title: Pharmacokinetics and pharmacodynamics of chlorambucil delivered in long-circulating nanoemulsion.
abstract: Chlorambucil was incorporated into a nanoemulsion modified with poly(ethylene glycol) to improve its pharmacokinetics and tissue distribution, and thus enhance its therapeutic efficacy. A long-circulating nanoemulsion (LNE) was prepared using soybean oil, egg lecithin, cholesterol and PEG(2000)DSPE. The LNE had an oil droplet size <200 nm with a surface charge of -32.2 to -35.6 mV. Approximately, 97% of the chlorambucil was encapsulated in the LNE. Intravenous (i.v.) administration of the chlorambucil LNE to C57 B/6 mice showed improved pharmacokinetic parameters with 1.4-fold higher area under the plasma concentration-time curve (AUC) and 1.3-fold longer half-life compared to a non-PEG-modified nanoemulsion, and 2.7-fold higher AUC and 7.6-fold longer half-life compared to chlorambucil solution. Tissue distribution studies after i.v. administration with LNE showed a considerable decrease in drug uptake in the reticulo-endothelial system containing organs compared to non-PEG-modified nanoemulsion. Additionally, the chlorambucil delivered in LNE significantly enhanced therapeutic efficacy in the subcutaneous colon-38 adenocarcinoma tumor mouse model with no apparent increase in toxicity. This study suggests that LNE could produce remarkably improved pharmacokinetic profile and therapeutic efficacy of chlorambucil compared to non-PEG-modified nanoemulsion and solution.
authors.affiliation: School of Pharmacy, The University of Auckland, Auckland, New Zealand.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ganta
authors.forename: Puneet
authors.initials: P
authors.lastname: Sharma
authors.forename: James W
authors.initials: JW
authors.lastname: Paxton
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.forename: Sanjay
authors.initials: S
authors.lastname: Garg
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002699:Chlorambucil / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007275:Injections, Intravenous; D051379:Mice; D015394:Molecular Structure; D049329:Nanostructures / Q000008:administration & dosage*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D014018:Tissue Distribution
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D002699:Chlorambucil