title: In vivo pharmacokinetics, biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle.
abstract: A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into novel-targeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax® in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC50 value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93 µM for Anzatax® and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax®. Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax®. Compared with Anzatax®, the Vd, T1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX.
authors.affiliation: a Department of Pharmaceutics .
authors.forename: Mahboubeh
authors.initials: M
authors.lastname: Rezazadeh
authors.affiliation: a Department of Pharmaceutics .
authors.forename: Jaber
authors.initials: J
authors.lastname: Emami
authors.affiliation: b Department of Medicinal Chemistry .
authors.forename: Farshid
authors.initials: F
authors.lastname: Hasanzadeh
authors.affiliation: c Department of Biotechnology , and.
authors.forename: Hojjat
authors.initials: H
authors.lastname: Sadeghi
authors.affiliation: d Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences , Isfahan University of Medical Sciences , Isfahan , Islamic Republic of Iran , and.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Minaiyan
authors.affiliation: a Department of Pharmaceutics .
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Mostafavi
authors.affiliation: b Department of Medicinal Chemistry .
authors.forename: Mahboubeh
authors.initials: M
authors.lastname: Rostami
authors.affiliation: e Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada.
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry*; D004337:Drug Carriers; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D011092:Polyethylene Glycols; D048271:Chitosan; D005492:Folic Acid; D017239:Paclitaxel
keywords: Biodistribution; Paclitaxel; in vivo anti-tumor effect; pharmacokinetics; targeted polymeric micelle