The acquired immune deficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV). Given the neurotropism of the HIV, it is important to develop AIDS therapeutics that are taken up by brain from the circulation. Such drugs must be capable of transport through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo. Until recently, there were few, if any, practical brain drug delivery strategies that allowed for safe delivery through the BBB of therapeutics for the treatment of cerebral AIDS. In the proposed studies, physiologic-based drug delivery strategies will be developed and include chimeric peptides, chimeric antisense oligonucleotides, and cationized antibodies. Chimeric peptides and chimeric oligonucleotides are first coupled to a brain drug transport vector, e.g., a monoclonal antibody to the transferrin receptor, which undergoes receptor-mediated transcytosis through the BBB. Cationized antibodies are formed by chemically raising the isolelectric point of the antibodies to the cationic level as cationic proteins undergo absorptive- mediated transcytosis through the BBB. The model chimeric peptide to be developed in these studies is a novel vasoactive intestinal peptide (VIP) analogue that has been designed specifically for covalent coupling into the transport vector using a disulfide linkage. The VIP analogue has been designed so that it is biologically active following cleavage from the transport vector. A model chimeric antisense oligonucleotide to be studied is a 21-mer antisense oligonucleotide to the tat gene. Both the chimeric peptide and the chimeric oligonucleotide will be coupled to an antitransferrin receptor monoclonal antibody transport vector through an avidin/biotin linkage. These studies will employ the development of avidin fusion proteins, wherein the coupling of avidin to the transport vector (the monoclonal antibody) allows for high efficiency coupling of any biotinylated peptide or oligonucleotide to the transport vector. The model cationized antibody to be studied is directed against a synthetic peptide encoding the sequences that include the active site of the rev protein. Each of the three sets of studies are subdivided into three homologous modules: drug synthesis, drug delivery, and drug action. The drug delivery strategies will be deemed successful if the delivery vehicle can generate in brain concentrations of drugs that are shown to be pharmacologically effective with the drug action studies. The drug action model will include measurements of HIV-1 replication in cultured human peripheral blood lymphocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028760-05
Application #
3143306
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1989-09-30
Project End
1996-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Bickel, U; Yoshikawa, T; Pardridge, W M (2001) Delivery of peptides and proteins through the blood-brain barrier. Adv Drug Deliv Rev 46:247-79
Wu, D; Boado, R J; Pardridge, W M (1996) Pharmacokinetics and blood-brain barrier transport of [3H]-biotinylated phosphorothioate oligodeoxynucleotide conjugated to a vector-mediated drug delivery system. J Pharmacol Exp Ther 276:206-11
Walus, L R; Pardridge, W M; Starzyk, R M et al. (1996) Enhanced uptake of rsCD4 across the rodent and primate blood-brain barrier after conjugation to anti-transferrin receptor antibodies. J Pharmacol Exp Ther 277:1067-75
Pardridge, W M; Kang, Y S; Diagne, A et al. (1996) Cationized hyperimmune immunoglobulins: pharmacokinetics, toxicity evaluation and treatment of human immunodeficiency virus-infected human-peripheral blood lymphocytes-severe combined immune deficiency mice. J Pharmacol Exp Ther 276:246-52
Wu, D; Pardridge, W M (1996) Central nervous system pharmacologic effect in conscious rats after intravenous injection of a biotinylated vasoactive intestinal peptide analog coupled to a blood-brain barrier drug delivery system. J Pharmacol Exp Ther 279:77-83
Kang, Y S; Boado, R J; Pardridge, W M (1995) Pharmacokinetics and organ clearance of a 3'-biotinylated, internally [32P]-labeled phosphodiester oligodeoxynucleotide coupled to a neutral avidin/monoclonal antibody conjugate. Drug Metab Dispos 23:55-9
Boado, R J; Kang, Y S; Wu, D et al. (1995) Rapid plasma clearance and metabolism in vivo of a phosphorothioate oligodeoxynucleotide with a single, internal phosphodiester bond. Drug Metab Dispos 23:1297-300
Pardridge, W M; Boado, R J; Kang, Y S (1995) Vector-mediated delivery of a polyamide (""peptide"") nucleic acid analogue through the blood-brain barrier in vivo. Proc Natl Acad Sci U S A 92:5592-6
Skarlatos, S; Yoshikawa, T; Pardridge, W M (1995) Transport of [125I]transferrin through the rat blood-brain barrier. Brain Res 683:164-71
Skarlatos, S; Pardridge, W M (1995) Targeting of an anti-CR3 (CD11b/CD18) monoclonal antibody to spleen but not brain, in vivo in mice. J Drug Target 3:9-14

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