We identified that the chemical linkage of the anticancer drug doxorubicin onto squalene, a natural lipid precursor of the cholesterol's biosynthesis, led to the formation of squalenoyl doxorubicin(SQ-Dox) nanoassemblies of 130-nm mean diameter, with an original "loop-train" structure. This unique nanomedicine demonstrates:(/) high drug payload, (//) decreased toxicity of the coupled anticancer compound, (/;';') improved therapeutic response, (/V)use of biocompatible transporter material, and (v) ease of preparation,all criteria that are not combined in the currently available nano-drugs. Cell culture viability tests and apoptosis assays showed that SQ-Dox nanoassemblies displayed comparable antiproliferative and cytotoxic effects than the native doxorubicin because of the high activity of apoptotic mediators, such as caspase-3 and poly(ADP-ribose) polymerase. In vivo experiments have shown that the SQ-Dox nanomedicine dramatically improved the anticancer efficacy,compared with free doxorubicin. Particularly, the M109 lung tumors that did not respond to doxorubicin treatment were found inhibited by 90% when treated with SQ-Dox nanoassemblies. SQ-Dox nano-assembly-treated MiaPaCa-2 pancreatic tumor xenografts in mice decreased by 95% compared with the tumors in the saline-treated mice, which was significantly higher than the 29% reduction achieved by native doxorubicin. Concerning toxicity, SQ-Dox nanoassemblies showed a five fold higher maximum-tolerated dose than the free drug, and moreover, the cardiotoxicity study has evidenced that SQ-Dox nanoassemblies did not cause any myocardial lesions,such as those induced by the free doxorubicin treatment. Taken together, these findings demonstrate that SQ-Dox nanoassemblies make tumor cells more sensitive to doxorubicin and reduce the cardiac toxicity, thus providing a remarkable improvement in the drug's therapeutic index.
Titolo: | A unique squalenoylated and non pegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity |
Autori Riconosciuti: | |
Autori: | A. Maksimenko; F. Dosio; J. Mougin; A. Ferrero; S. Wack; L.H. Reddy; A. Weyn; E. Lepeltier; C. Bourgaux; B. Stella; L. Cattel; P. Couvreur |
Data di pubblicazione: | 2014 |
Abstract: | We identified that the chemical linkage of the anticancer drug doxorubicin onto squalene, a natural lipid precursor of the cholesterol's biosynthesis, led to the formation of squalenoyl doxorubicin(SQ-Dox) nanoassemblies of 130-nm mean diameter, with an original "loop-train" structure. This unique nanomedicine demonstrates:(/) high drug payload, (//) decreased toxicity of the coupled anticancer compound, (/;';') improved therapeutic response, (/V)use of biocompatible transporter material, and (v) ease of preparation,all criteria that are not combined in the currently available nano-drugs. Cell culture viability tests and apoptosis assays showed that SQ-Dox nanoassemblies displayed comparable antiproliferative and cytotoxic effects than the native doxorubicin because of the high activity of apoptotic mediators, such as caspase-3 and poly(ADP-ribose) polymerase. In vivo experiments have shown that the SQ-Dox nanomedicine dramatically improved the anticancer efficacy,compared with free doxorubicin. Particularly, the M109 lung tumors that did not respond to doxorubicin treatment were found inhibited by 90% when treated with SQ-Dox nanoassemblies. SQ-Dox nano-assembly-treated MiaPaCa-2 pancreatic tumor xenografts in mice decreased by 95% compared with the tumors in the saline-treated mice, which was significantly higher than the 29% reduction achieved by native doxorubicin. Concerning toxicity, SQ-Dox nanoassemblies showed a five fold higher maximum-tolerated dose than the free drug, and moreover, the cardiotoxicity study has evidenced that SQ-Dox nanoassemblies did not cause any myocardial lesions,such as those induced by the free doxorubicin treatment. Taken together, these findings demonstrate that SQ-Dox nanoassemblies make tumor cells more sensitive to doxorubicin and reduce the cardiac toxicity, thus providing a remarkable improvement in the drug's therapeutic index. |
Volume: | 111 |
Fascicolo: | 2 |
Pagina iniziale: | E217 |
Pagina finale: | E226 |
Digital Object Identifier (DOI): | 10.1073/pnas.1313459110 |
Parole Chiave: | drug deivery |
Rivista: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA |
Appare nelle tipologie: | 03A-Articolo su Rivista |
File in questo prodotto:
File | Descrizione | Tipologia | Licenza | |
---|---|---|---|---|
A unique squalenoylated and nonpegylated doxorubicin nanomedicine with systemic long.docx | postprint | 1 Ver. finale autore | Open Access Visualizza/Apri |