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Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model

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Summary

Results of clinical trials with oxaliplatin in treating glioblastoma are dismal. Previous works showed that intravenous (i.v.) delivery of oxaliplatin did not increase the survival of F98 glioma-bearing Fisher rats. Low accumulation of the drug in tumor cells is presumed to be responsible for the lack of antitumor effect. In the present study, convection-enhanced delivery (CED) was used to directly inject oxaliplatin in brain tumor implanted in rats. Since CED can led to severe toxicity, the liposomal formulation of oxaliplatin (Lipoxal™) was also assessed. The maximum tolerated dose (MTD) of oxaliplatin was 10 μg, while that of Lipoxal™ was increased by 3-times reaching 30 μg. Median survival time (MeST) of F98 glioma-bearing rats injected with 10 μg oxaliplatin by CED was 31 days, 7.5 days longer than untreated control (p = 0.0002); while CED of 30 μg Lipoxal™ reached the same result. Compared to previous study on i.v. delivery of these drugs, their injection by CED significantly increased their tumoral accumulations as well as MeSTs in the F98 glioma bearing rat model. The addition of radiotherapy (15 Gy) to CED of oxaliplatin or Lipoxal™ increased the MeST by 4.0 and 3.0 days, respectively. The timing of radiotherapy (4 h or 24 h after CED) produced similar results. However, the treatment was better tolerated when radiotherapy was performed 24 h after CED. In conclusion, a better tumoral accumulation was achieved when oxaliplatin and Lipoxal™ were injected by CED. The liposomal encapsulation of oxaliplatin reduced its toxic, while maintaining its antitumor potential.

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Acknowledgments

We would like to thank Dr. T. Boulikas for generously providing Lipoxal™, Dr. A-M Crous-Tsanaclis for her assistance in reviewing the histological samples and Dr. A.D. Bass for helpful suggestions and corrections.

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Authors and Affiliations

  1. Center for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Heath Science, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada

    Minghan Shi, Benoit Paquette & Léon Sanche

  2. Department of Surgery, Division of Neurosurgery, Centre Hospitalier Universitaire de Sherbrooke (D.F.), Sherbrooke, Québec, J1H 5N4, Canada

    David Fortin

Authors
  1. Minghan Shi
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  2. David Fortin
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  3. Benoit Paquette
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  4. Léon Sanche
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Corresponding author

Correspondence to Benoit Paquette.

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Funding

This work was supported by Canadian Institutes of Health Research (grant # MOP 81356). David Fortin, Léon Sanche and Benoit Paquette are members of the Centre de Recherche du CHUS supported by the Fonds de la Recherche du Québec en Santé.

Electronic Supplementary Material

Table S1

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Table S2

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Fig. S1

Experimental plan for survival studies: Ten μl of a 1 μg/μl oxaliplatin or 10 μl of a 3 μg/μl LipoxalTM were injected via CED. Radiotherapy was performed either at 4 or 24 h after CED. (DOCX 37 kb)

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Shi, M., Fortin, D., Paquette, B. et al. Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model. Invest New Drugs 34, 269–276 (2016). https://doi.org/10.1007/s10637-016-0340-0

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  • DOI: https://doi.org/10.1007/s10637-016-0340-0

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