Limits...
Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine.

Noble CO, Guo Z, Hayes ME, Marks JD, Park JW, Benz CC, Kirpotin DB, Drummond DC - Cancer Chemother. Pharmacol. (2009)

Bottom Line: Nanoliposome 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).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.

View Article: PubMed Central - PubMed

Affiliation: Hermes Biosciences Inc, South San Francisco, CA 94080, USA.

ABSTRACT

Purpose: 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.

Methods: 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.

Results: Nanoliposome 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.

Conclusions: These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized.

Show MeSH

Related in: MedlinePlus

In vivo pharmacokinetic evaluation of the liposomal drug formulation stability and circulation as indicated by % injected dose of the liposomal phospholipid (open square) and VCR (filled square) components of the Ls-VCR formulation (101.6 nm, 104.5 g VCR/mol phospholipid) (a) and liposomal phospholipid (open diamond) and VBL (filled diamond) of the Ls-VBL formulation (99.5 nm, 152.4 g VBL/mol phospholipid) (b). Stability as indicated by retention of the drug within the liposome is shown for Ls-VCR (open square) and Ls-VBL (open diamond) as % original drug/lipid ratio (c)
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2717390&req=5

Fig3: In vivo pharmacokinetic evaluation of the liposomal drug formulation stability and circulation as indicated by % injected dose of the liposomal phospholipid (open square) and VCR (filled square) components of the Ls-VCR formulation (101.6 nm, 104.5 g VCR/mol phospholipid) (a) and liposomal phospholipid (open diamond) and VBL (filled diamond) of the Ls-VBL formulation (99.5 nm, 152.4 g VBL/mol phospholipid) (b). Stability as indicated by retention of the drug within the liposome is shown for Ls-VCR (open square) and Ls-VBL (open diamond) as % original drug/lipid ratio (c)

Mentions: The blood circulation characteristics of two liposomal vinca alkaloids, Ls-VCR (Fig. 3a) and Ls-VBL (Fig. 3b), were studied in rats. Ls-VBL demonstrates the advantage of liposomal encapsulation with regard to circulation by exhibiting an AUC of 1,076 μg h/ml which is 2 orders of magnitude greater than that typically observed for unencapsulated VBL [47]. The Ls-VBL formulation was highly stable in circulation as indicated by the encapsulated drug/liposomal phospholipid ratio over time where 73.1% of the VBL remains within the liposome after 48 h in circulation, and the drug release T1/2 was calculated to be 41.3 h (Fig. 3c). With this liposomal VBL formulation, drug disposition is controlled by the slow release rate of VBL from liposomes in vivo, and thus the drug’s apparent PK parameters are similar to the liposomal PK parameters.Fig. 3


Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine.

Noble CO, Guo Z, Hayes ME, Marks JD, Park JW, Benz CC, Kirpotin DB, Drummond DC - Cancer Chemother. Pharmacol. (2009)

In vivo pharmacokinetic evaluation of the liposomal drug formulation stability and circulation as indicated by % injected dose of the liposomal phospholipid (open square) and VCR (filled square) components of the Ls-VCR formulation (101.6 nm, 104.5 g VCR/mol phospholipid) (a) and liposomal phospholipid (open diamond) and VBL (filled diamond) of the Ls-VBL formulation (99.5 nm, 152.4 g VBL/mol phospholipid) (b). Stability as indicated by retention of the drug within the liposome is shown for Ls-VCR (open square) and Ls-VBL (open diamond) as % original drug/lipid ratio (c)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2717390&req=5

Fig3: In vivo pharmacokinetic evaluation of the liposomal drug formulation stability and circulation as indicated by % injected dose of the liposomal phospholipid (open square) and VCR (filled square) components of the Ls-VCR formulation (101.6 nm, 104.5 g VCR/mol phospholipid) (a) and liposomal phospholipid (open diamond) and VBL (filled diamond) of the Ls-VBL formulation (99.5 nm, 152.4 g VBL/mol phospholipid) (b). Stability as indicated by retention of the drug within the liposome is shown for Ls-VCR (open square) and Ls-VBL (open diamond) as % original drug/lipid ratio (c)
Mentions: The blood circulation characteristics of two liposomal vinca alkaloids, Ls-VCR (Fig. 3a) and Ls-VBL (Fig. 3b), were studied in rats. Ls-VBL demonstrates the advantage of liposomal encapsulation with regard to circulation by exhibiting an AUC of 1,076 μg h/ml which is 2 orders of magnitude greater than that typically observed for unencapsulated VBL [47]. The Ls-VBL formulation was highly stable in circulation as indicated by the encapsulated drug/liposomal phospholipid ratio over time where 73.1% of the VBL remains within the liposome after 48 h in circulation, and the drug release T1/2 was calculated to be 41.3 h (Fig. 3c). With this liposomal VBL formulation, drug disposition is controlled by the slow release rate of VBL from liposomes in vivo, and thus the drug’s apparent PK parameters are similar to the liposomal PK parameters.Fig. 3

Bottom Line: Nanoliposome 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).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.

View Article: PubMed Central - PubMed

Affiliation: Hermes Biosciences Inc, South San Francisco, CA 94080, USA.

ABSTRACT

Purpose: 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.

Methods: 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.

Results: Nanoliposome 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.

Conclusions: These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized.

Show MeSH
Related in: MedlinePlus