Liposomal imatinib–mitoxantrone combination: Formulation development and therapeutic evaluation in an animal model of prostate cancer

Authors

  • Ana Catarina Pinto,

    1. Faculty of Pharmacy, Laboratory of Pharmaceutical Technology, University of Coimbra, Coimbra, Portugal
    2. Bluepharma, Indústria Farmacêutica S.A., S. Martinho do Bispo, Coimbra, Portugal
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  • João Nuno Moreira,

    1. Faculty of Pharmacy, Laboratory of Pharmaceutical Technology, University of Coimbra, Coimbra, Portugal
    2. Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
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  • Sérgio Simões

    Corresponding author
    1. Faculty of Pharmacy, Laboratory of Pharmaceutical Technology, University of Coimbra, Coimbra, Portugal
    2. Bluepharma, Indústria Farmacêutica S.A., S. Martinho do Bispo, Coimbra, Portugal
    3. Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
    • Faculty of Pharmacy, Department of Pharmaceutical Technology, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
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Abstract

BACKGROUND

Mitoxantrone plus prednisone is a palliative treatment for hormone-refractory prostate cancer (HRPC) but without survival benefit. Imatinib has shown activity against HRPC but only in the preclinical setting. Our previous in vitro cytotoxicity screening study established that their free combination act additively to inhibit proliferation of PC-3 cells. We aim to develop a liposomal imatinib–mitoxantrone (LIM) formulation with improved in vivo therapeutic activity.

METHODS

Imatinib and mitoxantrone were simultaneously co-loaded into DSPC/Chol liposomes by means of a (NH4)2SO4-generated proton gradient method. The optimized formulation was characterized in terms of mean size diameter, loading parameters and drug retention in human serum. In vivo antitumor activity of developed LIM formulation was evaluated in a nude mice bearing subcutaneous PC-3 xenograft model.

RESULTS

LIM formulation exhibited maximal encapsulation efficiency (>95%) and enhanced drug retention for both drugs. Additionally, this LIM formulation, administered at a low mitoxantrone dose (0.5 mg/kg), showed a tumor inhibition activity (TGI = 66.7% and 4.0-fold tumor volume increase) slightly superior to that of liposomal mitoxantrone (LM) at 2 mg/kg (TGI = 53.0% and 4.2-fold volume increase). Therefore, therapeutic activity of mitoxantrone was significantly improved by co-loading with imatinib since a four times lower dose was needed to achieve an equivalent growth inhibition effect.

CONCLUSIONS

The loading parameters and drug retention properties of our LIM formulation, combined with its in vivo antitumor activity, make this formulation an excellent strategy to improve the therapeutic index of mitoxantrone and a promising candidate for clinical development in prostate cancer therapy. Prostate 71: 81–90, 2011. © 2010 Wiley-Liss, Inc.

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