Identification of vesicle properties that enhance the antitumour activity of liposomal vincristine against murine L1210 leukemia

Abstract

The influence of vesicle lipid composition, size and drug-to-lipid ratio on the antitumour activity of liposomal vincristine was assessed in the murine L1210 ascitic leukemia model. A pH gradient-dependent entrapment procedure was used to encapsulate vincristine and allowed such vesicle properties to be independently varied. Free vincristine delivered i.v. at the maximum tolerated dose (2.0 mg/kg) resulted in a 27.8% increase in the life span (ILS) of mice inoculated i.p. with L1210 cells. Encapsulation of the drug in egg phosphatidylcholine/cholesterol vesicles did not significantly increase the antitumour efficacy of vincristine (ILS, 38.9%). In contrast, administration of vincristine entrapped in vesicles composed of distearoylphosphatidylcholine (DSPC)/cholesterol resulted in ILS values as high as 133%. This enhanced antitumour activity of the DSPC/cholesterol formulations was sensitive to the size of the liposomes; increasing the vesicle size from 100 nm to 1 micron decreased the ILS from 133.3% to 55.6% at a drug dose of 2.0 mg/kg. Decreasing the drug-to-lipid ratio from 0.1:1 to 0.05:1 (w/w) had negligible effects on the activity of liposomal vincristine; however, a further decrease in the drug-to-lipid ratio to 0.01:1 (w/w) decreased the antitumour potency at all drug doses studied. Pharmacology studies indicated that the antitumour activities of free and various liposomal forms of vincristine correlated well with the residence time of the drug in the circulation. These studies indicate that efforts to enhance the therapeutic activity of vincristine through liposome encapsulation must address not only the circulation lifetime of the vesicle systems but also the capacity of the liposomes to retain entrapped drug in vivo.

Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors

“…The liposomal encapsulation of VCR protects the drug from the early phase of rapid elimination that is observed with nonliposomal VCR [15] . Previous studies have demonstrated that increasing VCR retention in liposomal systems improves the therapeutic index by increasing the duration of drug exposure to the tumor tissue [8,10,[16][17][18] . These PK properties of VSLI may potentially increase VCR accumulation in tumors and obtain greater efficacy over conventional VCR.…”

Acoustically-active microbubbles conjugated to liposomes: Characterization of a proposed drug delivery vehicle

“…Liposomes are membrane-enclosed vesicles composed of a lipid bilayer shell (which can trap hydrophobic and amphipathic drugs) surrounding an aqueous core (which can encapsulate hydrophilic drugs) [19][20][21]. In contrast to microbubbles, liposomes have been shown to efficiently carry drugs such as doxorubicin and vincristine [22][23][24], and intravenous injection of drug-carrying liposomes can increase accumulation at the tumor site by 50 to 100 fold compared to the administration of free drug [25][26][27]. Moreover, monodisperse liposomes can be manufactured with an optimized diameter, typically chosen to be near 100 nm to maximize extravasation from tumor vasculature and fusion with cell membranes.…”

In vivo administration of liposomal vincristine sensitizes drug‐resistant human solid tumors

“…11 Moreover, encapsulation of vincristine (VCR) in liposomes increased the antitumor efficacy in mice bearing L-1210 and P-388 murine leukemias, compared to the free drug. 12,13 Liposomal formulation of anticancer drugs has been evaluated in clinical studies. Most efforts have focused on anthracyclines, which exhibited therapeutic activity against AIDS-related Kaposi's sarcoma.…”