Optimal Structure Requirements for Pluronic Block Copolymers in Modifying P-glycoprotein Drug Efflux Transporter Activity in Bovine Brain Microvessel Endothelial Cells
- 1 February 2003
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 304 (2), 845-854
- https://doi.org/10.1124/jpet.102.043307
Abstract
Pluronic block copolymer P85 was shown to inhibit the P-glycoprotein (Pgp) drug efflux system and to increase the permeability of a broad spectrum of drugs in the blood-brain barrier (BBB). However, there is an entire series of Pluronics varying in lengths of propylene oxide and ethylene oxide and overall lipophilicity. This study identifies those structural characteristics of Pluronics required for maximal impact on drug efflux transporter activity in bovine brain microvessel endothelial cells (BBMECs). Using a wide range of block copolymers, differing in hydrophilic-lipophilic balance (HLB), this study shows that lipophilic Pluronics with intermediate length of propylene oxide block (from 30 to 60 units) and HLB <20 are the most effective at inhibiting Pgp efflux in BBMECs. The methods used included 1) cellular accumulation studies with the Pgp substrate rhodamine 123 in BBMECs to assess Pgp activity; 2) luciferin/luciferase ATP assay to evaluate changes in cellular ATP; 3) 1,6-diphenyl-1,3,5-hexatriene membrane microviscosity studies to determine alterations in membrane fluidity; and 4) Pgp ATPase assays using human Pgp-expressing membranes. Pluronics with intermediate lipophilic properties showed the strongest fluidization effect on the cell membranes along with the most efficient reduction of intracellular ATP synthesis in BBMEC monolayers. The relationship between the structure of Pluronic block copolymers and their biological response-modifying effects in BBMECs are useful for determining formulations with maximal efficacy for increasing BBB permeability.Keywords
This publication has 22 references indexed in Scilit:
- Effect of ethylene oxide and propylene oxide block copolymers on the permeability of bilayer lipid membranes to small solutes including doxorubicinBiochimica et Biophysica Acta (BBA) - Biomembranes, 2000
- BIOCHEMICAL, CELLULAR, AND PHARMACOLOGICAL ASPECTS OF THE MULTIDRUG TRANSPORTERAnnual Review of Pharmacology and Toxicology, 1999
- Block copolymeric biotransport carriers as versatile vehicles for drug deliveryExpert Opinion on Investigational Drugs, 1998
- Effects of pluronic P85 unimers and micelles on drug permeability in polarized BBMEC and Caco-2 cells.Pharmaceutical Research, 1998
- Use of rhodamine 123 to examine the functional activity of P-glycoprotein in primary cultured brain microvessel endothelial cell monolayersLife Sciences, 1996
- Photometric Microtiter Assay of Inorganic Phosphate in the Presence of Acid-Labile Organic PhosphatesAnalytical Biochemistry, 1995
- Comparisons of the relative effects of polyhydroxyl compounds on local versus long-range motions in the mitochondrial inner membrane. Fluorescence recovery after photobleaching, fluorescence lifetime, and fluorescence anisotropy studiesBiochimica et Biophysica Acta (BBA) - Biomembranes, 1994
- Micellization of Poly(ethylene oxide)-Poly(propylene oxide)-Poly(ethylene oxide) Triblock Copolymers in Aqueous Solutions: Thermodynamics of Copolymer AssociationMacromolecules, 1994
- MTT colorimetric assay for testing macrophage cytotoxic activity in vitroJournal of Immunological Methods, 1990
- A new procedure for the synthesis of polyethylene glycol-protein adducts; Effects on function, receptor recognition, and clearance of superoxide dismutase, lactoferrin, and α2-macroglobulinAnalytical Biochemistry, 1983