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Preclinical Studies of Pegylated- and Non-Pegylated Liposomal Forms of Doxorubicin as Radiosensitizer on Orthotopic High-Grade Glioma Xenografts

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Abstract

Purpose

Free doxorubicin (DXR) is not currently used to treat brain tumors because (i) the blood–brain barrier limits the drug deposition into the brain (ii) lethal toxic effects occur when combined with radiation therapy. Since encapsulation of DXR within liposomal carriers could overcome these drawbacks, the present study aimed at evaluating the radiosensitizing properties of non-pegylated (NPL-DXR) and pegylated (PL-DXR) liposomal doxorubicin on orthotopic high-grade glioma xenografts (U87).

Methods

DXR accumulation in brain tissues was assessed by a high-performance liquid chromatography method and antitumor efficacy was evaluated by mice survival determination.

Results

We showed that encapsulation of DXR ensured a preferential deposition of DXR in tumoral tissue in comparison with normal brain tissue: the best AUC tumor tissue/AUC normal tissue ratio depended greatly on the schedule. Overall, thanks to the optimization of the delivery schedule, we demonstrated a radiosensitizing effect for both liposomal DXR without toxicity of this combination on the U87 human malignant glioma orthotopic xenografts.

Conclusion

This study shows that the use of nanocarriers, allowing targeting of intracerebral tumor, renders relevant the combination of anthracyclin with radiation therapy to treat brain tumors, opening a new field of therapeutic applications. However, our results point out that, for each new delivery system, the administration schedules need to be rigorously optimized.

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Abbreviations

AUC:

Area under the curve

BBB:

Blood–brain barrier

BTB:

Blood–tumor barrier

CNS:

Central nervous system

DXR:

Doxorubicin

MTD:

maximal tolerated dose

NPL-DXR:

Non-pegylated liposomal doxorubicin

NT:

Non-tumor brain hemisphere

PL-DXR:

Pegylated liposomal doxorubicin

RT:

Radiotherapy

TT:

Tumor brain hemisphere

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Acknowledgments and Disclosures

We are very grateful to the French “Ligue Contre le Cancer, Comités Lorrains” for financial supports. We thank S. Leclerc and J.M. Escanyé (Service Commun de RMN, Institut Jean Barriol, Université de Lorraine) for technical assistance.

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Authors and Affiliations

  1. Université de Lorraine, CRAN UMR 7039, Campus Sciences BP70239, Vandoeuvre-les-Nancy, 54500, France

    P. Chastagner, J. Mriouah, M. Barberi-Heyob & S. Pinel

  2. CNRS, CRAN, UMR 7039, Campus Sciences BP70239, Vandoeuvre-les-Nancy, 54500, France

    P. Chastagner, J. Mriouah, M. Barberi-Heyob & S. Pinel

  3. CHRU Nancy, Hôpital d’Enfants-Service d’Oncologie et Hématologie Pédiatriques, Vandoeuvre-les-Nancy, 54500, France

    P. Chastagner & H. Sudour

  4. Département de Radiothérapie, Institut de Cancérologie de Lorraine, Avenue de Bourgogne, Vandoeuvre-les-Nancy, 54500, France

    V. Bernier-Chastagner

  5. Faculté de Médecine, CRAN, UMR 7039 UL - CNRS, 9 avenue de la Forêt de Haye, 54500, Vandoeuvre-les-Nancy, France

    S. Pinel

Authors
  1. P. Chastagner
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  2. H. Sudour
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  4. M. Barberi-Heyob
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  5. V. Bernier-Chastagner
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  6. S. Pinel
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Corresponding author

Correspondence to S. Pinel.

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Chastagner, P., Sudour, H., Mriouah, J. et al. Preclinical Studies of Pegylated- and Non-Pegylated Liposomal Forms of Doxorubicin as Radiosensitizer on Orthotopic High-Grade Glioma Xenografts. Pharm Res 32, 158–166 (2015). https://doi.org/10.1007/s11095-014-1452-x

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  • DOI: https://doi.org/10.1007/s11095-014-1452-x

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