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  • 1
    Language: English
    In: Journal of Microencapsulation, 01 February 2013, Vol.30(1), pp.49-54
    Description: In 1995 it was reported for the first time that nanoparticles could be used for the delivery of drugs across the blood-brain barrier (BBB) following intravenous injection. In vitro and in vivo experiments show that the underlying mechanism is receptor-mediated endocytosis followed by transcytosis. No opening of the tight junctions was observed. Due to the overcoating of the nanoparticles with polysorbate 80 or poloxamers 188, apolipoproteins A-I and/or E are adsorbed from the blood on to the particle surface after injection. These apolipoproteins mediate the interaction with LDL or scavenger receptors on the BBB followed by the above brain uptake processes. Likewise, covalent attachment of these apolipoproteins or of transferrin, insulin or antibodies against the respective receptors also enables a similar nanoparticle-mediated drug transport across the BBB. From these results it can be concluded that the nanoparticles act as "Trojan Horses" taking advantage of physiological receptor-mediated transport processes across the BBB.
    Keywords: Nanoparticles ; Brain Delivery ; Blood-Brain Barrier ; BBB ; Glioblastoma ; Nerve Growth Factor ; Doxorubicin ; Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0265-2048
    E-ISSN: 1464-5246
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  • 2
    Language: English
    In: International Journal of Pharmaceutics, 28 February 2012, Vol.423(2), pp.562-570
    Description: Nicotinic acid was grafted on (poly(ɛ-caprolactone)) -poly(ethylene glycol) copolymers that were used for the preparation of nanoparticles with the objectives to monitor particle size and to optimize the drug loading capacity as well as the release profile of the particles. Increasing amounts of grafting nicotinic acid increased the particle size as a result of an enhanced hydrophobicity of the copolymer. Ibuprofen and indomethacin with two different molecular characteristics were selected as model drugs to be bound to the nanoparticles. The presence of grafting nicotinic acid enhanced the loading capacity for both drugs compared to the nanoparticles without nicotinic acid. However, no correlation between amount of grafting nicotinic acid and loading capacity was observed. The release characteristic of both drugs was fitted to the Higuchi model indicating Fickian diffusion. The release characteristic of indomethacin mainly depended on the crystalline property of the copolymer whereas that of ibuprofen was additionally influenced by the hydrogen bonding between drug and grafted copolymer.
    Keywords: Ibuprofen ; Indomethacin ; Nanoparticle ; Nicotinic Acid ; Poly(Ɛ-Caprolactone) ; Poly(Ethylene Glycol) ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0378-5173
    E-ISSN: 1873-3476
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  • 3
    Language: English
    In: International Journal of Pharmaceutics, 12 December 2011, Vol.421(1), pp.151-159
    Description: Poly[lactic-co-glycolide] (PLGA) nanoparticles, chitosan-dextran sulphate microparticles, and DOTAP-liposomes were prepared as vaccine adjuvants and drug carriers for a small hydrophilic model peptide, and their different physico-chemical properties (size, PDI, zeta-potential, pH-value and peptide loading) were investigated. The model peptide's encapsulation efficiency (EE) in PLGA particles amounted to 15%, for DOTAP-liposomes to 20% and for chitosan particles up to 90%. The structural appearance of the particles was visualized by SEM and TEM. The stability of the aqueous formulations and the corresponding lyophilisates was monitored for 12 weeks (stored at = 2–8 °C). The freeze-drying process and the addition of an appropriate cryoprotective agent (sucrose) proved to be essential for all carrier systems. As a result of this study, three different peptide-loaded drug delivery systems with different properties were successfully manufactured and showed sufficient product stability of their freeze-dried formulations over 12 weeks of storage.
    Keywords: Plga ; Dotap-Liposomes ; Chitosan ; Particles ; Micro-Flow-Imaging ; Adjuvant ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0378-5173
    E-ISSN: 1873-3476
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  • 4
    Language: English
    In: Journal of Controlled Release, 20 July 2012, Vol.161(2), pp.264-273
    Description: The central nervous system is well protected by the blood–brain barrier (BBB) which maintains its homeostasis. Due to this barrier many potential drugs for the treatment of diseases of the central nervous system (CNS) cannot reach the brain in sufficient concentrations. One possibility to deliver drugs to the CNS is the employment of polymeric nanoparticles. The ability of these carriers to overcome the BBB and to produce biologic effects on the CNS was shown in a number of studies. Over the past few years, progress in understanding of the mechanism of the nanoparticle uptake into the brain was made. This mechanism appears to be receptor-mediated endocytosis in brain capillary endothelial cells. Modification of the nanoparticle surface with covalently attached targeting ligands or by coating with certain surfactants enabling the adsorption of specific plasma proteins are necessary for this receptor-mediated uptake. The delivery of drugs, which usually are not able to cross the BBB, into the brain was confirmed by the biodistribution studies and pharmacological assays in rodents. Furthermore, the presence of nanoparticles in the brain parenchyma was visualized by electron microscopy. The intravenously administered biodegradable polymeric nanoparticles loaded with doxorubicin were successfully used for the treatment of experimental glioblastoma. These data, together with the possibility to employ nanoparticles for delivery of proteins and other macromolecules across the BBB, suggest that this technology holds great promise for non-invasive therapy of the CNS diseases. Reprinted from Begley et al. with permission of the copyright holder, Elsevier, Amsterdam.
    Keywords: Nanoparticles ; Drug Delivery ; Brain Targeting ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0168-3659
    E-ISSN: 1873-4995
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  • 5
    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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  • 6
    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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  • 7
    Language: English
    In: Advanced Drug Delivery Reviews, December 2012, Vol.64, pp.213-222
    Description: The blood–brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics, antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, especially neuropeptides. One of the possibilities to overcome this barrier is a drug delivery to the brain using nanoparticles. Drugs that have successfully been transported into the brain using this carrier include the hexapeptide dalargin, the dipeptide Kyotorphin, loperamide, tubocurarine, the NMDA receptor antagonist MRZ 2/576, and doxorubicin. The nanoparticles may be especially helpful for the treatment of the disseminated and very aggressive brain tumors. Intravenously injected doxorubicin-loaded polysorbate 80-coated nanoparticles were able to lead to a 40% cure in rats with intracranially transplanted glioblastomas 101/8. The mechanism of the nanoparticle-mediated transport of the drugs across the blood–brain barrier at present is not fully elucidated. The most likely mechanism is endocytosis by the endothelial cells lining the brain blood capillaries. Nanoparticle-mediated drug transport to the brain depends on the overcoating of the particles with polysorbates, especially polysorbate 80. Overcoating with these materials seems to lead to the adsorption of apolipoprotein E from blood plasma onto the nanoparticle surface. The particles then seem to mimic low density lipoprotein (LDL) particles and could interact with the LDL receptor leading to their uptake by the endothelial cells. After this the drug may be released in these cells and diffuse into the brain interior or the particles may be transcytosed. Other processes such as tight junction modulation or P-glycoprotein (Pgp) inhibition also may occur. Moreover, these mechanisms may run in parallel or may be cooperative thus enabling a drug delivery to the brain.
    Keywords: Nanoparticles ; Blood–Brain Barrier ; Drug Delivery to the Brain ; Brain Tumors ; Glioblastomas ; Biology ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0169-409X
    E-ISSN: 1872-8294
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  • 8
    Language: English
    In: Advanced Drug Delivery Reviews, May 2014, Vol.71, pp.2-14
    Description: Nanoparticles enable the delivery of a great variety of drugs including anticancer drugs, analgesics, anti-Alzheimer's drugs, cardiovascular drugs, protease inhibitors, and several macromolecules into the brain after intravenous injection of animals. The mechanism of the nanoparticle-mediated drug transport across the BBB appears to be receptor-mediated endocytosis followed by transcytosis into the brain or by drug release within the endothelial cells. Modification of the nanoparticle surface with covalently attached targeting ligands or by coating with certain surfactants that lead to the adsorption of specific plasma proteins after injection is necessary for this receptor-mediated uptake. A very critical and important requirement for nanoparticulate brain delivery is that the employed nanoparticles are biocompatible and, moreover, rapidly biodegradable, i.e. over a time frame of a few days. In addition to enabling drug delivery to the brain, nanoparticles, as with doxorubicin, may importantly reduce the drug's toxicity and adverse effects due to an alteration of the body distribution. Because of the possibility to treat severe CNS diseases such as brain tumours and to even transport proteins and other macromolecules across the blood–brain barrier, this technology holds great promise for a non-invasive therapy of these diseases.
    Keywords: Nanoparticles ; Drug Delivery ; Brain Targeting ; Brain Tumours ; Glioblastomas ; Biology ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0169-409X
    E-ISSN: 1872-8294
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  • 9
    Language: English
    In: Pharmaceutics, 01 February 2015, Vol.7(1), pp.3-9
    Description: Little attention so-far has been paid to the influence of chronobiology on the processes of nanoparticle uptake and transport into the brain, even though this transport appears to be chronobiologically controlled to a significant degree. Nanoparticles with specific surface properties enable the transport across the blood–brain barrier of many drugs that normally cannot cross this barrier. A clear dependence of the central antinociceptive (analgesic) effects of a nanoparticle-bound model drug, i.e., the hexapeptide dalargin, on the time of day was observable after intravenous injection in mice. In addition to the strongly enhanced antinociceptive effect due to the binding to the nanoparticles, the minima and maxima of the pain reaction with the nanoparticle-bound drug were shifted by almost half a day compared to the normal circadian nociception: The maximum in the pain reaction after i.v. injection of the nanoparticle-bound dalargin occurred during the later rest phase of the animals whereas the normal pain reaction and that of a dalargin solution was highest during the active phase of the mice in the night. This important shift could be caused by an enhanced endo- and exocytotic particulates transport activity of the brain capillary endothelial cells or within the brain during the rest phase.
    Keywords: Nanoparticles ; Blood–Brain Barrier ; Chronobiology ; Dalargin ; Day Time Dependent Transport ; Neurosciences ; Pharmacy, Therapeutics, & Pharmacology
    E-ISSN: 1999-4923
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  • 10
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(9), p.e107603
    Description: The genetic treatment of neurodegenerative diseases still remains a challenging task since many approaches fail to deliver the therapeutic material in relevant concentrations into the brain. As viral vectors comprise the risk of immune and inflammatory responses, human serum albumin (HSA) nanoparticles were found to represent a safer and more convenient alternative. Their ability to cross the blood-brain barrier (BBB) and deliver drugs into the brain in order to enhance gene-based therapy has been previously demonstrated. The present study deals with the development of pGL3-PEI-coated HSA nanoparticles and subsequent in vitro testing in cerebellar granular and HeLa cells. The luciferase control vector pGL3 was chosen as reporter plasmid encoding for the firefly luciferase protein, linear polyethylenimine (22 kDa) as endosomolytic agent for enhancing the cells' transfection. Studies on particle characteristics, their cellular uptake into aforementioned cell lines and on subcellular localisation, and transfection efficiency in the cerebellar cells proved the feasibility of nanoparticle-based gene delivery.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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