Evaluation of antitumor activity and cardiac toxicity of a bone-targeted ph-sensitive liposomal formulation in a bone metastasis tumor model in mice.
Chemotherapy for bone tumors is a major challenge because of the inability of therapeutics to penetrate dense bone mineral. We hypothesize that a nanostructured formulation with high affinity for bone could deliver drug to the tumor while minimizing off-target toxicity. Here, we evaluated the efficacy and toxicity of a novel bone-targeted, pH-sensitive liposomal formulation containing doxorubicin in an animal model of bone metastasis. Biodistribution studies with the liposome showed good uptake in tumor, but low accumulation of doxorubicin in the heart. Mice treated with the bone-targeted liposome formulation showed a 70% reduction in tumor volume, compared to 35% reduction for free doxorubicin at the same dose. Both cardiac toxicity and overall mortality were significantly lower for animals treated with the bone-targeted liposomes compared to free drug. Bone-targeted, pH-sensitive, doxorubicin containing liposomes represent a promising approach to selectively delivering doxorubicin to bone tumors while minimizing cardiac toxicity.
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil. Electronic address: ferreira@nmr.mgh.harvard.edu.
Diego
D
Dos Santos Ferreira
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: bluis.oliveira@gmail.com.
Bruno Luís
BL
Jesus de Oliveira Pinto
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: vidhya.kumar55@gmail.com.
Vidhya
V
Kumar
Department of Clinical and Toxicology Analyses, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil. Electronic address: valbertcardoso@yahoo.com.br.
Valbert Nascimento
VN
Cardoso
Department of Clinical and Toxicology Analyses, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil. Electronic address: simoneodilia@yahoo.com.br.
Simone Odília
SO
Fernandes
Department of Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil. Electronic address: cms.souza@yahoo.com.br.
Cristina Maria
CM
Souza
Department of Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil. Electronic address: cassalig@icb.ufmg.br.
Geovanni Dantas
GD
Cassali
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: amoore@helix.mgh.harvard.edu.
Anna
A
Moore
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: sosnovik@nmr.mgh.harvard.edu.
David E
DE
Sosnovik
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: cfarrar@mgh.harvard.edu.
Christian T
CT
Farrar
Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil. Electronic address: leite_elaine@hotmail.com.
Elaine Amaral
EA
Leite
Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil. Electronic address: ricardodylan@farmacia.ufmg.br.
Ricardo José
RJ
Alves
Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil. Electronic address: monica@farmacia.ufmg.br.
Mônica Cristina
MC
de Oliveira
Department of Diagnostic Radiology, Oregon Health & Sciences University, Portland, OR 97239, USA. Electronic address: guimaraa@ohsu.edu.
Alexander Ramos
AR
Guimarães
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: caravan@nmr.mgh.harvard.edu.
Peter
P
Caravan
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000633:toxicity; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D066126:Cardiotoxicity; D004317:Doxorubicin / Q000008:administration & dosage* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D051379:Mice; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin
Bisphosphonates; Bone tumor; Cardiotoxicity; Doxorubicin; Hydroxyapatite-targeting