9 research outputs found
Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine
Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo.
The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo.
Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t
1/2Â =Â 9.7Â h) relative to vincristine (t
1/2Â =Â 18.5Â h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine.
These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized
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Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine.
PurposeLiposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo.MethodsThe pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo.ResultsNanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t (1/2) = 9.7 h) relative to vincristine (t (1/2) = 18.5 h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine.ConclusionsThese results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized
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Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine
Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo.
The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo.
Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t
1/2Â =Â 9.7Â h) relative to vincristine (t
1/2Â =Â 18.5Â h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine.
These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized
Improved Pharmacokinetics and Efficacy of a Highly Stable Nanoliposomal Vinorelbine
Effective liposomal formulations of vinorelbine (5′
nor-anhydro-vinblastine; VRL) have been elusive due to vinorelbine's
hydrophobic structure and resulting difficulty in stabilizing the drug inside
the nanocarrier. Triethylammonium salts of several polyanionic trapping agents
were used initially to prepare minimally pegylated nanoliposomal vinorelbine
formulations with a wide range of drug release rates. Sulfate,
poly(phosphate), and sucrose octasulfate were used to stabilize vinorelbine
intraliposomally while in circulation, with varying degrees of effectiveness.
The release rate of vinorelbine from the liposomal carrier was affected by
both the chemical nature of the trapping agent and the resulting drug-to-lipid
ratio, with liposomes prepared using sucrose octasulfate displaying the
longest half-life in circulation (9.4 h) and in vivo retention in the
nanoparticle (t1/2 = 27.2 h). Efficacy was considerably
improved in both a human colon carcinoma (HT-29) and a murine (C-26) colon
carcinoma model when vinorelbine was stably encapsulated in liposomes using
triethylammonium sucrose octasulfate. Early difficulties in preparing highly
pegylated formulations were later overcome by substituting a neutral
distearoylglycerol anchor for the more commonly used anionic
distearoylphosphatidylethanolamine anchor. The new pegylated nanoliposomal
vinorelbine displayed high encapsulation efficiency and in vivo drug
retention, and it was highly active against human breast and lung tumor
xenografts. Acute toxicity of the drug in immunocompetent mice slightly
decreased upon encapsulation in liposomes, with a maximum tolerated dose of
17.5 mg VRL/kg for free vinorelbine and 23.8 mg VRL/kg for nanoliposomal
vinorelbine. Our results demonstrate that a highly active, stable, and
long-circulating liposomal vinorelbine can be prepared and warrants further
study in the treatment of cancer