Intra and inter-molecular interactions dictate the aggregation state of irinotecan co-encapsulated with floxuridine inside liposomes

Awa Dicko, April A. Frazier, Barry D. Liboiron, Anne Hinderliter, Jeff F. Ellena, Xiaowei Xie, Connie Cho, Tom Weber, Paul G. Tardi, Donna Cabral-Lilly, David S. Cafiso, Lawrence D. Mayer

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1702-1713
Number of pages12
JournalPharmaceutical research
Volume25
Issue number7
DOIs
StatePublished - Jul 1 2008

Keywords

  • CPX-1
  • Copper gluconate
  • Rotational diffusion
  • Spectroscopy
  • Triethanolamine

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