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Use of cholesterol-rich nanoparticles that bind to lipoprotein receptors as a vehicle to paclitaxel in the treatment of breast cancer: pharmacokinetics, tumor uptake and a pilot clinical study

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Abstract

Purpose

In animal experiments paclitaxel oleate associated with a cholesterol-rich nanoemulsion concentrated in the neoplastic tissues and showed reduced toxicity and increased antitumor activity compared with paclitaxel-Cremophor EL. Here, a clinical study was performed in breast cancer patients to evaluate the tumoral uptake, pharmacokinetics and toxicity of paclitaxel associated to nanoemulsions.

Methods

Twenty-four hours before mastectomy [3H]-paclitaxel oleate associated with [14C]-cholesteryl oleate-nanoemulsion or [3H]-paclitaxel in Cremophor EL were injected into five patients for collection of blood samples and fragments of tumor and normal breast tissue. A pilot clinical study of paclitaxel-nanoemulsion administered at 3-week intervals was performed in four breast cancer patients with refractory advanced disease at 175 and 220 mg/m2 dose levels.

Results

T1/2 of paclitaxel oleate associated to the nanoemulsion was greater than that of paclitaxel (t1/2 = 15.4 ± 4.7 and 3.5 ± 0.80 h). Uptake of the [14C]-cholesteryl ester nanoemulsion and [3H]-paclitaxel oleate by breast malignant tissue was threefold greater than the normal breast tissue and toxicity was minimal at the two dose levels.

Conclusions

Our results suggest that the paclitaxel-nanoemulsion preparation can be advantageous for use in the treatment of breast cancer because the pharmacokinetic parameters are improved, the drug is concentrated in the neoplastic tissue and the toxicity of paclitaxel is reduced.

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Acknowledgments

The authors grateful to Ms. Maria das Dores Pereira for the technical assistance. This study was supported by Fundação do Amparo à Pesquisa do Estado de São Paulo (FAPESP) and The Zerbini Foundation, both in São Paulo, Brazil. Dr. Maranhão is a 1A Research Awardee of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasilia, Brazil.

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Authors and Affiliations

  1. Lipid Metabolism Laboratory, Heart Institute (InCor), University of São Paulo Medical School Hospital, Av. Dr. Eneas de Carvalho Aguiar, 44, 1° subsolo, São Paulo, 05403-000, Brazil

    Luís A. Pires, Claudete J. Valduga, Sílvia R. Graziani, Débora G. Rodrigues & Raul C. Maranhão

  2. Gynecology and Obstetrics Department, Medical School Hospital, University of São Paulo, São Paulo, Brazil

    Luís A. Pires, Roberto Hegg & Sílvia R. Graziani

  3. Bandeirante University of São Paulo, São Paulo, Brazil

    Claudete J. Valduga

  4. Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil

    Raul C. Maranhão

Authors
  1. Luís A. Pires
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  2. Roberto Hegg
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  3. Claudete J. Valduga
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  4. Sílvia R. Graziani
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  5. Débora G. Rodrigues
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  6. Raul C. Maranhão
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Correspondence to Raul C. Maranhão.

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Pires, L.A., Hegg, R., Valduga, C.J. et al. Use of cholesterol-rich nanoparticles that bind to lipoprotein receptors as a vehicle to paclitaxel in the treatment of breast cancer: pharmacokinetics, tumor uptake and a pilot clinical study. Cancer Chemother Pharmacol 63, 281–287 (2009). https://doi.org/10.1007/s00280-008-0738-2

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