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Intra and Inter-Molecular Interactions Dictate the Aggregation State of Irinotecan Co-Encapsulated with Floxuridine Inside Liposomes

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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.

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Acknowledgment

The authors would like to thank Dr. Sharon Johnstone for helpful discussions and Brianne O’Callaghan for technical support. We would like to recognize the superior NMR service provided by Drs. Maria Ezhova and Nick Burlinson at the University of British Columbia NMR Facility. We are also grateful to Goran Karlsson and Dr. Katarina Edwards at Uppsala University in Sweden for the cryo-EM work.

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Authors and Affiliations

  1. Celator Pharmaceuticals Corp., 1779 W 75th Avenue, Vancouver, British Columbia, V6P 6P2, Canada

    Awa Dicko, April A. Frazier, Barry D. Liboiron, Xiaowei Xie, Connie Cho, Tom Weber, Paul G. Tardi & Lawrence D. Mayer

  2. Department of Chemistry and Biochemistry, College of Science and Engineering, University of Minnesota-Duluth, 1039 University Drive, Duluth, Minesota, 55812-3020, USA

    Anne Hinderliter

  3. Department of Chemistry, University of Virginia, McCormick Road, P.O. Box 400319, Charlottesville, Virginia, 22904-4319, USA

    Jeff F. Ellena & David S. Cafiso

  4. Celator Pharmaceuticals Inc., 303B College Road East, Princeton, New Jersey, 08540, USA

    Donna Cabral-Lilly

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  1. Awa Dicko
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Correspondence to Lawrence D. Mayer.

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Dicko, A., Frazier, A.A., Liboiron, B.D. et al. Intra and Inter-Molecular Interactions Dictate the Aggregation State of Irinotecan Co-Encapsulated with Floxuridine Inside Liposomes. Pharm Res 25, 1702–1713 (2008). https://doi.org/10.1007/s11095-008-9561-z

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  • DOI: https://doi.org/10.1007/s11095-008-9561-z

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