Delivery of antisense oligonucleotides to leukemia cells by RNA bacteriophage capsids

Min Wu, Trevor Sherwin, William L. Brown, Peter G. Stockley

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Background: Acute myelogenous leukemia (AML) is the most common type of acute leukemia in adults. Because conventional treatments are associated with substantial side effects, novel therapeutic strategies are required. Antisense oligodeoxynucleotides (ODNs) have shown promise as the basis of emerging therapies for fighting cancer, although in vivo application is hampered by high sensitivity to cellular nuclease degradation. Encapsidation of ODNs in a drug-delivery capsule would reduce such degradation, thereby increasing the potency of therapy. MS2 bacteriophage capsid proteins may be used as novel virus-like particles (VLPs) to deliver ODNs. Here we report an analysis of the uptake mechanism of this VLP system and preliminary examples of its use to deliver a number of ODNs, including some targeting p120 messenger RNAs, a biomarker overexpressed in myelogenous leukemia cells. Methods: The ODNs were synthesized as covalent extensions to the translational repressor/assembly initiation signal (TR), a 19 nt stem-loop, of the RNA phage MS2. The VLPs were constructed by soaking ODN-TR directly into recombinant RNA-free capsid shells. Targeting of the encapsidated ODNs into cells was achieved by a receptor-mediated endocytosis pathway identified by immunofluorescence microscopy or by transmission electron microscopy with gold-labeled antibodies. Results: After covalent decoration with transferrin on their surface, the VLPs containing ODNs demonstrated increased effectiveness in killing target leukemia cells expressing transferrin receptors, suggesting that this system is worthy of more extensive analysis. Conclusions: The findings suggest that RNA phage VLPs may be useful as a new nanomaterial for targeted delivery of antisense ODNs, or other macromolecular drug candidates.

Original languageEnglish (US)
Pages (from-to)67-76
Number of pages10
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume1
Issue number1
DOIs
StatePublished - Mar 2005

Bibliographical note

Funding Information:
Supported by grants from the United Kingdom Biotechnology and Biological Sciences Research Council. We thank Chris Adams, PhD, and James Murray, PhD, for their expert help and guidance in the production of chimeric ODNs, and Keith Gull, PhD, for his suggestions about the microscopy studies and access to equipment.

Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.

Keywords

  • Antisense therapy
  • Colocalization
  • Drug delivery
  • Endocytosis
  • Internalization
  • Virus-like particles

Fingerprint

Dive into the research topics of 'Delivery of antisense oligonucleotides to leukemia cells by RNA bacteriophage capsids'. Together they form a unique fingerprint.

Cite this