title: Prolonged circulation and in vivo efficacy of recombinant human granulocyte colony-stimulating factor encapsulated in polymeric micelles.
abstract: To improve the pharmacokinetics of granulocyte colony-stimulating factor (G-CSF) and decrease dosing frequency, polyethylene glycol polyglutamate block copolymers were used as delivery carriers. The block copolymers are partially substituted with hydrophobic octyl or benzyl groups to form a micellar structure in aqueous media and encapsulate the protein. G-CSF is encapsulated in the polymeric micelles with a diameter of 60-70nm. The present study was designed to evaluate the plasma pharmacokinetics, G-CSF release and in vivo efficacy of G-CSF-encapsulating micelles. Pharmacokinetic studies in rats showed highly enhanced plasma retention of the micelles compared with native G-CSF. The AUC (area under the curve) of the octyl-based polymer formulation showed a 5-fold increase, compared with native G-CSF. Size-exclusion chromatography of the blood from rats injected with the micelles demonstrated the release of G-CSF from the micelles in the blood circulation. The pharmacokinetic behavior supports the in vivo studies showing that the micelles display a comparable efficacy to PEGylated G-CSF. Simultaneous pharmacokinetic analysis of released and encapsulated G-CSF plasma levels showed that the G-CSF release occurs with the first-order kinetics and the half-life is 4.8h. In conclusion, G-CSF is endowed by the polymeric micelles with prolonged half-life and increased efficacy without any chemical modification.
authors: Research Division, NanoCarrier Co. Ltd., 5-4-19 Kashiwanoha, Kashiwa, Chiba, Japan.
authors: Mitsunori
authors: M
authors: Harada
authors: Miho
authors: M
authors: Ohuchi
authors: Tatsuyuki
authors: T
authors: Hayashi
authors: Yasuki
authors: Y
authors: Kato
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D000069585:Filgrastim; D018698:Glutamic Acid / Q000737:chemistry*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000097:blood* / Q000494:pharmacology; D006207:Half-Life; D007958:Leukocyte Count; D008297:Male; D008823:Micelles; D015394:Molecular Structure; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D012995:Solubility; D013997:Time Factors
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D018698:Glutamic Acid; D011092:Polyethylene Glycols; D000069585:Filgrastim