Linked Life Data

9811482

Source:http://linkedlifedata.com/resource/pubmed/id/9811482

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
1998-12-23
pubmed:abstractText
Antisense oligonucleotides (ODNs) and peptide nucleic acids (PNAs) are potential therapeutics for eradication of malignancies, viral infections, and other pathologies. However, ODNs and PNAs in general are unable to cross cellular membranes and blood-tissue barriers, such as the blood-brain barrier (BBB), which is only permeable to lipophilic molecules of molecular weight <600 Da. Cellular delivery systems based on conjugates of streptavidin (SA) and the OX26 monoclonal antibody directed to the transferrin receptor may be employed as a universal carrier for the transport of mono-biotinylated peptides, ODNs, or PNAs. 3'-Biotinylation of phosphodiester (PO)-ODN produces complete protection of ODN against serum and cellular 3'-exonucleases, facilitating the conjugation to avidin-based delivery systems and maintaining the activation of RNase H. These delivery systems markedly increased the cellular uptake and antisense efficacy of 3'-biotinylated ODNs in models of Alzheimer's disease and HIV-AIDS. In vivo brain delivery studies demonstrated that 3'-protected PO-ODNs and PO-phosphorothioate(PS)-ODN hybrids containing a single PO linkage are subjected to endonuclease degradation in vivo. On the contrary PS-ODNs, which were also protected at 3'-terminus by biotinylation, are metabolically stable in vivo and resistant to exo/endonuclease degradation. However, because of the strong binding of these oligomers to plasma protein, PS-ODNs are poorly transported into the brain through the BBB by the OX26-SA delivery vector following intravenous administration. PNAs are also resistant to exo/endonuclease and protease degradation, and these molecules biotinylated at the amino terminal group were transported into the brain by the OX26-SA delivery system with brain uptake levels comparable to that of morphine. Using the rev gene of HIV as a model target, RNase protection assays and cell-free translation arrest showed that the PNA-OX26-SA conjugate maintained active recognition and inactivation of target mRNA, respectively. The overall experimental evidence suggests that PNA-OX26-SA conjugates represent optimal antisense molecules for drug delivery to the brain.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0022-3549
pubmed:author
pubmed:issnType
Print
pubmed:volume
87
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1308-15
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1998
pubmed:articleTitle
Drug delivery of antisense molecules to the brain for treatment of Alzheimer's disease and cerebral AIDS.
pubmed:affiliation
Department of Medicine and Brain Research Institute, UCLA School of Medicine, Los Angeles, California 90095, USA. rboado@med1.medsch.ucla.edu
pubmed:publicationType
Journal Article, Review, Research Support, Non-U.S. Gov't