title: Formulation and evaluation of paclitaxel-loaded polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer.
abstract: To develop potent paclitaxel (PTX) formulations for cancer chemotherapy, we formulated PTX into polymeric nanoparticles composed of polyethylene glycol (PEG) and polylactic acid (PLA) block copolymer (PN-PTX). First, the physicochemical properties of PN-PTX prepared were assessed; the mean particle size was around 80 nm and the zeta potential was found to be almost neutral. Next, the in vitro PTX release property was assessed by a dialysis method. Although rapid release of PTX was observed just after dosing, around 70% of PTX was stably incorporated in polymeric nanoparticles for a long time in the presence of serum. Then, the in vivo pharmacokinetics of PN-PTX after intravenous administration was investigated in Colon-26 (C26) tumor-bearing mice. Both polymeric nanoparticles and PTX incorporated exhibited a long blood circulating property, leading to enhanced permeability and retention (EPR) effect-driven, time-dependent tumor disposition of PTX. Tumor distribution increased gradually for 24 h, and tissue uptake clearance of polymeric nanoparticles in the liver and spleen was lower than that of PEG liposomes. Since these results indicated that the in vivo disposition characteristics of PN-PTX were very favorable, we then evaluated the anti-tumor effect of PN-PTX in C26 tumor-bearing mice. However, PN-PTX did not exhibit any significant anti-tumor effect, presumably due to the poor PTX release from polymeric nanoparticles. From these results, it is considered that the favorable pharmacokinetic properties of nanoparticles and the drug incorporated do not always lead to its potent in vivo pharmacological activity, suggesting the importance of PTX release properties within tumor tissues.
authors.affiliation: Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Araki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kono
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ogawara
authors.forename: Takaichi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ono
authors.forename: Toshikiro
authors.initials: T
authors.lastname: Kimura
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004337:Drug Carriers / Q000378:metabolism / Q000493:pharmacokinetics*; D019344:Lactic Acid / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D010316:Particle Size; D011091:Polyesters; D011092:Polyethylene Glycols / Q000378:metabolism / Q000493:pharmacokinetics*; D011108:Polymers / Q000378:metabolism / Q000493:pharmacokinetics*; D013154:Spleen / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D017239:Paclitaxel