title: Delivery of doxorubicin-loaded PLGA nanoparticles into U87 human glioblastoma cells.
abstract: The paramount problem in the therapy of brain tumors is the inability of most drugs to cross the blood-brain barrier. PLGA nanoparticles overcoated with poloxamer 188 could overcome this problem and enabled a high anti-tumoral effect against the very aggressive intracranial 101.8 glioblastoma in rats that closely resembles human grade IV glioblastomas. The basis for the transport of these particles across the blood-brain barrier appears to be adsorption of blood apolipoproteins (ApoE or ApoA-I) on the nanoparticle surface caused by the poloxamer 188-coating, followed by receptor-mediated transcytosis of the nanoparticles. The objective of the present study is the elucidation of the mechanism by which the poloxamer 188-coated nanoparticles then enter the brain tumor cells. Their intracellular fate, therefore, was investigated using the U87 human glioma cell line. The main mechanism of the PLGA nanoparticle internalization by U87 cells was clathrin-mediated endocytosis. Within 1h free doxorubicin was released from late endosomes and could reach its target site, i.e. the DNA in the nuclei without degradation, whereas the PLGA nanoparticles, which were labeled with Cy5.5, still were observed in the endo-lysosomal compartment. These results demonstrate that the underlying mechanism of action in the brain cells is by diffusive doxorubicin release from the nanoparticles rather than by their intracellular degradation.
authors.affiliation: Drugs Technology LLC, Rabochaya st. 2A, 141400 Khimki, Moscow Region, Russian Federation.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Malinovskaya
authors.affiliation: Research and Education Center for Medical Nanobiotechnology, Pirogov Russian National Research Medical University, Ostrovityanova st., 117997 Moscow, Russian Federation.
authors.forename: Pavel
authors.initials: P
authors.lastname: Melnikov
authors.affiliation: Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, Federal Biomedical Agency of the Russian Federation, Orekhoviy blvd 2, 115682 Moscow, Russian Federation.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Baklaushev
authors.affiliation: Research and Education Center for Medical Nanobiotechnology, Pirogov Russian National Research Medical University, Ostrovityanova st., 117997 Moscow, Russian Federation.
authors.forename: Anna
authors.initials: A
authors.lastname: Gabashvili
authors.affiliation: Drugs Technology LLC, Rabochaya st. 2A, 141400 Khimki, Moscow Region, Russian Federation.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Osipova
authors.affiliation: Drugs Technology LLC, Rabochaya st. 2A, 141400 Khimki, Moscow Region, Russian Federation.
authors.forename: Sergey
authors.initials: S
authors.lastname: Mantrov
authors.affiliation: Drugs Technology LLC, Rabochaya st. 2A, 141400 Khimki, Moscow Region, Russian Federation.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ermolenko
authors.affiliation: Drugs Technology LLC, Rabochaya st. 2A, 141400 Khimki, Moscow Region, Russian Federation.
authors.forename: Olga
authors.initials: O
authors.lastname: Maksimenko
authors.affiliation: Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Leninsky pr 29, 19991 Moscow, Russian Federation.
authors.forename: Marina
authors.initials: M
authors.lastname: Gorshkova
authors.affiliation: Drugs Technology LLC, Rabochaya st. 2A, 141400 Khimki, Moscow Region, Russian Federation.
authors.forename: Vadim
authors.initials: V
authors.lastname: Balabanyan
authors.affiliation: Drugs Technology LLC, Rabochaya st. 2A, 141400 Khimki, Moscow Region, Russian Federation; Institute of Pharmaceutical Technology, Biocenter Niederursel, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
authors.affiliation: Drugs Technology LLC, Rabochaya st. 2A, 141400 Khimki, Moscow Region, Russian Federation. Electronic address: svetlana.gelperina@gmail.com.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gelperina
mesh_terms: D001812:Blood-Brain Barrier; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D065546:Drug Liberation; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin
keywords: Doxorubicin; Endocytosis; PLGA nanoparticles; Poloxamer 188; U87 human glioma cell line