Novel 5-Fluorouracil Carbonate-Loaded Liposome: Preparation, In Vitro, and In Vivo Evaluation as an Antitumor Agent.

5-Fluorouracil (5-FU) is a chemotherapeutic drug against many types of cancers, especially colorectal cancer. However, its short plasma half-life and serious adverse reactions limit its wide clinical applications. To overcome these shortcomings, a novel lipophilic 5-FU carbonate [XL-01, (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl tetradecyl carbonate] was designed, synthesized, and encapsulated into liposome (LipoXL-01) by a thin-film dispersion method through formulation screening and optimization. LipoXL-01 was characterized by a particle size of around 100 nm, polydispersity index of 0.200, ζ-potential value of -41 mV, encapsulation efficiency of 93.9%, and drug-loading efficiency of 11.6%. The cellular uptake of LipoXL-01 was increased in a concentration-dependent manner on HCT15 cells. LipoXL-01 could enhance the induction of cell apoptosis and the inhibition of cell migration and arrest the ability of the cell cycle at the S-phase on HCT15 cells better than 5-FU. Additionally, LipoXL-01 exhibited a slow drug release profile with a cumulative release rate of 12% in 8 h. The results of pharmacokinetic and biodistribution studies revealed that LipoXL-01 had a long plasma half-life (7.21 h) and a high tumor accumulation (733 nmol/g at 8 h). The in vivo antitumor effect study also showed that LipoXL-01 had more potent efficacy than 5-FU (65 vs 48% of the tumor-inhibition rate). Simultaneously, negligible systemic toxicity was observed via analyzing the body weight as well as hematological and pathological parameters in the tested mice. The current study suggested that LipoXL-01 might be a promising nanocandidate for chemotherapy of colorectal cancer.

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 µmol/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 °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 water-solubility and short plasma half-life into attractive nanomedicines.