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Liposomal imatinib–mitoxantrone combination: Formulation development and therapeutic evaluation in an animal model of prostate cancer
Author(s) -
Pinto Ana Catarina,
Moreira João Nuno,
Simões Sérgio
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21224
Subject(s) - mitoxantrone , in vivo , medicine , imatinib , pharmacology , liposome , therapeutic index , prostate cancer , prostate , drug , cancer , chemotherapy , chemistry , biology , myeloid leukemia , microbiology and biotechnology , biochemistry
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 (NH 4 ) 2 SO 4 ‐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.