A series of new polyisoprenoyl
prodrugs of
gemcitabine, which can be formulated as nanoassemblies are described. These
prodrugs were designed to improve
gemcitabine efficacy and to overcome the limitations due to the systemic toxicity of this anticancer compound. In vitro biological assessment showed that these polyisoprenoyl
gemcitabine nanoassemblies displayed notable cytotoxicity on several
cancer cell lines, including murine
melanoma cell line B16F10, human
pancreatic carcinoma cell line MiaPaCa-2, human lung
carcinoma cell line A549 and human breast
adenocarcinoma cell line MCF7. Interestingly, it was observed that the anticancer efficacy of these nanoassemblies was dependant on the size of polyisoprenoyl moiety. The polyisoprenoyl
prodrug of
gemcitabine containing three
isoprene units (2d) was the more active on all the
cancer cell lines tested. The antitumor efficacy of the nanoassemblies (
NAs) constructed with the most active
prodrug 2d was further evaluated on a human pancreatic (MiaPaCa-2)
carcinoma xenograft model in mice. The
prodrug 2d
NAs showed an increased antitumor efficacy as compared to free
gemcitabine or to
squalene-
gemcitabine (SQ-gem, 2a) nanoassemblies. Interestingly, MiaPaCa-2
tumors that did not respond to
gemcitabine were inhibited by 76%
after treatment with
prodrug 2d
NAs, whereas SQ-gem-treated MiaPaCa-2
tumor xenografts decreased only by 41% compared to saline or to
gemcitabine-treated mice. Together, these findings demonstrated that the modulation of the length of nanoassemblies polyisoprenoyl moiety made
tumor cells more sensitive to
gemcitabine treatment without flagrant toxicity, thus providing a significant improvement in the drug therapeutic index.