title: Enhanced cellular accumulation of a P-glycoprotein substrate, rhodamine-123, by Caco-2 cells using low molecular weight methoxypolyethylene glycol-block-polycaprolactone diblock copolymers.
abstract: A series of diblock copolymers based on methoxypolyethylene glycol-block-poly(caprolactone) (MePEG-b-PCL) was synthesized and evaluated for enhancing the cellular accumulation of a P-glycoprotein (P-gp) substrate, rhodamine-123 (R-123), into caco-2 cells. Altering MePEG:caprolactone feed weight ratio allowed diblocks with varying PCL lengths to be synthesized onto MePEG of molecular weight 750 or 2000. The critical micelle concentration (CMC) and the hydrophilic-lipophilic balance all decreased with increasing degree of polymerization of PCL. R-123 accumulation by caco-2 cells increased to a maximum in the presence of increasing concentrations of MePEG-b-PCL diblock copolymers (compared to R-123 alone) beginning at concentrations at or above the CMC, with little or no R-123 accumulation enhancement observed below the CMC. Further increases in MePEG-b-PCL concentration resulted in a decrease in R-123 uptake back to baseline levels. It is suggested that the higher concentrations of diblock above the CMC were required to serve as a 'depot' for free unimer partitioning into the cell membrane in order to obtain a critical concentration of diblock in the membrane for P-gp modulation. Alternatively, MePEG-b-PCL micelles may increase R-123 accumulation via endocytosis of micellized R-123.
authors.affiliation: Faculty of Pharmaceutical Sciences, Vancouver, BC, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Zastre
authors.forename: John
authors.initials: J
authors.lastname: Jackson
authors.forename: Mandeep
authors.initials: M
authors.lastname: Bajwa
authors.forename: Richard
authors.initials: R
authors.lastname: Liggins
authors.forename: Famida
authors.initials: F
authors.lastname: Iqbal
authors.forename: Helen
authors.initials: H
authors.lastname: Burt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D011091:Polyesters / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D020112:Rhodamine 123 / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011091:Polyesters; D020112:Rhodamine 123; C016240:polycaprolactone; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol