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  • 1
    Electronic Resource
    Electronic Resource
    Combined Use of Carboxyl-Directed Protein Pegylation and Vector-Mediated Blood-Brain Barrier Drug Delivery System Optimizes Brain Uptake of Brain-Derived Neurotrophic Factor Following Intravenous Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 576-582 
    Details
    ISSN: 1573-904X
    Keywords: pegylation ; blood-brain barrier ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Peptide drug delivery to the brain requires optimization of (a) plasma pharmacokinetics and (b) blood-brain barrier (BBB) permeability. In the present studies, plasma pharmacokinetics are improved with protein pegylation and BBB transport is facilitated with the use of vector-mediated drug delivery using the OX26 monoclonal antibody (MAb) to the rat transferrin receptor, which undergoes receptor-mediated transcytosis through the BBB in vivo. Methods. A conjugate of OX26 and streptavidin (SA), designated OX26/SA, was prepared in parallel with the carboxyl-directed pegylation of brain-derived neurotrophic factor (BDNF). A novel bifunctional polyethyleneglycol (PEG) was used in which a hydrazide (Hz) was attached at one end and a biotin moiety was attached to the other end. This allowed for conjugation of BDNF-PEG-biotin to OX26/SA. Results. The brain uptake of BDNF-PEG-biotin was increased following conjugation to OX26/SA to a level of 0.144 ± 0.004% injected dose per g brain and a BBB permeability-surface area product of 2.0 ± 0.2 μL/min/g. Conclusions. These studies demonstrate that peptide drug delivery to the brain can be achieved with advanced formulation of protein-based therapeutics. The formulation is intended to (a) minimize rapid systemic clearance of the peptide, and (b) allow for vector-mediated drug delivery through the BBB in vivo. Following this dual formulation, the brain uptake of a neurotrophin such as BDNF achieves a value that is approximately 2-fold greater than that of morphine, a neuroactive small molecule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011981927620
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Blood-Brain Barrier Transport of Reduced Folic Acid (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 415-419 
    Details
    ISSN: 1573-904X
    Keywords: folate receptor ; folic acid ; blood-brain barrier ; drug delivery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The brain is relatively resistant to folic acid deficiency, indicating specialized transport systems may exist for this vitamin localized within the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo. The present studies quantify the BBB transport of [3H]-methyltetrahydrofolic acid (MTFA) in vivo and in isolated human brain capillaries in vitro. Methods. BBB transport of [3H]-MTFA was compared to that of [14C]-sucrose, a plasma volume marker, following either intravenous injection or intracarotid perfusion in anesthetized rats. Competition by 10 μM MTFA or 10 μM folic acid was examined to determine whether folic acid is also transported by the MTFA uptake system. Results. The BBB permeability-surface area (PS) product of [3H]-MTFA, 1.1± 0.3 μL/min/g, was 6-fold greater than that of [14C]-sucrose following intravenous injection. The BBB PS product determined by intracarotid arterial perfusion was not significantly different from the BBB PS product calculated following intravenous injection. A time- and temperature- dependent uptake of [3H]-MTFA in human brain capillaries was observed. The uptake of [3H]-MTFA by either rat brain in vivo or by human brain capillaries in vitro was equally inhibited by 10 μM concentrations of either unlabeled MTFA or unlabeled folic acid. Conclusions. (1) A saturable transport system exists at the BBB for folic acid derivatives and since this transport is equally inhibited by either folic acid or MTFA, it is inferred that this transport system is the folic acid receptor, and not the reduced folic acid carrier. (2) The presence of a folate transport system at the BBB may offer an endogenous transport system for brain drug delivery of conjugates of folates and drugs that do not normally cross the BBB in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018829920158
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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