Tumor targeting of baculovirus displaying a lymphatic homing peptide.

Abstract

BACKGROUND:

Tumor-associated cells and vasculature express attractive molecular markers for site-specific vector targeting. To attain tumor-selective tropism, we recently developed a baculovirus vector displaying the lymphatic homing peptide LyP-1, originally identified by ex vivo/in vivo screening of phage display libraries, on the viral envelope by fusion to the transmembrane anchor of vesicular stomatitis virus G-protein.

METHODS:

In the present study, we explored the specificity and kinetics of viral binding and internalization as well as in vivo tumor homing of the LyP-1 displaying virus to elucidate the applicability of baculovirus for targeted therapies.

RESULTS:

We demonstrated that the LyP-1 peptide contributes to saturable binding of baculovirus in human MDA-MB-435 and HepG2 carcinoma cells and escalates the kinetics of viral internalization leading to earlier nuclear accumulation and enhanced transgene expression. The LyP-1 displaying virus also showed stronger competitiveness against transduction with wild-type baculovirus, suggesting involvement of a specific receptor in cellular attachment and entry. Following intravenous injections, the modified virus accumulated within the human MDA-MB-435 and MDA-MB-231 carcinoma xenografts in mice with higher specificity and efficiency than the control virus. Targeting of the modified virus was more specific in the MDA-MB-435 than in the MDA-MB-231 xenografts as demonstrated by higher tumor accumulation and lower distribution in nontarget organs. No apparent cytotoxicity was associated with the surface modification.

CONCLUSIONS:

This first demonstration of in vivo tumor targeting of a systemically administered, tropism-modified baculoviral vector highlights the potential of baculovirus-mediated targeted therapies.

• Authors: Anna R Mäkelä, Juulia Enbäck, Johanna P Laakkonen, Maija Vihinen-Ranta, Pirjo Laakkonen, Christian Oker-Blom
• Journal: The journal of gene medicine (J Gene Med) Vol. 10 Issue 9 Pg. 1019-31 (Sep 2008) ISSN: 1521-2254 [Electronic] England
• PMID: 18655234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2008 John Wiley & Sons, Ltd.

Chemical References

• G protein, vesicular stomatitis virus
• LyP-1 peptide
• Membrane Glycoproteins
• Peptides, Cyclic
• Viral Envelope Proteins

Topics

• Animals
• Baculoviridae (genetics)
• Binding Sites
• Cell Line, Tumor
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors
• Humans
• Lymphatic Vessels (metabolism)
• Membrane Glycoproteins (genetics)
• Mice
• Mice, Nude
• Neoplasms (genetics, therapy)
• Peptides, Cyclic (genetics, metabolism)
• Transduction, Genetic
• Transgenes
• Viral Envelope Proteins (genetics)