@article{dcf1678215cb4c68856c7d8860035715,
title = "Intra and inter-molecular interactions dictate the aggregation state of irinotecan co-encapsulated with floxuridine inside liposomes",
abstract = "PURPOSE: The inter/intramolecular interactions between drugs (floxuridine, irinotecan) and excipients (copper gluconate, triethanolamine) in the dual-drug liposomal formulation CPX-1 were elucidated in order to identify the physicochemical properties that allow coordinated release of irinotecan and floxuridine and maintenance of the two agents at a fixed, synergistic 1:1 molar ratio. METHODS: Release of irinotecan and floxuridine from the liposomes was assessed using an in vitro-release assay. Fluorescence, Nuclear Magnetic Resonance spectroscopy (NMR) and UV-Vis were used to characterize the aggregation state of the drugs within the liposomes. RESULTS: Coordinated release of the drugs from liposomes was disrupted by removing copper gluconate. Approximately 45% of the total irinotecan was detectable in the copper-containing CPX-1 formulation by NMR, which decreased to 19% without copper present in the liposomal interior. Formation of higher order, NMR-silent aggregates was associated with slower and uncoordinated irinotecan release relative to floxuridine and loss of the synergistic drug/drug ratio. Solution spectroscopy and calorimetry revealed that while all formulation components were required to achieve the highest solubility of irinotecan, direct drug-excipient binding interactions were absent. CONCLUSIONS: Long-range interactions between irinotecan, floxuridine and excipients modulate the aggregation state of irinotecan, allowing for simultaneous release of both drugs from the liposomes.",
keywords = "Antimetabolites, Antineoplastic, Antineoplastic Agents, Phytogenic, Calorimetry, Camptothecin, Chemistry, Pharmaceutical, Chemistry, Physical, Cholesterol, Copper, Drug Carriers, Drug Compounding, Excipients, Floxuridine, Gluconates, Liposomes, Magnetic Resonance Spectroscopy, Microscopy, Electron, Transmission, Phosphatidylcholines, Phosphatidylglycerols, Physicochemical Phenomena, Solubility, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet",
author = "Awa Dicko and Frazier, {April A} and Liboiron, {Barry D} and Anne Hinderliter and Ellena, {Jeff F} and Xiaowei Xie and Connie Cho and Tom Weber and Tardi, {Paul G} and Donna Cabral-Lilly and Cafiso, {David S} and Mayer, {Lawrence D}",
year = "2008",
doi = "10.1007/s11095-008-9561-z",
language = "English",
volume = "25",
pages = "1702--13",
journal = "Pharmaceutical Research",
issn = "0724-8741",
publisher = "Springer New York LLC",
number = "7",
}