Liposomal imatinib-mitoxantrone combination: formulation development and therapeutic evaluation in an animal model of prostate cancer.
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.
Pinto
Ana Catarina
AC
Faculty of Pharmacy, Laboratory of Pharmaceutical Technology, University of Coimbra, Coimbra, Portugal.
Moreira
João Nuno
JN
Simões
Sérgio
S
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001549:Benzamides; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D000068877:Imatinib Mesylate; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008942:Mitoxantrone / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D008081:Liposomes; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D008942:Mitoxantrone