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.
OBJECTIVE
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 receptormediated 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 microL/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.
Pardridge
W M
WM
Department of Medicine UCLA School of Medicine 90095-1682, USA. wpardrid@med1.medsch.ucla.edu
Wu
D
D
Sakane
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics; D001710:Biotin / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000276:immunology; D011994:Recombinant Proteins / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D019208:Brain-Derived Neurotrophic Factor; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D001710:Biotin