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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

Transmission electron micrograph of the Sq-Ara-C nanoaggregates (A). Interaction between [3H]CHE radiolabeled Sq-Ara-C and the different cancer cell lines (B). Confocal laser scanning micrograph (C), relative three-dimensional image (D) and 4× zoom (E) showing the interaction between MCF-7 cells and the fluorescein-DHPE-labeled Sq-Ara-C nanoaggregates after 3 hours of incubation.
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f1-ijn-7-2535: Transmission electron micrograph of the Sq-Ara-C nanoaggregates (A). Interaction between [3H]CHE radiolabeled Sq-Ara-C and the different cancer cell lines (B). Confocal laser scanning micrograph (C), relative three-dimensional image (D) and 4× zoom (E) showing the interaction between MCF-7 cells and the fluorescein-DHPE-labeled Sq-Ara-C nanoaggregates after 3 hours of incubation.

Mentions: Dynamic light scattering and transmission electron microscopic analysis of the nanosystems showed a mean size of about 150 nm, with a polydispersity index of approximately 0.1 (highly homogenous size distribution, Table 1, Figure 1A). Moreover, a surface charge of about −25 mV was obtained, confirming the results of previous investigations.20 These values represent ideal parameters able to assure ideal biopharmaceutical properties for the nanoaggregates; in fact, various studies have demonstrated that the mean size and surface charge can influence biodistribution of a colloidal formulation after intravenous administration. In particular, a mean size of less than 200 nm allows a long circulation time.11


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)

Transmission electron micrograph of the Sq-Ara-C nanoaggregates (A). Interaction between [3H]CHE radiolabeled Sq-Ara-C and the different cancer cell lines (B). Confocal laser scanning micrograph (C), relative three-dimensional image (D) and 4× zoom (E) showing the interaction between MCF-7 cells and the fluorescein-DHPE-labeled Sq-Ara-C nanoaggregates after 3 hours of incubation.
© Copyright Policy
Related In: Results  -  Collection

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

f1-ijn-7-2535: Transmission electron micrograph of the Sq-Ara-C nanoaggregates (A). Interaction between [3H]CHE radiolabeled Sq-Ara-C and the different cancer cell lines (B). Confocal laser scanning micrograph (C), relative three-dimensional image (D) and 4× zoom (E) showing the interaction between MCF-7 cells and the fluorescein-DHPE-labeled Sq-Ara-C nanoaggregates after 3 hours of incubation.
Mentions: Dynamic light scattering and transmission electron microscopic analysis of the nanosystems showed a mean size of about 150 nm, with a polydispersity index of approximately 0.1 (highly homogenous size distribution, Table 1, Figure 1A). Moreover, a surface charge of about −25 mV was obtained, confirming the results of previous investigations.20 These values represent ideal parameters able to assure ideal biopharmaceutical properties for the nanoaggregates; in fact, various studies have demonstrated that the mean size and surface charge can influence biodistribution of a colloidal formulation after intravenous administration. In particular, a mean size of less than 200 nm allows a long circulation time.11

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