Cancer Chemotherapy and Pharmacology

, Volume 55, Issue 6, pp 565–576 | Cite as

Improvement of paclitaxel therapeutic index by derivatization and association to a cholesterol-rich microemulsion: in vitro and in vivo studies

  • Debora G. Rodrigues
  • Durvanei A. Maria
  • Denise C. Fernandes
  • Claudete J. Valduga
  • Ricardo D. Couto
  • Olga C. M. Ibañez
  • Raul C. Maranhão
Original Article


A cholesterol-rich microemulsion or nanoparticle termed LDE concentrates in cancer tissues after injection into the bloodstream. Here the cytotoxicity, pharmacokinetics, toxicity to animals and therapeutic action of a paclitaxel lipophilic derivative associated to LDE is compared with those of the commercial paclitaxel. Results show that LDE-paclitaxel oleate is stable. The cytostatic activity of the drug in the complex is diminished compared with the commercial paclitaxel due to the cytotoxicity of the vehicle Cremophor EL used in the commercial formulation. Competition experiments in neoplastic cultured cells show that paclitaxel oleate and LDE are internalized together by the LDL receptor pathway. LDE-paclitaxel oleate arrests the G2/M phase of cell cycle, similarly to commercial paclitaxel. Tolerability to mice is remarkable, such that the lethal dose (LD50) was ninefold greater than that of the commercial formulation (LD50 = 326 μM and 37 μM, respectively). LDE concentrates paclitaxel oleate in the tumor roughly fourfold relative to the normal adjacent tissues. At equimolar doses, the association of paclitaxel oleate with LDE results in remarkable changes in the drug pharmacokinetic parameters when compared to commercial paclitaxel (t1/2=218 min and 184 min, AUC=1,334 μg h/ml and 707 μg h/ml and CL=0.125 ml/min and 0.236 ml/min, respectively). Finally, the therapeutic efficacy of the complex is pronouncedly greater than that of the commercial paclitaxel, as indicated by the reduction in tumor growth, increase in survival rates and % cure of treated mice. In conclusion, LDE-paclitaxel oleate is a stable complex and compared with paclitaxel toxicity is considerably reduced and activity is enhanced, which may lead to improved therapeutic index in clinical use.


Nanoparticles Paclitaxel Emulsions Cholesterol Low-density lipoprotein receptors Cancer treatment Drug targeting 



This study was supported by Fundação do Amparo à Pesquisa do Estado de São Paulo (FAPESP), São Paulo, Brazil (Grant 99/01229-2). Dr Maranhão has a Research Award from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasilia, Brazil.


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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Debora G. Rodrigues
    • 1
    • 2
  • Durvanei A. Maria
    • 3
  • Denise C. Fernandes
    • 1
  • Claudete J. Valduga
    • 1
  • Ricardo D. Couto
    • 1
    • 2
  • Olga C. M. Ibañez
    • 3
  • Raul C. Maranhão
    • 1
    • 2
  1. 1.Lipid Metabolism Laboratory, Heart Institute (InCor)University of São Paulo Medical School HospitalSao PauloBrazil
  2. 2.Faculty of Pharmaceutical SciencesUniversity of São PauloSao PauloBrazil
  3. 3.Laboratory of Immunogenetics of the Butantan InstituteSao PauloBrazil

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