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Title: Blood-brain barrier transport of cationized immunoglobulin G: Enhanced delivery compared to native protein

IgG molecules are potential neuropharmaceuticals that may be used for therapeutic or diagnostic purposes. However, IgG molecules are excluded from entering brain, owing to a lack of transport of these plasma proteins through the brain capillary wall, or blood-brain barrier (BBB). The possibility of enhanced IgG delivery through the BBB by cationization of the proteins was explored in the present studies. Native bovine IgG molecules were cationized by covalent coupling of hexamethylenediamine and the isoelectric point was raised to greater than 10.7 based on isoelectric focusing studies. Native and cationized IgG molecules were radiolabeled with /sup 125/I and chloramine T. Cationized IgG, but not native IgG, was rapidly taken up by isolated bovine brain microvessels, which were used as an in vitro model system of the BBB. Cationized IgG binding was time and temperature dependent and was saturated by increasing concentrations of unlabeled cationized IgG (dissociation constant of the high-affinity binding site, 0.90 +/- 0.37 microM; Bmax, 1.4 +/- 0.4 nmol per mg of protein). In vivo studies documented enhanced brain uptake of 125I-labeled cationized IgG relative to (3H)albumin, and complete transcytosis of the 125I-labeled cationized IgG molecule through the BBB and into brain parenchyma was demonstrated by thaw-mount autoradiographymore » of frozen sections of rat brain obtained after carotid arterial infusions of 125I-labeled cationized IgG. These studies demonstrate that cationization of IgG molecules greatly facilitates the transport of these plasma proteins through the BBB in vivo, and this process may provide a new strategy for IgG delivery through the BBB.« less
Authors:
; ; ;
Publication Date:
OSTI Identifier:
5879199
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proc. Natl. Acad. Sci. USA; (United States); Journal Volume: 86:12
Research Org:
Univ. of California, Los Angeles (USA)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; BLOOD-BRAIN BARRIER; PERMEABILITY; IMMUNOGLOBULINS; MEMBRANE TRANSPORT; ALBUMINS; BIOCHEMICAL REACTION KINETICS; BRAIN; CAPILLARIES; CATIONS; CATTLE; IN VITRO; IODINE 132; RATS; SPECIFICITY; TEMPERATURE DEPENDENCE; TIME DEPENDENCE; TRITIUM COMPOUNDS; ANIMALS; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; BLOOD VESSELS; BODY; CARDIOVASCULAR SYSTEM; CENTRAL NERVOUS SYSTEM; CHARGED PARTICLES; DOMESTIC ANIMALS; GLOBULINS; HOURS LIVING RADIOISOTOPES; INTERMEDIATE MASS NUCLEI; IODINE ISOTOPES; IONS; ISOTOPES; KINETICS; LABELLED COMPOUNDS; MAMMALS; NERVOUS SYSTEM; NUCLEI; ODD-ODD NUCLEI; ORGANIC COMPOUNDS; ORGANS; PROTEINS; RADIOISOTOPES; REACTION KINETICS; RODENTS; RUMINANTS; VERTEBRATES 550201* -- Biochemistry-- Tracer Techniques