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Toxicological Study and Efficacy of Blank and Paclitaxel-Loaded Lipid Nanocapsules After i.v. Administration in Mice

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Abstract

Purpose

Lipid nanocapsules (LNCs) are solvent-free drug nanocarriers permitting entrapment of paclitaxel and increasing its antitumoural effect in animal models after i.v. injection. The tolerance and efficacy of LNCs after repeated dose i.v. administration were assessed in mice. The maximum tolerated dose (MTD) and 50% lethal dose (LD50) were studied.

Methods

Paclitaxel-loaded LNC formulation was given i.v. at the dose of 12 mg/kg per day for 5 consecutive days in comparison with blank LNCs and saline. Histological examination, complete blood counts and biochemical quantification were performed after a recovery of 7 days. Growth of NCI-H460 subcutaneous xenografts in nude mice receiving one of the aforementioned schedules was assessed. MTD and LD50 were determined by Irwin test.

Results

No mortality was observed in repeated injections studies. Histological studies revealed no lesions and no accumulation of lipids. Blood studies were normal. The tumoural growth was significantly reduced in the group treated by paclitaxel-loaded LNCs. The MTDs/LD50s of Taxol®, paclitaxel-loaded LNCs and blank LNCs were 12/19.5, 96/216 and above 288/288 mg/kg, respectively.

Conclusions

This study demonstrates that a five-day i.v. injection schedule of paclitaxel-loaded LNC dispersions induces no histological or biochemical abnormalities in mice and improves paclitaxel efficacy and therapeutic index in comparison with Taxol®.

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ACKNOWLEDGEMENTS

The authors would like to thank Prof. J.-L. Racineux (Pulmonology Department, Academic Hospital, Angers, France) for his support, Prof. Zandecki (Haematology Laboratory, Academic Hospital, Angers, France) for carrying out the complete blood counts, Dr. Tourmen (Biochemistry Department, Academic Hospital, Angers, France) for carrying out the biochemical analysis, Joël Guillemain (Biopharm Consulting) for advice on toxicological studies, Pierre Legras and Jérôme Roux (University of Angers, Faculty of Medicine, Angers, France) for help in the animal studies. This study was supported by grants from the Comité Départemental du Maine-et-Loire de la Ligue Contre le Cancer, the Cancéropôle Grand Ouest and the Régions Bretagne, Centre, Pays de la Loire et Poitou-Charentes.

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Authors and Affiliations

  1. Pulmonology Department, Academic Hospital, Angers, 49933, France

    José Hureaux, Frédéric Gagnadoux & Thierry Urban

  2. INSERM U646, IFR 132, University of Angers, 10, rue Boquel, Angers, 49100, France

    José Hureaux, Frédéric Lagarce & Jean-Pierre Benoit

  3. Team PYVER, University of Angers, Angers, 49933, France

    José Hureaux, Frédéric Gagnadoux & Thierry Urban

  4. Pharmacy Department, Academic Hospital, Angers, 49933, France

    Frédéric Lagarce & Jean-Pierre Benoit

  5. Cell and Tissue Pathology Department, Academic Hospital, Angers, 49933, France

    Marie-Christine Rousselet

  6. Biochemistry Department, Academic Hospital, Angers, 49933, France

    Valérie Moal

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  1. José Hureaux
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  2. Frédéric Lagarce
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Correspondence to José Hureaux.

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Hureaux, J., Lagarce, F., Gagnadoux, F. et al. Toxicological Study and Efficacy of Blank and Paclitaxel-Loaded Lipid Nanocapsules After i.v. Administration in Mice. Pharm Res 27, 421–430 (2010). https://doi.org/10.1007/s11095-009-0024-y

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