HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

A unique squalenoylated and nonpegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity.

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: (i) high drug payload, (ii) decreased toxicity of the coupled anticancer compound, (iii) improved therapeutic response, (iv) use of biocompatible transporter material, and (v) ease of preparation, all criteria that are not combined in the currently available nanodrugs. 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 nanoassembly-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 fivefold 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.
AuthorsAndrei Maksimenko, Franco Dosio, Julie Mougin, Annalisa Ferrero, Severine Wack, L Harivardhan Reddy, Andrée-Anne Weyn, Elise Lepeltier, Claudie Bourgaux, Barbara Stella, Luigi Cattel, Patrick Couvreur
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 2 Pg. E217-26 (Jan 14 2014) ISSN: 1091-6490 [Electronic] United States
PMID24385587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Troponin T
  • Squalene
  • Doxorubicin
Topics
  • Analysis of Variance
  • Animals
  • Apoptosis (drug effects, physiology)
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Chromatography, High Pressure Liquid
  • Cryoelectron Microscopy
  • Doxorubicin (chemistry, metabolism, pharmacokinetics, pharmacology)
  • Female
  • Fluorescence
  • Heart (anatomy & histology, drug effects)
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Molecular Conformation
  • Molecular Structure
  • Nanomedicine (methods)
  • Rats
  • Squalene (chemistry, metabolism)
  • Troponin T (blood)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: