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.