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  • Khalansky, As  (10)
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  • 1
    Language: English
    In: Journal of Controlled Release, 2011, Vol.154(1), pp.103-107
    Description: Drug delivery to the brain is restricted due to the blood–brain barrier (BBB). Previously, it has been shown that surfactant-coated doxorubicin-loaded nanoparticles were successful in overcoming the BBB and were effective in the treatment of rat brain tumours. However, drug distribution in brain tissue after crossing the BBB was never determined. To distinguish between the amounts of drug in the whole brain and the fraction of drug in the brain parenchyma after crossing the BBB a capillary depletion technique was employed. For this purpose rats were intravenously treated with a doxorubicin solution in 1% polysorbate 80, or doxorubicin-loaded poly-(n-butyl cyanoacrylate) (PBCA) nanoparticles without and with 1% polysorbate 80 coating, respectively. The dosage of doxorubicin was 5 mg per kg of rat body weight. At 30 min, 2 h, and 4 h following intravenous injection into the tail vein, the rats were sacrificed and their brains removed. Homogenates of the brains were prepared. In addition, one part of the homogenate was separated by centrifugation into a pellet (vascular elements) and supernatant (parenchyma) using a well established capillary depletion technique. The time-dependent distribution of doxorubicin in these brain fractions was studied. Clinically effective concentrations in all investigated brain fractions could only be detected in rats treated with surfactant-coated nanoparticles, indicating a significant transcytosis across the BBB. Only low concentrations were observed after 0.5 and 2 h with the uncoated nanoparticles. No uptake of doxorubicin into the brain was observable after administration of drug solution alone. These observations demonstrate the great potential of surface-coated PBCA nanoparticles for the delivery of drugs to the central nervous system. Doxorubicin concentration in different rat brain fractions 2 h after intravenous injection of 5 mg/kg doxorubicin solution, doxorubicin-loaded poly(butyl cyanoacrylate) (PBCA) nanoparticles (NP), or doxorubicin-loaded PBCA-NP coated with polysorbate 80 (PS80).
    Keywords: Nanoparticles ; Capillary Depletion ; Drug Targeting ; Blood–Brain Barrier ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0168-3659
    E-ISSN: 1873-4995
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  • 2
    Language: English
    In: PLoS ONE, 2011, Vol.6(5), p.e19121
    Description: Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods. ; The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA) or human serum albumin (PLGA/HSA) as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA) were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3×2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density. ; The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Oncology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: International Journal of Pharmaceutics, 2011, Vol.415(1), pp.244-251
    Description: Glioblastomas belong to the most devastating cancer diseases. For this reason, polysorbate 80 (Tween 80 )-coated poly(isohexyl cyanoacrylate) (PIHCA) (Monorex ) nanoparticles loaded with doxorubicin were developed and tested for their use for the treatment of glioblastomas. The preparation of the nanoparticles resulted in spherical particles with high doxorubicin loading. The physico-chemical properties and the release of doxorubicin from the PIHCA-nanoparticles were analysed, and the influence on cell viability of the rat glioblastoma 101/8-cell line was investigated. In vitro, the empty nanoparticles did not show any toxicity, and the anti-cancer effects of the drug-loaded nanoparticles were increased in comparison to doxorubicin solution, represented by IC values. The in vivo efficacy was then tested in intracranially glioblastoma 101/8-bearing rats. Rats were treated with 3 × 1.5 mg/kg doxorubicin and were sacrificed 18 days after tumour transplantation. Histological and immunohistochemical analyses were carried out to assess the efficacy of the nanoparticles. Tumour size, proliferation activity, vessel density, necrotic areas, and expression of glial fibrillary acidic protein demonstrated that doxorubicin-loaded PIHCA-nanoparticles were much more efficient than the free drug. The results suggest that poly(isohexyl cyanoacrylate) nanoparticles hold great promise for the non-invasive therapy of human glioblastomas.
    Keywords: Doxorubicin ; Nanoparticles ; Poly(Isohexyl Cyanoacrylate) ; Glioblastoma ; Histology ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0378-5173
    E-ISSN: 1873-3476
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  • 4
    Language: English
    In: Neuroscience Letters, 1991, Vol.133(2), pp.284-286
    Description: Neurochordins are a family of high M r P-epitope-bearing neural tissue glycoproteins. Comparison of SDS-agarose electrophoretic patterns of extracts from human, rat, mouse and chicken brain after immunostaining of blots with an anti-P-epitope MAb At5 demonstrated that in each case neurochordins from the A, B and C group were present. A similar result was obtained when polyclonal serum against total human neurochordin was used. The data favours the idea of high evolutional conservatism of neurochordins of higher vertebrate species. Expression of the P-epitope on glial cells in culture was studied. Strong immunostaining of oligodendrocytes with MAb At5 and the absence of this staining in astrocytes and Schwann cells make it possible to use At5 for identification of cell types in tissue culture experiments as well as for differential diagnostics of brain tumours.
    Keywords: Neurochordin ; Neural Tissue Specificity ; High Mr Glycoprotein ; Evolutionary Conservatism ; Oligodendrocyte ; Medicine ; Anatomy & Physiology
    ISSN: 0304-3940
    E-ISSN: 1872-7972
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  • 5
    Language: English
    In: Drug Delivery, 03 April 2015, Vol.22(3), pp.276-285
    Description: Targeted drug delivery for brain tumor treatment is one of the important objectives in nanomedicine. Human glioblastoma is the most frequent and aggressive type of brain tumors. The preferential expression of membrane protein connexin 43 (Cx43) and brain-specific anion transporter (BSAT1) in...
    Keywords: Connexin-43 ; Glioblasoma Multiforme ; Monoclonal Antibody ; Nanogels ; Targeted Delivery ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1071-7544
    E-ISSN: 1521-0464
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  • 6
    Language: English
    In: Bulletin of Experimental Biology and Medicine, 2009, Vol.148(6), pp.896-898
    Description: Hepatitis C virus (HCV) strains were isolated from human sera in vitro . NGUK-1 rat neurinoma neural cells [1] were selected as the experimental model of HCV. The cells were infected after attaining the confluence. The virus caused no cytopathic effect during its multiplication. After monolayer infection (24-96 h), culture fluid samples were tested for HCV RNA by classical PCR with electrophoretic detection of the reaction products and by quantitative real time PCR. All samples from infected culture were positive, control samples (intact cultures) were negative. Coefficient of correlations in quantitative PCR was 0.99. The results are reliable, conform to the normal values for this series of the test system, and indicate that HCV is replicated in continuous NGUK-1 cells. This in vitro model can be used for isolation of HCV.
    Keywords: hepatitis C virus ; continuous NGUK-1 cell culture ; polymerase chain reaction
    ISSN: 0007-4888
    E-ISSN: 1573-8221
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  • 7
    Language: English
    In: International Journal of Cancer, 01 May 2004, Vol.109(5), pp.759-767
    Description: Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood‐brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate‐coated nanoparticles crossed the intact blood‐brain barrier, thus reaching therapeutic concentrations in the brain. Here, we investigated the therapeutic potential of this formulation of doxorubicin using an animal model created by implantation of 101/8 glioblastoma tumor in rat brains. Groups of 5–8 glioblastoma‐bearing rats (total = 151) were subjected to 3 cycles of 1.5–2.5 mg/kg body weight of doxorubicin in different formulations, including doxorubicin bound to polysorbate‐coated nanoparticles. The animals were analyzed for survival (% median increase of survival time, Kaplan‐Meier). Preliminary histology including immunocytochemistry (glial fibrillary acidic protein, ezrin, proliferation and apoptosis) was also performed. Rats treated with doxorubicin bound to polysorbate‐coated nanoparticles had significantly higher survival times compared with all other groups. Over 20% of the animals in this group showed a long‐term remission. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. All groups of animals treated with polysorbate‐containing formulations also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. Additionally, binding to nanoparticles may reduce the systemic toxicity of doxorubicin. This study showed that therapy with doxorubicin bound to nanoparticles offers a therapeutic potential for the treatment of human glioblastoma. © 2004 Wiley‐Liss, Inc.
    Keywords: Nanoparticles ; Doxorubicin ; Glioblastoma ; Chemotherapy ; Histology
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 8
    Language: English
    In: Clinical neuropathology, 2009, Vol.28(3), pp.153-64
    Description: The objective of this study was to investigate the therapeutic effects of doxorubicin bound to polysorbate-coated nanoparticles that had previously been shown to significantly enhance survival in the orthotopic rat 101/8 glioblastoma model. Tumor-bearing animals were subjected to chemotherapy using doxorubicin in solution (Dox-sol) or doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (Dox-np) injected intravenously on Days 2, 5 and 8 post tumor implantation. The antitumor effect was assessed on Days 10, 14 and 18 post tumor implantation. Tumors showed signs of malignancy including invasion of brain tissue, brisk mitotic activity, microvascular proliferation, necrosis and increased proliferation resembling human glioblastoma. Dox-np produced a considerably more pronounced antitumor effect exhibited as a reduced tumor size, lower proliferation, and a decreased necrotic area compared to Dox-sol and to untreated control groups. A drastic effect of Dox-np on vascularization indicated an antiangiogenic mode of action.
    Keywords: Drug Delivery Systems ; Angiogenesis Inhibitors -- Administration & Dosage ; Brain Neoplasms -- Drug Therapy ; Doxorubicin -- Administration & Dosage ; Glioblastoma -- Drug Therapy
    ISSN: 0722-5091
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 9
    Language: English
    In: Journal of Drug Targeting, 01 January 2006, Vol.14(2), pp.97-105
    Description: It was recently shown that doxorubicin (DOX) bound to polysorbate-coated nanoparticles (NP) crossed the intact blood-brain barrier (BBB), and thus reached therapeutic concentrations in the brain. Here, we investigated the biodistribution in...
    Keywords: Blood-Brain Barrier ; Glioblastoma ; Nanoparticles ; Doxorubicin ; Polysorbate 80 ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1061-186X
    E-ISSN: 1029-2330
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  • 10
    Language: English
    In: Toxicology Letters, 2002, Vol.126(2), pp.131-141
    Description: Polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (NP) were shown to enable the transport of a number of drugs including the anti-tumour antibiotic doxorubicin (DOX) across the blood-brain barrier (BBB) to the brain after intravenous administration and to considerably reduce the growth of brain tumours in rats. The objective of the present study was to evaluate the acute toxicity of DOX associated with polysorbate 80-coated NP in healthy rats and to establish a therapeutic dose range for this formulation in rats with intracranially implanted 101/8 glioblastoma. Single intravenous administration of empty poly(butyl cyanoacrylate) NP in the dose range 100-400 mg/kg did not cause mortality within the period of observation. NP also did not affect body weight or weight of internal organs. Association of DOX with poly(butyl cyanoacrylate) NP did not produce significant changes of quantitative parameters of acute toxicity of the anti-tumour agent. Likewise, the presence of polysorbate 80 in the formulations was not associated with changes in toxicity compared with free or nanoparticulate drug. Dose regimen of 3 x 1.5 mg/kg on days 2, 5, 8 after tumour implantation did not cause drug-induced mortality. The results in tumour-bearing rats were similar to those in healthy rats. These results demonstrate that the toxicity of DOX bound to NP was similar or even lower than that of free DOX.
    Keywords: Doxorubicin ; Glioblastoma ; Nanoparticles ; Poly(Butyl Cyanoacrylate) ; Polysorbate ; Toxicology ; Rats ; Pharmacy, Therapeutics, & Pharmacology ; Public Health
    ISSN: 0378-4274
    E-ISSN: 1879-3169
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