Improvement of paclitaxel therapeutic index by derivatization and association to a cholesterol-rich microemulsion: in vitro and in vivo studies
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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.
KeywordsNanoparticles 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.
- 4.Entin I, Plotnikov A, Korenstein R, Keisari Y (2003) Tumor growth retardation, cure, and induction of antitumor immunity in B16 Melanoma-bearing mice by low eletric field-enhanced chemotherapy. Clin Cancer Res 9:3190–3197Google Scholar
- 5.Gal D, Ohashi M, MacDonald PC, Buchsbaum HJ, Simpson ER (1981) Low-density lipoprotein as a potential vehicle for chemotherapeutic agents and radionucleotides in the management of gynecologic neoplasms. Am J Obstret Gynecol 139:877–885Google Scholar
- 6.Ginsberg H, Gilbert HS, Gibson JC, Ngoc-Anh L, Virgil BW (1986) Increased low-density-lipoprotein catabolism in myeloproliferative disorders. Ann Intern Med 96: 311–316Google Scholar
- 7.Ginsburg GS, Small DM, Atkinson D (1982) Microemulsions of phospholipids and cholesterol esters. Protein-free models of low density lipoprotein. J Biol Chem 57:8216–8277Google Scholar
- 8.Goble S, Bear HD (2003) Emerging role of taxanes in adjuvant and neoadjuvant therapy for breast cancer: the potential and the questions. Surg Clin North Am 83(4):943–971Google Scholar
- 12.Hungria VTM, Latrilha MC, Rodrigues DG, Bydlowski SP, Chiattone CS, Maranhão RC (2004) Metabolism of a cholesterol-rich microemulsion (LDE) in patients with multiple myeloma and a preliminary clinical study of LDE as a drug vehicle for the treatment of the disease. Cancer Chem Pharmacol 53:51–60CrossRefGoogle Scholar
- 15.Maranhão RC, Cesar TB, Pedroso MTB, Hirata MH, Mesquita CH (1993) Metabolic behavior in rats of a nonprotein microemulsion resembling LDL. Lipids 28:691–696Google Scholar
- 16.Maranhão RC, Garicochea B, Silva EL, Dorlhiac-Llacer P, Cadena SMS, Coelho IJC, Meneghetti JC, Pileggi FJC, Chamone DAF (1994) Plasma kinetics and biodistribution of a lipid emulsion resembling low-density lipoprotein in patients with acute leukemia. Cancer Res 54:4660–4666Google Scholar
- 19.Plowman J, Dykes DJ, Hollingshead M, Simpson H, Alley MC (1997) Human tumor xenograft models in NCI development. In: Teicher BA (ed) Anticancer drug development: preclinical screening, clinical trials and approval. Humana, Totowa, pp 101–125Google Scholar
- 25.Verluis AJ, Rensen PC, Rump ET, Van Berkel TJ, Bijsterbosch MK (1998) Low density lipoprotein receptor-mediated delivery of a lipophilic daunorubicin derivative to B16 tumours in mice using apolipoprotein E-enriched liposomes. Br J Cancer 78(12):1607–1614Google Scholar