Therapy of mouse mammary carcinomas with vincristine and doxorubicin encapsulated in sterically stabilized liposomes

Abstract

This study tested the therapeutic effects of vincristine sulfate and doxorubicin hydrochloride, each drug in 2 different formulations: (i) as a solution in saline, and (ii) encapsulated in sterically stabilized, long-circulating liposomes composed of hydrogenated soy-phosphatidylcholine/cholesterol/polyethylene-glycerol-disteroyl++ +- phosphatidylethanolamine. The 4 drug preparations were used to treat s.c. implants of the mouse mammary carcinoma MC2. The drugs were given by i.v. injection over 15 to 18 days, starting 3 days after tumor implantation. The single-drug therapeutic effects of vincristine (S-VCR) and doxorubicin (Doxil) in liposomes were compared, and the 2 preparations were also tested in alternate and in simultaneous combinations. These new liposome formulations of vincristine and doxorubicin were significantly more effective than the free drugs in curing the mice. Alternate, semi-weekly injection of both drugs gave the best therapeutic effect. Prolonged circulation time with increased accumulation in tumors are considered likely reasons for the improved therapeutic efficacy of both drugs when encapsulated in these liposomes.

In Vitro and in Vivo Characterization of Doxorubicin and Vincristine Coencapsulated within Liposomes through Use of Transition Metal Ion Complexation and pH Gradient Loading

“…Results presented here as well as those of Vaage et al (37) suggest that coadministration of liposomal doxorubicin and liposomal vincristine results in less than additive activity or antagonism. In an effort to gain a better understanding about the cytotoxic effects of vincristine and doxorubicin when used in combination, in vitro cytotoxicity studies were completed using MDA435/LCC6 cells as the target cell population.…”

“…and liposomal doxorubicin did not provide improved therapy when simultaneously injected (37). Their results suggested that liposomal vincristine inhibited the activity of liposomal doxorubicin.…”

“…Their results suggested that liposomal vincristine inhibited the activity of liposomal doxorubicin. These authors proposed that reduced activity could have been a consequence of the effects of vincristine on the cell cycle, which prevented/delayed progression into S phase in which the impact of doxorubicin could be greatest (37). Alternatively, they argued that inhibition of activity could have been a consequence of dosing schedules and liposome-mediated drug delivery, where liposomal vincristine administration may have interfered with the delivery of liposomal doxorubicin to the tumor.…”

Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models

“…Several reports have documented the ability of a variety of liposomes to decrease the toxicity and/or improve the efficacy of vincristine (Layton and Trouet, 1980;Mayer et al, 1990aMayer et al, , 1993Mayer et al, , 1995Vaage et al, 1993;Boman et al, 1994). Early studies revealed that vincristine is relatively permeable to the phospholipid membranes, a characteristic that limits the use of lipids containing unsaturated fatty acids, such as egg PC (Mayer et al, 1990a).…”

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

“…Moreover, the PEG modification avoids liposome aggregation improving stability of preparations. Vaage et al (1993) formulated vincristine-loaded PEGylated liposomes. Compared to SM/Chol liposomes, the particle size (about 100 nm) and trapping efficiency (495%) was similar to conventional liposomes, but the surface charges of these two formulations were different (the electrophoretic mobility of SM/Chol and PEGylated liposomes was 0.0 and À0.83 Â 10 À4 cm 2 /Vs) at pH 7.0 (Webb et al, 1998).…”