The human immunodeficiency virus (HIV) is known to readily infect the brains of most individuals suffering from the autoimmune deficiency syndrom (AIDS). The neurotropism of the HIV presents a problem for the ultimate treatment of patients with AIDS using pharmaceticals designed to kill the HIV. This is because all drugs thus far developed to treat AIDS and kill the HIV do not cross the brain capillary wall , i.e., the blood brain barrier (BBB). Therefore, it is imperative to develop drugs that capable of kill the AIDS virus in the peripheral tissues, but is not able to kill the virus in the brain sanctuary. The present investigations will use a new physiologic-based strategy for drug delivery involves the covalent coupling of a nontransportable drug, i.e., a drug which does not cross the BBB, to a transportable drug or vector which does cross the BBB. Four different classes of AIDS pharmaceuticals will be studied: azidothymidine (AZT) or dideoxycytidine (DDC), soluble CD4. CD4-toxin chimeras, and GM-CSF. These nontransportable drugs will be coupled to transportable vectors including cationized albumin or histone, which recent studies indicate are capable of crossing the BBB via absorptive- mediated transcytosis. Six different types of experiments will be performed: (1) synthesis of chimeric peptides; (2) in vitro assay of BBB transport using isolated bovine brain capillaries; (3) in vivo transcytosis through the rat BBB of iodinated chimeric peptides using an internal carotid artery perfusion technique and a capillary depletion technique; (4) morphologic evidence for chimeric peptide transoytosis using electron microscopic autoradiography; (5) measurements of clearance of iodinated chimeric peptides by brain and other organs following intravenous administration to determine the relative brain selectivity of the uptake of the chimeric peptide versus other organs; (6) use of cationized monoclonal antibodies to the human brain capillary as a brain specific transport vector for the delivery of AIDS pharmaceuticals across the human BBB.
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