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 IC50 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.
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 evidenced. The squalenoyl-Ara-C conjugate (Sq−Ara-C) self-assembled nanosystems were obtained by the nanoprecipitation method and characterized in vitro and in vivo. This new nanomedicine, which has a mean diameter of ~150 nm, improved the in vitro antitumoral activity of Ara-C on different cancer cell lines (L1210, K562 and MCF-7 cells). The Sq−Ara-C nanomedicine allowed the reduction of the IC50 value with respect to the free drug and was also active against leukemic drug-resistant cells (L1210R). A noticeable increase in the survival rate of mice affected with an aggressive metastatic leukemia L1210R was observed after treatment with Sq-Ara-C (at 50 mg/kg), as compared to the free active compound (100 mg/kg). Finally, the evaluation of the biodistribution and pharmacokinetic profiles of the drug evidenced the fact that the nanoaggregates preferentially localized in the liver and spleen; moreover, the nanomedicine provided the drug compound with protection from the physiological metabolization processes. Squalenoylation of cytarabine offers several pharmacological benefits both in vitro and in vivo.
Self-assembled squalenoyl-cytarabine nanostructures as a potent nanomedicine for the effective treatment of leukemic diseases
Fresta M;COSCO D;Paolino D
2012-01-01
Abstract
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 evidenced. The squalenoyl-Ara-C conjugate (Sq−Ara-C) self-assembled nanosystems were obtained by the nanoprecipitation method and characterized in vitro and in vivo. This new nanomedicine, which has a mean diameter of ~150 nm, improved the in vitro antitumoral activity of Ara-C on different cancer cell lines (L1210, K562 and MCF-7 cells). The Sq−Ara-C nanomedicine allowed the reduction of the IC50 value with respect to the free drug and was also active against leukemic drug-resistant cells (L1210R). A noticeable increase in the survival rate of mice affected with an aggressive metastatic leukemia L1210R was observed after treatment with Sq-Ara-C (at 50 mg/kg), as compared to the free active compound (100 mg/kg). Finally, the evaluation of the biodistribution and pharmacokinetic profiles of the drug evidenced the fact that the nanoaggregates preferentially localized in the liver and spleen; moreover, the nanomedicine provided the drug compound with protection from the physiological metabolization processes. Squalenoylation of cytarabine offers several pharmacological benefits both in vitro and in vivo.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
