Improved Pharmacokinetics and Efficacy of a Highly Stable Nanoliposomal Vinorelbine

Abstract

Effective liposomal formulations of vinorelbine (5Ј nor-anhydrovinblastine; 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 ϭ 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.Nanoparticles such as small unilamellar liposomes have been shown to improve the pharmacokinetics and tumor localization of encapsulated drugs, modify the toxicities associated with a particular drug, and ultimately enhance antitumor efficacy compared with the nonencapsulated drug (Drummond et al., 2008). For the success of liposomal drug delivery, the stable encapsulation of an amphipathic drug in the lumen (Mayer et al., 1985;Haran et al., 1993;Webb et al., 1995;Drummond et al., 2008) of liposomes with long-circulating properties (Allen et al., 2006;Drummond et al., 2008) is preferred, resulting in the ability of such liposomes to localize preferentially in solid tumors through the enhanced permeability and retention effect (Matsumura and Maeda, 1986;Drummond et al., 1999). A liposomal drug is in effect a prodrug, inactive until released from the confines of its carrier, rendering it bioavailable and capable of subsequently acting on its molecular target. Therefore, the ability of the carrier to deliver the active chemical agent to the site of disease, and to subsequently release the drug so as to achieve the desired therapeutic outcome, ar...

Pharmacokinetics and tissue distribution studies of orally administered nanoparticles encapsulated ethionamide used as potential drug delivery system in management of multi-drug resistant tuberculosis

“…The increase in AUC 0-∞ of ethionamide in the case of drug-loaded nanoparticles may also be explained by the prolonged release of ethionamide from nanoparticles in the blood as well as decreased clearance of drug from the circulation. Similar results have been reported in mice and guinea pigs following administration of other drug-loaded PLGA nanoparticles (Radwan et al, 1999;Pandey et al, 2003a;Hariharan et al, 2006;Drummond et al, 2009;Kalaria et al, 2009;Veera Reddy et al, 2009).…”

A New Lipid-Based Nano Formulation of Vinorelbine

“…Thus, a new strategy is needed for aqueous injections of vinorelbine. Recently, different laboratories have been developing sterically stabilized liposomal formulations of vinorelbine, but stable high drug loading with high PEGylation has been difficult to achieve (11,12). Here, we describe a new lipid-based formulation of VLB using PEGylated phospholipid micelles, which should overcome the loading and stability problems of stealth liposomal formulations of VLB.…”

“…Two milliliters of dialysis medium were withdrawn at 0.5, 1, 2, 3, 4,6,8,10,12,20,22,24,28, and 48 h of the experiment. Samples were also taken from the dialysis membrane tubing before and after the experiment.…”

Pharmacokinetics and Tissue Distribution of Dual-Targeting Daunorubicin Liposomes in Mice

“…When comparing the concentration-time profile of free daunorubicin with that of daunorubicin liposomes, daunorubicin blood exposure was clearly extended by the pegylated liposomes, showing a long-circulatory effect [9][10][11] . Pegylation with PEG 2000 -DSPE prevents adsorption of opsonin proteins onto the surface of daunorubicin liposomes, thereby prolonging the circulation time of the liposomes by avoiding rapid uptake by the reticuloendothelial system [12][13][14] .…”