PMID- 9587954
OWN - NLM
STAT- MEDLINE
DCOM- 19980723
LR  - 20190818
IS  - 0724-8741 (Print)
IS  - 0724-8741 (Linking)
VI  - 15
IP  - 4
DP  - 1998 Apr
TI  - 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.
PG  - 576-82
AB  - 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 
      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.
FAU - Pardridge, W M
AU  - Pardridge WM
AD  - Department of Medicine UCLA School of Medicine 90095-1682, USA. 
      wpardrid@med1.medsch.ucla.edu
FAU - Wu, D
AU  - Wu D
FAU - Sakane, T
AU  - Sakane T
LA  - eng
GR  - NS-34698/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Pharm Res
JT  - Pharmaceutical research
JID - 8406521
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Receptors, Transferrin)
RN  - 0 (Recombinant Proteins)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 6SO6U10H04 (Biotin)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/chemistry/pharmacokinetics
MH  - Biotin/chemistry
MH  - Blood-Brain Barrier/*physiology
MH  - Brain/*metabolism
MH  - Brain-Derived Neurotrophic Factor/blood/chemistry/*pharmacokinetics
MH  - *Drug Delivery Systems
MH  - Humans
MH  - Injections, Intravenous
MH  - Male
MH  - Mice
MH  - Polyethylene Glycols/chemistry
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Transferrin/immunology
MH  - Recombinant Proteins/pharmacokinetics
EDAT- 1998/05/20 00:00
MHDA- 1998/05/20 00:01
CRDT- 1998/05/20 00:00
PHST- 1998/05/20 00:00 [pubmed]
PHST- 1998/05/20 00:01 [medline]
PHST- 1998/05/20 00:00 [entrez]
AID - 10.1023/a:1011981927620 [doi]
PST - ppublish
SO  - Pharm Res. 1998 Apr;15(4):576-82. doi: 10.1023/a:1011981927620.