. 2003;266:77–84.
D'Souza AJ, Topp EM. Release from polymeric prodrugs: linkages and their degradation. J Pharm Sci. 2004;93:1962–79.
Lee BS, Yuan X, Xu Q, McLafferty FS, Petersen BA, Collette JC, et al. Stimuli-responsive antioxidant nanoprodrugs of NSAIDs. Int J Pharm. 2009;372:112–4.
Virgolini I, Müller C, Klepetko W, Angelberger P, Bergmann H, O'Grady J, et al. Decreased hepatic function in patients with hepatoma or liver metastasis monitored by a hepatocyte specific galactosylated radioligand. Br J Cancer. 1990;61:937–41.
Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs. 1997;54(S4):15–21.
Wu NZ, Da D, Rudoll TL, Needham D, Whorton AR, Dewhirst MW. Increased microvascular permeability contributes to preferential accumulation of stealth liposomes in tumor tissue. Cancer Res. 1993;53:3765–70.
Park JW, Hong K, Kirpotin DB, Meyer O, Papahadjopoulos D, Benz CC. Anti-HER2 immunoliposomes for targeted therapy of human tumors. Cancer Lett. 1997;118:153–60.
Kirpotin DB, Drummond DC, Shao Y, Shalaby MR, Hong K, Nielsen UB, et al. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res. 2006;66:6732–40.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, S., Xu, H., Xu, J. et al. Sustained Liver Targeting and Improved Antiproliferative Effect of Doxorubicin Liposomes Modified with Galactosylated Lipid and PEG-Lipid. AAPS PharmSciTech 11, 870–877 (2010). https://doi.org/10.1208/s12249-010-9450-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12249-010-9450-8