Abstract
Liposomes are widely used as carriers for anticancer drugs due to their ability to prolong the retention of encapsulated drugs in blood plasma while directing their distribution increasingly into tumor tissue. We report on the development of stealth liposomal formulations for the common chemotherapy drug 5-fluorouracil, where pharmacokinetic studies were undertaken using a microdialysis probe to specifically quantify drug accumulation in tumor, which was contrasted to drug exposure to healthy tissue. Greater accumulation of the drug into the tumor than into healthy subcutaneous tissue was observed for neutral and cationic liposomal 5-fluorouracil polymer complexes in comparison to the conventional delivery by an injected solution. Increased drug accumulation in tumor also correlated to reduced tumor growth. This research has generated new mechanistic insight into liposomal-specific delivery to tumors with potential to improve the efficacy and reduce the toxicity of chemotherapy.
Highlights
Distribution Kinetics UsingLiposomes are widely recognized as effective carriers for anticancer drugs due to their high biocompatibility and their capacity to prolong retention of the encapsulated drugs in plasma and increase their distribution into tumors [1,2,3]
This study reported that the disposition of the anticancer agent, oxaliplatin, in tumor tissues when administered intravenously in cationic polyethylene glycol (PEG) liposomes was different from that of neutral liposomes; namely, that encapsulated anticancer drugs may distribute into tumor tissue more rapidly from cationic liposomes than from neutral liposomes and may be eliminated more slowly from tumor tissue [15]
Liposomes were fabricated with 30 mol% cholesterol and 5 mol% DSPE-PEG2000 for the remainder of the study, which led to mono-dispersed liposomes between 114 and 128 nm in diameter (PDI 0.168) with a 5-FU encapsulation efficiency of 16.0 ± 2.2%, which corresponded to a drug loading of 16.6 ± 2.3%
Summary
Distribution Kinetics UsingLiposomes are widely recognized as effective carriers for anticancer drugs due to their high biocompatibility and their capacity to prolong retention of the encapsulated drugs in plasma and increase their distribution into tumors [1,2,3]. Cationic liposomes can target angiogenic endothelial cells in tumors selectively [5,6,7], due to key biological characteristics of angiogenic tumor blood vessels [8]. Tumor endothelia lack the glycocalyx layer that usually covers vascular endothelial cells of normal healthy tissue, exposing a negatively charged cell surface. Among the microvessel-associated target structures, there are negatively charged cell surface molecules such as glycoproteins, anionic phospholipids, and proteoglycans [9,10,11], which exist as potential binding sites for cationic liposomes and offer the possibility for selectively targeting of diagnostic or therapeutic agents contained within cationic liposomes to tumor endothelial cells. The most-studied anticancer drug to have successfully been encapsulated in cationic liposomes for passive tumor-targeting is paclitaxel (EndoTAG-1® ).
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