Pharmacokinetics and anti‐tumor activity of vincristine encapsulated in sterically stabilized liposomes

Abstract

Vincristine is used clinically for the treatment of various types of cancer. Recent significant therapeutic improvements obtained by entrapping anthracyclines in sterically stabilized liposomes raised the question whether the therapeutic index of vincristine can be similarly increased by formulation into such long-circulating liposomes. Encapsulation of vincristine in sterically stabilized liposomes (SL-VCR) prolonged the drug's distribution phase plasma half-life in rats from 0.22 to 10.5 hr. There was no significant difference in LD50 (> < or = 2.5 mg/kg, i.v.), but mice given sublethal doses of SL-VCR experienced significantly less weight loss than those given the same dose of free drug. Compared to free drug, SL-VCR was most effective against i.p. or s.c. implanted tumors. However, i.v. tumor inoculation nullified the therapeutic advantage of encapsulation. A single i.v. 2 mg/kg dose of SL-VCR increased the life span of mice bearing i.v. implanted P388 cells by only 44%, while the life span of i.p. P388 implanted mice was increased by 199%. In an s.c. implanted murine colon carcinoma, multiple doses of free drug did little to slow the growth of the tumors, but SL-VCR was able to produce long-term survivors in several dose regimens. These results indicate that prolonged circulation time increases the therapeutic index of VCR entrapped in liposomes against s.c. or i.p. implanted tumors, but does not improve the drug's activity against rapidly growing i.v. disseminated leukemias.

Insertion of poly(ethylene glycol) derivatized phospholipid into pre‐formed liposomes results in prolonged in vivo circulation time

“…Functional insertion would presumably increase plasma circulation time of the liposomes in proportion to the final concentration of MPEG]o00-DSPE. To test this hypothesis, we prepared pre-formed liposomes containing 2 mol% DPPG to ensure rapid clearance in the absence of inserted, functional MPEG]900-DSPE (tv: <1 h, [2,15]). The main endothermic phase transition (To) of HSPC is approximately 58°C (data not shown), so we prepared a two-factor, uniform shell design experimental matrix to exam- ine insertion below (50°C), at (60°C), and above (70°C) the Tc as a function of time.…”

A new zebrafish model for experimental leukemia therapy

“…[20][21][22][23][24] In particular, the typical feature of both ZL1 and P388 leukemic lines is fast and synchronous death of the inoculated animals with median survival 9-13 d, quick dissemination of tumor growth and development of ascites in the terminal stage of leukemia. Moreover, the effective therapeutic doses of CY in the murine model are 100-400 mg/kg vs. 200-400 mg/L in fish and for VCR-0.1-2.5 mg/kg in mice vs. 2.5-4 mg/L in fish.…”

Are PEGylated liposomes better than conventional liposomes? A special case for vincristine

“…This effect might be due to longer circulating time of liposomal vincristine, consequently resulting in increased drug accumulation in the tumor. Allen et al (1995) confirmed this finding and they found that liposomal vincristine was more effective against s.c. or i.p. implanted tumors than i.v.…”