Sustained Liver Targeting and Improved Antiproliferative Effect of Doxorubicin Liposomes Modified with Galactosylated Lipid and PEG-Lipid

Abstract

Abstract. In this study, a cleavable PEG-lipid (methoxypolyethyleneglycol 2000-cholesteryl hemisuccinate, PEG 2000 -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 PEG 2000 -CHEMS, PEG-CL), and pegylated galactosylated liposomes (modified with CHS-ED-LA and PEG 2000 -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 PEG 2000 -CHEMS, and CHS-ED-LA represents a potentially advantageous strategy in the therapy of liver cancers or other liver diseases.

Cleavable PEGylation: a strategy for overcoming the “PEG dilemma” in efficient drug delivery

“…It is a quite promising drug delivery system for cancer diagnosis and treatment in the future (Kuai et al, 2011). vinyl ether bond tumor interstitial fluid (pH 6.5-7.2); endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0) (Shin et al, 2003;Komeda et al, 2013) mPEG-b-P(ATMC-co- (Kale & Torchilin, 2007b;Prabaharan et al, 2009;Chen et al, 2010;Swati et al, 2011;Chen et al, 2012;Koren et al, 2012;Zhou et al, 2012;Sawant et al, 2012;Dong et al, 2013;Jiang et al, 2013;Koutroumanis et al, 2013;Quader et al, 2014;Wang et al, 2014a;Du et al, 2015) Hydrolyse ( (Ishida et al, 2001;Wang et al, 2010b;Chen et al, 2011;Hammer et al, 2014;Tang et al, 2014) Enzymolysis (MPP is expressed highly) (Zhang et al, 2...…”

The possible protective role of 6-gingerol on a model of hepatic injury induced by carbon tetrachloride in adult male albino rats: Histological and immunohistochemical study

“…The liver deals with most of the chemicals entering the body so, it is at high risk of damage. Hepatocytes are the main functional cells of the liver and constitute 60 ~ 80% of the mass of the liver tissue [3] .…”

Local Targeted Therapy of Liver Metastasis from Colon Cancer by Galactosylated Liposome Encapsulated with Doxorubicin

“…Many investigators reported that liposomes modified with galactosylated lipid could specifically deliver their contents to liver, elevate drug concentration in liver and promote anti-tumor effect [35], [36], [37], [38]. However, very few studies, to our knowledge, about their application in liver metastasis from primary tumors have been reported.…”