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.
OBJECTIVE
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 [(3)H]-paclitaxel oleate associated with [(14)C]-cholesteryl oleate-nanoemulsion or [(3)H]-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/m(2) dose levels.


RESULTS
T (1/2) of paclitaxel oleate associated to the nanoemulsion was greater than that of paclitaxel (t (1/2) = 15.4 +/- 4.7 and 3.5 +/- 0.80 h). Uptake of the [(14)C]-cholesteryl ester nanoemulsion and [(3)H]-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.
Pires
Luís A
LA
Lipid Metabolism Laboratory, Heart Institute (InCor), University of São Paulo Medical School Hospital, Av. Dr. Eneas de Carvalho Aguiar, 44, 1 degrees subsolo, São Paulo 05403-000, Brazil.
Hegg
Roberto
R
Valduga
Claudete J
CJ
Graziani
Sílvia R
SR
Rodrigues
Débora G
DG
Maranhão
Raul C
RC
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004655:Emulsions; D005260:Female; D006801:Humans; D008875:Middle Aged; D053758:Nanoparticles / Q000737:chemistry*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D010865:Pilot Projects; D018110:Receptors, Lipoprotein / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D004655:Emulsions; D018110:Receptors, Lipoprotein; D002784:Cholesterol; D017239:Paclitaxel