title: Interactions of Pluronic nanocarriers with 2D and 3D cell cultures: Effects of PEO block length and aggregation state.
abstract: This work reveals how the physicochemical properties of Pluronic block copolymers influence significantly their interactions with cancer cells, whether in monolayer or spheroid cultures, and how different clinical applications can be foreseen. Two-dimensional (2D) and three-dimensional (3D) cell culture models were used to investigate the interactions of Pluronic carriers with different PEO block length and aggregation state (unimers versus cross-linked micelles) in HeLa and U87 cancer cells. Stabilized micelles of Pluronic P94 or F127 were obtained by polymerization of a crosslinking agent in the micelles hydrophobic core. Nanocarriers were functionalized with a fluorescent probe for visualization, and with a chelator for radiolabeling with Indium-111 and gamma-quantification. The 2D cell models revealed that the internalization pathways and ultimate cellular localization of the Pluronic nanocarriers depended largely on both the PEO block size and aggregation state of the copolymers. The smaller P94 unimers with an average radius of 2.1nm and the shortest PEO block mass (1100gmol(-1)) displayed the highest cellular uptake and retention. 3D tumor spheroids were used to assess the penetration capacity and toxicity potential of the nanocarriers. Results showed that cross-linked F127 micelles were more efficiently delivered across the tumor spheroids, and the penetration depth depends mostly on the transcellular transport of the carriers. The Pluronic P94-based carriers with the shortest PEO block length induced spheroid toxicity, which was significantly influenced by the spheroid cellular type.
authors.affiliation: Institut Charles Sadron (CNRS), 23 rue du Loess, 67034 Strasbourg, France. Electronic address: alexandra.arranja@ics-cnrs.unistra.fr.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Arranja
authors.affiliation: Department of Radiation Science and Technology, Delft University of Technology, Mekelweg 15, 2629 JB Delft, The Netherlands.
authors.forename: Antonia G
authors.initials: AG
authors.lastname: Denkova
authors.affiliation: Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281, 9000 Ghent, Belgium.
authors.forename: Karolina
authors.initials: K
authors.lastname: Morawska
authors.affiliation: Institut Charles Sadron (CNRS), 23 rue du Loess, 67034 Strasbourg, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Waton
authors.affiliation: Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281, 9000 Ghent, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: van Vlierberghe
authors.affiliation: Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281, 9000 Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Dubruel
authors.affiliation: Institut Charles Sadron (CNRS), 23 rue du Loess, 67034 Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Schosseler
authors.affiliation: Department of Chemical Engineering, Delft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Mendes
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002614:Chelating Agents; D003432:Cross-Linking Reagents; D004337:Drug Carriers / Q000737:chemistry*; D004705:Endocytosis / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D005456:Fluorescent Dyes; D006367:HeLa Cells; D006801:Humans; D007205:Indium Radioisotopes / Q000008:administration & dosage; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D020442:Poloxamer / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D005456:Fluorescent Dyes; D007205:Indium Radioisotopes; D008823:Micelles; D020442:Poloxamer; D011092:Polyethylene Glycols
keywords: Endocytosis; Exocytosis; Micelles; Pluronic; Tumor spheroids; Unimers