Liposomes with entrapped doxorubicin exhibit extended blood residence times

Canadian Liposome Co. Ltd, North Vancouver, Canada.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 04/1990; 1023(1):133-9. DOI: 10.1016/0005-2736(90)90018-J
Source: PubMed

ABSTRACT The blood residence time of liposomes with entrapped doxorubicin is shown to be significantly longer than for identically prepared empty liposomes. Liposomal doxorubicin systems with a drug-to-lipid ratio of 0.2 (w/w) were administered at a dose of 100 mg lipid/kg. Both doxorubicin and liposomal lipid were quantified in order to assess in vivo stability and blood residence times. For empty vesicles composed of phosphatidylcholine (PC)/cholesterol (55:45, mole ratio) and sized through filters of 100 nm pore size, 15-25% of the administered lipid dose was recovered in the blood 24 h after i.v. injection. The percentage of the dose retained in the circulation at 24 h increased 2-3-fold when the liposomes contain entrapped doxorubicin. For 100 nm distearoyl PC/chol liposomal doxorubicin systems, as much as 80% of the injected dose of lipid and drug remain within the blood compartment 24 h after i.v. administration.

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    • "A variety of liposomal properties or formulation methods play important roles in determining the degree of stability and hence the rate of drug release from the liposomal carrier. A careful choice of liposomal lipids, including the inclusion of highly saturated phospholipids (Bally et al., 1990; Gabizon et al., 1993), the presence of cholesterol (Papahadjopoulos et al., 1972; Drummond et al., 1999), and appropriate mixtures of sphingomyelin and cholesterol (Kirby and Gregoriadis, 1983; Webb et al., 1995), all regulate the permeability of the liposomal membrane to encapsulated drugs. Drug retention is equally dependent on the physicochemical properties of the drug to be encapsulated and the use of transmembrane gradients to both load and stabilize liposomal formulations of weakly basic amphipathic drugs. "
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    ABSTRACT: Effective liposomal formulations of vinorelbine (5' nor-anhydro-vinblastine; VRL) have been elusive due to vinorelbine's hydrophobic structure and resulting difficulty in stabilizing the drug inside the nanocarrier. Triethylammonium salts of several polyanionic trapping agents were used initially to prepare minimally pegylated nanoliposomal vinorelbine formulations with a wide range of drug release rates. Sulfate, poly(phosphate), and sucrose octasulfate were used to stabilize vinorelbine intraliposomally while in circulation, with varying degrees of effectiveness. The release rate of vinorelbine from the liposomal carrier was affected by both the chemical nature of the trapping agent and the resulting drug-to-lipid ratio, with liposomes prepared using sucrose octasulfate displaying the longest half-life in circulation (9.4 h) and in vivo retention in the nanoparticle (t(1/2) = 27.2 h). Efficacy was considerably improved in both a human colon carcinoma (HT-29) and a murine (C-26) colon carcinoma model when vinorelbine was stably encapsulated in liposomes using triethylammonium sucrose octasulfate. Early difficulties in preparing highly pegylated formulations were later overcome by substituting a neutral distearoylglycerol anchor for the more commonly used anionic distearoylphosphatidylethanolamine anchor. The new pegylated nanoliposomal vinorelbine displayed high encapsulation efficiency and in vivo drug retention, and it was highly active against human breast and lung tumor xenografts. Acute toxicity of the drug in immunocompetent mice slightly decreased upon encapsulation in liposomes, with a maximum tolerated dose of 17.5 mg VRL/kg for free vinorelbine and 23.8 mg VRL/kg for nanoliposomal vinorelbine. Our results demonstrate that a highly active, stable, and long-circulating liposomal vinorelbine can be prepared and warrants further study in the treatment of cancer.
    Journal of Pharmacology and Experimental Therapeutics 11/2008; 328(1):321-30. DOI:10.1124/jpet.108.141200 · 3.97 Impact Factor
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    • "The plasma and tissue samples were kept at K20 8C until analysis. A previous HPLC analysis of biological samples carried out by Bally et al. [24] indicated that O98% of the fluorescence detected was due to nonmetabolized DOX after mice receiving liposomal DOX. In our studies, the concentrations of DOX in plasma and tissue samples were assayed by a spectrofluorometric method described by Mayer et al [25]. "
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    ABSTRACT: This paper described the synthesis of a novel galactosylated lipid with mono-galactoside moiety, (5-Cholesten-3beta-yl) 4-oxo-4-[2-(lactobionyl amido) ethylamido] butanoate (CHS-ED-LA), and the targetability of doxorubicin (DOX), a model drug, in liposomes containing 10% mol/mol CHS-ED-LA (galactosylated liposomes, GalL) to the liver was studied. The weighted-average overall drug targeting efficiency (Te(*)) was used to evaluate the liver targetability of GalL DOX. The results showed that GalL DOX gave a relatively high (Te(*))(liver) value of 64.6%, while DOX in conventional liposome (CL DOX) only gave a (Te(*))(liver) value of 21.8%. In the liver, the GalL DOX was mainly taken up by parenchymal cells (88% of the total hepatic uptake). Moreover, preinjection of asialofetuin significantly inhibited the liver uptake of GalL DOX (from 70 to 12% of the total injected dose). It was suggested that liposomes containing such novel galactosylated lipid, CHS-ED-LA, had a great potential as drug delivery carriers for hepatocyte-selective targeting.
    European Journal of Pharmaceutics and Biopharmaceutics 02/2006; 62(1):32-8. DOI:10.1016/j.ejpb.2005.07.004 · 3.38 Impact Factor
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    • "Clinical trials and animal studies, or studies with cells in culture using liposomes as carriers of DOX show a reduction of complications and side effects, enhanced antitumor activity, and improved therapeutic index (Mayer et al, 1989). These advantages are thought to arise from a sustained release of the liposomal drug into the blood stream (Bally et al, 1990). "
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    ABSTRACT: Summary Recently, liposomes have gained a special interest as gene delivery systems: over 30 human clinical trials for gene delivery using cationic liposomes have been approved; all these delivery methods use intratumoral, subcutaneous and other local delivery but not systemic delivery due to the toxicity of cationic lipids. Stealth liposomes (coated with polyethyleneglyc ol to camouflage the liposome and evade detection by the immune system) have a remarkable longevity in body fluids, have negligible toxicity with respect to their lipid components, reduce the toxicity of the encapsulated drug, and can deliver efficiently their doxorubicin payload (DOXIL) or cis-platin to tumor lesions. The mechanism of stealth liposome accumulation in tumors involves their extravasation through gaps in the endothelium of tumor vessels. DOXIL can sustain a much higher concentration of Doxorubicin in tumor tissue compared to free drug administration at comparable doses. Liposomes tagged with folate-PEG or with antibodies can target specific tissues. We propose that "stealth" liposomes, could find future applications to systemically deliver plasmid DNA with therapeutic genes ( p53 , HSV- tk , angiostatin) to primary tumors and their metastases leading to complete cancer eradication. Abbreviations: AUC, area-under-the-plasma concentration vs time curve CHOL, cholesterol CL, cardiolipin DDAB, dimethyldioctadecylammonium bromide DOGS, dioctadecylamidoglycylspermine DOPE, dioleyl phosphatidylethanolamine DOSPA , (2,3-dioleyloxy-N-(20({2,5-bis((3- aminopropyl)amino)-1-oxypentyl}amino)ethyl)- N,N-dimethyl-2,3-bis(9-octadecenyloxy)-1- propanaminium trifluoroacetate DOTMA or lipofectin, N-(1-(2,3-dioleyloxy) propyl)-N, N, N trimethylammonium chloride
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