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Imaging Gene Expression in the Brain with Peptide Nucleic Acid (PNA) Antisense Radiopharmaceuticals and Drug Targeting Technology

  • Ruben J. Boado
  • William M. Pardridge
Chapter
  • 645 Downloads
Part of the Medical Intelligence Unit book series (MIUN)

Abstract

Antisense oligomers are potential pharmaceutical and radiopharmaceutical agents that can be used to modulate and image gene expression. Progress with in vivo gene targeting using antisense-based therapeutics has been slower than expected during the last decade, owing to poor trans-cellular delivery of antisense agents. This chapter suggests that if antisense pharmacology is merged with drug targeting technology, then membrane barriers can be circumvented and antisense agents can be delivered to tissues in vivo. Without the application of drug targeting, the likelihood of success for an antisense drug development program is low, particularly for the brain which is protected by the blood-brain barrier (BBB). Among the different classes of antisense agents, peptide nucleic acids (PNA) present advantages for in vivo applications over conventional and modified oligodeoxynucleotides (ODN), including phosphorothioates (PS)-ODN. Some advantages of PNAs include their electrically neutral backbone, low toxicity to neural cells, resistance to nucleases and peptidases, and lack of bind-ing to plasma proteins. PNAs are poorly transported through cellular membranes, including the BBB and the brain cell membrane (BCM). Because the mRNA target for the antisense agent lies within the cytosol of the target cell, the BBB and the BCM must be circumvented in vivo, which is possible with the use of chimeric peptide drug targeting technology. Chimeric peptides are formed by conjugation of a nontransportable drug, such as a PNA, to a drug delivery vector. The vector undergoes receptor-mediated transcytosis (RMT) through the BBB and receptor-mediated endocytosis through the BCM in vivo. When labeled with a radioisotope (e.g., 125I or 111In), the antisense chimeric peptide provides imaging of gene expression in the brain in vivo in a sequence-specific manner. Further development of antisense radio-pharmaceutical agents may allow for in vivo imaging of genes in pathological states, and may provide tools for the analysis of novel genes with functional genomics.

Keywords

Peptide Nucleic Acid Brain Gene Expression Chimeric Peptide Antisense Molecule Antisense Oligomer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Authors and Affiliations

  • Ruben J. Boado
    • 1
  • William M. Pardridge
    • 1
  1. 1.Department of MedicineUCLALos AngelesUSA

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