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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

Survival profile of mice inoculated intravenously with 1 × 105 L1210R cells and treated with the different formulations.
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f2-ijn-7-2535: Survival profile of mice inoculated intravenously with 1 × 105 L1210R cells and treated with the different formulations.

Mentions: As mentioned, weight loss is a clear sign of leukemia and is related directly to the severity of the disease, ie, the greater the weight loss the more severe the leukemic pathology. Treatment of mice with the various Ara-C formulations resulted in a weight reduction with respect to the untreated animals in the following decreasing order: Sq-Ara-C nanomedicine 50 mg/kg > Ara-C 100 mg/kg and a physical mixture of Ara-C/squalenoyl nanosystems > squalenoyl nanosystems. The increased antileukemic effectiveness of the Sq-Ara-C nanomedicine was confirmed further by evaluating survival of leukemic-bearing mice as a function of time. As shown by the data on the survival rates for mice treated with the different formulations reported in Figure 2, the control group showed the same survival profile as mice treated with the squalenoyl nanosystems, while the Sq-Ara-C nanomedicine provided the greatest antileukemic effect. The Ara-C and the physical mixture of Ara-C/squalenoyl nanosystems induced the same variation in percentage of mouse survival, demonstrating that the active compound has to be covalently linked to squalenic acid in order to improve its antileukemic efficacy.


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)

Survival profile of mice inoculated intravenously with 1 × 105 L1210R cells and treated with the different formulations.
© Copyright Policy
Related In: Results  -  Collection

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

f2-ijn-7-2535: Survival profile of mice inoculated intravenously with 1 × 105 L1210R cells and treated with the different formulations.
Mentions: As mentioned, weight loss is a clear sign of leukemia and is related directly to the severity of the disease, ie, the greater the weight loss the more severe the leukemic pathology. Treatment of mice with the various Ara-C formulations resulted in a weight reduction with respect to the untreated animals in the following decreasing order: Sq-Ara-C nanomedicine 50 mg/kg > Ara-C 100 mg/kg and a physical mixture of Ara-C/squalenoyl nanosystems > squalenoyl nanosystems. The increased antileukemic effectiveness of the Sq-Ara-C nanomedicine was confirmed further by evaluating survival of leukemic-bearing mice as a function of time. As shown by the data on the survival rates for mice treated with the different formulations reported in Figure 2, the control group showed the same survival profile as mice treated with the squalenoyl nanosystems, while the Sq-Ara-C nanomedicine provided the greatest antileukemic effect. The Ara-C and the physical mixture of Ara-C/squalenoyl nanosystems induced the same variation in percentage of mouse survival, demonstrating that the active compound has to be covalently linked to squalenic acid in order to improve its antileukemic efficacy.

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