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Self-assembled squalenoyl-cytarabine nanostructures as a potent nanomedicine for treatment of leukemic diseases.

Cosco D, Rocco F, Ceruti M, Vono M, Fresta M, Paolino D - Int J Nanomedicine (2012)

Bottom Line: Squalenoyl-Ara-C conjugate (Sq-Ara-C) self-assembled nanosystems were obtained by the nanoprecipitation method and characterized in vitro and in vivo.Sq-Ara-C nanomedicine allowed reduction of the IC(50) value with respect to the free drug and was also active against drug-resistant leukemic cells (L1210R).Squalenoylation of cytarabine offers several pharmacological benefits both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences, University Magna Græcia, Catanzaro, Italy.

ABSTRACT

Background: In this investigation, the antileukemic activity of a new nanomedicine based on the conjugation of 1,1',2-tris-nor-squalenic acid with cytarabine (Ara-C) was evaluated.

Methods: Squalenoyl-Ara-C conjugate (Sq-Ara-C) self-assembled nanosystems were obtained by the nanoprecipitation method and characterized in vitro and in vivo.

Results: This new nanomedicine, which had a mean diameter of approximately 150 nm, improved the in vitro antitumoral activity of Ara-C in different cancer cell lines (L1210, K562, and MCF-7). Sq-Ara-C nanomedicine allowed reduction of the IC(50) value with respect to the free drug and was also active against drug-resistant leukemic cells (L1210R). A noticeable increase in the survival rate of mice with aggressive metastatic L1210R leukemia was observed after treatment with Sq-Ara-C (50 mg/kg) as compared with the free active compound (100 mg/kg). Finally, evaluation of the biodistribution and pharmacokinetic profiles of the drug demonstrated that these nanoaggregates preferentially localized to the liver and spleen, and protected the drug from physiological metabolism.

Conclusion: Squalenoylation of cytarabine offers several pharmacological benefits both in vitro and in vivo.

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Related in: MedlinePlus

Pharmacokinetic profiles for free Ara-C and Sq-Ara-C in DBA/2 mice following intravenous administration of a 1 mg/kg dose.Note: Data are the mean of three independent experiments ± standard deviation.
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f4-ijn-7-2535: Pharmacokinetic profiles for free Ara-C and Sq-Ara-C in DBA/2 mice following intravenous administration of a 1 mg/kg dose.Note: Data are the mean of three independent experiments ± standard deviation.

Mentions: Evidence of the protective role played by the squalenic chain in the plasma metabolism of Sq-Ara-C and its improved biopharmaceutical features was determined by evaluating the pharmacokinetic profile of the Sq-Ara-C nanomedicine with respect to the Ara-C solution after intravenous administration. The Sq-Ara-C nanomedicine extended the drug half-life in plasma, which increased surprisingly by 6.0-fold in comparison with the native Ara-C (Figure 4). Moreover, free Ara-C was completely undetectable 12 hours after administration, while quantification of the active compound was possible in the nanomedicine even after 24 hours.


Self-assembled squalenoyl-cytarabine nanostructures as a potent nanomedicine for treatment of leukemic diseases.

Cosco D, Rocco F, Ceruti M, Vono M, Fresta M, Paolino D - Int J Nanomedicine (2012)

Pharmacokinetic profiles for free Ara-C and Sq-Ara-C in DBA/2 mice following intravenous administration of a 1 mg/kg dose.Note: Data are the mean of three independent experiments ± standard deviation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3367491&req=5

f4-ijn-7-2535: Pharmacokinetic profiles for free Ara-C and Sq-Ara-C in DBA/2 mice following intravenous administration of a 1 mg/kg dose.Note: Data are the mean of three independent experiments ± standard deviation.
Mentions: Evidence of the protective role played by the squalenic chain in the plasma metabolism of Sq-Ara-C and its improved biopharmaceutical features was determined by evaluating the pharmacokinetic profile of the Sq-Ara-C nanomedicine with respect to the Ara-C solution after intravenous administration. The Sq-Ara-C nanomedicine extended the drug half-life in plasma, which increased surprisingly by 6.0-fold in comparison with the native Ara-C (Figure 4). Moreover, free Ara-C was completely undetectable 12 hours after administration, while quantification of the active compound was possible in the nanomedicine even after 24 hours.

Bottom Line: Squalenoyl-Ara-C conjugate (Sq-Ara-C) self-assembled nanosystems were obtained by the nanoprecipitation method and characterized in vitro and in vivo.Sq-Ara-C nanomedicine allowed reduction of the IC(50) value with respect to the free drug and was also active against drug-resistant leukemic cells (L1210R).Squalenoylation of cytarabine offers several pharmacological benefits both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences, University Magna Græcia, Catanzaro, Italy.

ABSTRACT

Background: In this investigation, the antileukemic activity of a new nanomedicine based on the conjugation of 1,1',2-tris-nor-squalenic acid with cytarabine (Ara-C) was evaluated.

Methods: Squalenoyl-Ara-C conjugate (Sq-Ara-C) self-assembled nanosystems were obtained by the nanoprecipitation method and characterized in vitro and in vivo.

Results: This new nanomedicine, which had a mean diameter of approximately 150 nm, improved the in vitro antitumoral activity of Ara-C in different cancer cell lines (L1210, K562, and MCF-7). Sq-Ara-C nanomedicine allowed reduction of the IC(50) value with respect to the free drug and was also active against drug-resistant leukemic cells (L1210R). A noticeable increase in the survival rate of mice with aggressive metastatic L1210R leukemia was observed after treatment with Sq-Ara-C (50 mg/kg) as compared with the free active compound (100 mg/kg). Finally, evaluation of the biodistribution and pharmacokinetic profiles of the drug demonstrated that these nanoaggregates preferentially localized to the liver and spleen, and protected the drug from physiological metabolism.

Conclusion: Squalenoylation of cytarabine offers several pharmacological benefits both in vitro and in vivo.

Show MeSH
Related in: MedlinePlus