Drug Delivery of Antisense Molecules to the Brain for Treatment of Alzheimer’s Disease and Cerebral AIDS

doi:10.1021/js9800836

Journal of Pharmaceutical Sciences

Volume 87, Issue 11, November 1998, Pages 1308-1315

https://doi.org/10.1021/js9800836 Get rights and content

Abstract

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 phosphodi-ester (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.

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Conference ReportsDrug Delivery of Antisense Molecules to the Brain for Treatment of Alzheimer’s Disease and Cerebral AIDS

Abstract

Mol. Med. Today

Pharmacol. Ther.

Adv. Drug Del. Rev.

Neurochem. Int.

Neurochem. Int.

Adv. Drug Del. Rev.

Exp. Neurol.

J. Biol. Chem.

Biochem. Pharmacol.

Metabolism

Neuron

Exp. Eye Res.

Neuron

Brain Res.

Clin. Ther.

Antisense approaches to cancer gene therapy

Cancer Gene Ther.

Antisense oligo-nucleotides: a new tool in neuroscience

Clin. Exp. Pharma-col. Physiol.

Application of antisense DNA method for the study of molecular bases of brain function and behavior

Behav. Genet.

Stability, clearance, and disposition of intraventricularly administered oligodeoxynucleotides: implications for therapeutic application within the central nervous system

Proc. Natl. Acad. Sci. U.S.A.

Antisense oligonucleotides: a possible approach for chemotherapy of AIDS

Chronic intrathecal infusion of phosphorothioate or phosphodiester antisense oligonucelotides against cytokine responsive gene-2/IP-10 in experimental allergic encephalomyelitis of Lewis rat

J. Pharmacol. Exp. Ther.

Complete inactivation of target mRNA by biotinylated antisense oligodeoxynucleotide-avidin conjugates

Bioconj. Chem.

Pharmacokinetics and organ clearance of a 3′-biotinylated, internally [32P]-labeled phosphodiester oligodeoxynucleotide coupled to a neutral avidin/monoclonal antibody conjugate

Drug Metab. Dispos.

Determination of postglomeru-lar perme-selectivity to neutral dextrans in the dog

Am. J. Physiol.

Desialation of transferrin by rat liver endothelium

J. Clin. Invest.

Comparison of cellular binding and uptake of antisense phosphodiester, phosphorothioate, and mixed phosphorothio-ate and methylphosphonate oligonucleotides

Antisense Res. Devel.

Chimeric oligodeoxy-nucleotide analogues: enhanced cell uptake of structures which direct ribonuclease H with high specificity

Anti-Cancer Drug Design

Use of partially phosphorothioated ‘antisense’ oligodeoxynucleotides for sequence-dependent modulation of hematopoiesis in culture

Antisense Res. Devel.

Mixed-backbone oligonucleotides as second generation antisense oligonucelotides: in vitro and in vivo studies

Proc. Natl. Acad. Sci. U.S.A.

Rapid plasma clearance and metabolism in vivo of a phosphorothio-ate oligodeoxynucleotide with a single, internal phosphodi-ester bond

Drug Metab. Dispos.

Complete protection of antisense oligonucleotides against serum nuclease degradation by an avidin-biotin system

Bioconj. Chem.

In vitro toxicology and pharmacokinetics of antisense oligonucleotides

Anti-Cancer Drug Design

In vivo treatment of human leukemia in a scid mouse model with c-myb antisense oligodeoxynucleotides

Proc. Natl. Acad. Sci. U.S.A.

Review of in vivo pharmaco-kinetics and toxicology of phosphorothioate oligonucleotides

J. Clin. Lab. Anal.

Conference Reports
Drug Delivery of Antisense Molecules to the Brain for Treatment of Alzheimer’s Disease and Cerebral AIDS