Lipid-like gemcitabine diester-loaded liposomes for improved chemotherapy of pancreatic cancer

Gemcitabine (GEM) is a non-selective chemotherapeutic agent used in the treatment of pancreatic cancer. Its antitumor efficacy is limited by a short plasma half-life and severe adverse reactions. To overcome these shortcomings, four novel lipid-like GEM diesters were synthesized and encapsulated into liposomes. Through optimization, dimyristoyl GEM (dmGEM)-loaded liposomes (LipodmGEM) were successfully obtained with an almost complete encapsulation efficiency. Compared to free GEM, LipodmGEM showed enhanced cellular uptake and cell apoptosis, improved inhibition of cell migration on AsPC-1 cells and a greatly extended half-life (7.22 vs. 1.78 h). LipodmGEM succeeded in enriching the drug in the tumor (5.28 vs. 0.03 mu mol/g at 8 h), overcoming a major shortcoming of GEM, showed excellent anticancer efficacy in vivo and negligible systemic toxicity, superior to GEM. Attractive as well, suspensions of LipodmGEM remained stable at 2-10(degrees)C away from light for no <2 years. Our results suggest that LipodmGEM might become of high interest for treating pancreatic cancer while the simple strategy we reported might be explored as well for converting other antitumor drugs with high watersolubility and short plasma half-life into attractive nanomedicines.

Automated summary

Four novel lipid-like GEM diesters were synthesized and encapsulated into liposomes to improve the antitumor efficacy of Gemcitabine. The liposomes loaded with dimyristoyl GEM (LipodmGEM) showed enhanced cellular uptake, improved inhibition of cell migration, and a greatly extended half-life compared to free Gemcitabine. LipodmGEM successfully enriched the drug in the tumor and exhibited excellent anticancer efficacy in vivo with negligible systemic toxicity.