A unique squalenoylated and non pegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity

Maksimenko, A.; Dosio, Franco; Mougin, J.; Ferrero, Annalisa; Wack, S.; Reddy, L. H.; Weyn, A.; Lepeltier, E.; Bourgaux, C.; Stella, Barbara; Cattel, Luigi; Couvreur, P.

doi:10.1073/pnas.1313459110

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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:	A. Maksimenko DOSIO, Franco J. Mougin FERRERO, ANNALISA S. Wack L. H. Reddy A. Weyn E. Lepeltier C. Bourgaux STELLA, Barbara CATTEL, Luigi P. Couvreur mostra contributor esterni nascondi contributor esterni
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

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