Enhanced cellular accumulation of a P-glycoprotein substrate, rhodamine-123, by caco-2 cells using low molecular weight methoxypolyethylene glycol- block-polycaprolactone diblock copolymers

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 54; no. 3; pp. 299 - 309
• Main Authors: Zastre, Jason, Jackson, John, Bajwa, Mandeep, Liggins, Richard, Iqbal, Famida, Burt, Helen
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01-11-2002; Elsevier Science
• Subjects: ATP-Binding Cassette, Sub-Family B, Member 1 - administration & dosage; ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry; ATP-Binding Cassette, Sub-Family B, Member 1 - pharmacokinetics; Biological and medical sciences; Caco-2 Cells; Critical micelle concentration; Diblock copolymers; Drug Delivery Systems - methods; General pharmacology; Humans; Medical sciences; Micelles; P-glycoprotein; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyesters - administration & dosage; Polyesters - chemistry; Polyesters - pharmacokinetics; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Rhodamine 123 - administration & dosage; Rhodamine 123 - chemistry; Rhodamine 123 - pharmacokinetics; P-glycoprotein; Critical micelle concentration; Diblock copolymers; Micelles; Human; Intracellular transport; Pharmaceutical technology; Targeting; Digestive system; Controlled release form; Control release polymer; Biological transport; P Glycoprotein; Micelle; Drug carrier; Ethylene oxide copolymer; In vitro; Caprolactone copolymer; Established cell line; Dosage form; Chemical synthesis; Molecular mass
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/S0939-6411(02)00119-4

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.