Methoxy poly(ethylene glycol)-block-poly(delta-valerolactone) copolymer micelles for formulation of hydrophobic drugs.
Six amphiphilic diblock copolymers based on methoxy poly(ethylene glycol) (MePEG) and poly(delta-valerolactone) (PVL) with varying hydrophilic and hydrophobic block lengths were synthesized via a metal-free cationic polymerization method. MePEG-b-PVL copolymers were synthesized using MePEG with Mn = 2000 or Mn = 5000 as the macroinitiator. 1H NMR and GPC analyses confirmed the synthesis of diblock copolymers with relatively narrow molecular weight distributions (Mn/Mw = 1.05-1.14). DSC analysis revealed that the melting temperatures (Tm) of the copolymers (47-58 degrees C) approach the Tm of MePEG as the PVL content is decreased. MePEG-b-PVL copolymer aggregates loaded with the hydrophobic anti-cancer drug paclitaxel were found to have effective mean diameters ranging from 31 to 970 nm depending on the composition of the copolymers. A MePEG-b-PVL copolymer of a specific composition was found to form drug-loaded micelles of 31 nm in diameter with a narrow size distribution and improve the apparent aqueous solubility of paclitaxel by more than 9000-fold. The biological activity of paclitaxel formulated in the MePEG-b-PVL micelles was confirmed in human MCF-7 breast and A2780 ovarian cancer cells. Furthermore, the biocompatibility of the copolymers was established in CHO-K1 fibroblast cells using a cell viability assay. The in vitro hydrolytic and enzymatic degradation of the micelles was also evaluated over a period of one month. The present study indicates that the MePEG-b-PVL copolymers are suitable biomaterials for hydrophobic drug formulation and delivery.
Lee
Helen
H
Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, and Faculty of Applied Science and Engineering, Division of Engineering Science, University of Toronto, 19 Russell St., Toronto, Ontario, Canada M5S 2S2.
Zeng
Faquan
F
Dunne
Mike
M
Allen
Christine
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001672:Biocompatible Materials / Q000737:chemistry*; D016466:CHO Cells; D002152:Calorimetry, Differential Scanning; D002412:Cations; D045744:Cell Line, Tumor; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006224:Cricetinae; D004337:Drug Carriers; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D046911:Macromolecular Substances / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry*; D013696:Temperature; D013997:Time Factors
D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D002412:Cations; D004337:Drug Carriers; D046911:Macromolecular Substances; D008823:Micelles; D011108:Polymers; D011753:Pyrones; C052207:delta-valerolactone; D011092:Polyethylene Glycols; D017239:Paclitaxel