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Therapeutic efficacy of Doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8

S. Wohlfart
, C. Bernreuther
, A. S. Khalansky
, S. Gelperina
, O. Maksimenko
, M. Glatzel
, J. Kreuter

Institute of Pharmaceutical Technology, Goethe University, Frankfurt, Germany,
Institute of Neuropathology, University
Medical Centre Hamburg-Eppendorf, Hamburg, Germany,
Institute of Human Morphology, Moscow, Russia,
Ltd., Moscow, Russia
Our earlier study showed that poly (lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 (Pluronic
F68) hold great promise as drug-carriers for brain delivery. The purpose of the present work was to investigate the anti-
tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles (Dox-PLGA) against rat glioblastoma using
histological and immunochemical methods.
Dox-PLGA particles were prepared by a high-pressure solvent evaporation technique using 1% PVA (Dox-PLGA/PVA) or
1% HSA (Dox-PLGA/HSA) as stabilizers. Additionally, Dox-PLGA/HSA containing lecithin were prepared (Dox-Lecithin-
PLGA/HSA). The resulting particles were freeze-dried, characterized for size and drug loading.
For animal experiments, Wistar rats, bearing intracranially implanted 101/8 glioblastoma, were randomly divided into 4
groups (n=6) and treated with Dox formulations (3 x 2.5mg/kg) coated with 1% poloxamer 188 on days 2, 5 and 8 after
tumour inoculation. Following formulations were tested: Dox solution, Dox-PLGA/PVA, Dox-PLGA/HSA and Dox-
Lecithin-PLGA/HSA. On day 18 after tumour implantation, the rats were sacrificed. The brains were removed and
processed for histological and immunohistochemical evaluation.
The efficacy of the chemotherapy was determined by measurement of tumour size and extent of necrotic areas in brain
sections stained with haematoxylin-eosin. Staining with antibodies against Ki67 was performed for proliferation analysis.
To determine the neovascularization index, staining with Isolectin B4 was performed. Besides GFAP and VEGF expression
was investigated.
Histological evaluation revealed an advantage of the nanoparticulate formulations in comparison with the Dox solution.
Especially a decrease in tumour size and a reduction of a number of proliferating cells were detectable. Additionally, the
treatment with nanoparticles led to lower necrosis and vessel density as well as to a diminished GFAP expression. The
overall best results were observed for the group of animals treated with Dox-Lecithin-PLGA/HSA. It is possible that, being a
plasticizing agent for PLGA, lecithin increases the release rate of doxorubicin thus enhancing the antitumour effect of this
These results demonstrate that poloxamer 188-coated PLGA nanoparticles are useful carriers for brain delivery. Doxorubicin
formulations based on these particles represent a very promising preparation for intravenous therapy of glioblastomas.