Tumor targeting of baculovirus displaying a lymphatic homing peptide.
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.
Mäkelä
Anna R
AR
NanoScience Center, Department of Biological and Environmental Science, University of Jyväskylä, Finland. anna.makela@bytl.jyu.fi
Enbäck
Juulia
J
Laakkonen
Johanna P
JP
Vihinen-Ranta
Maija
M
Laakkonen
Pirjo
P
Oker-Blom
Christian
C
D000818:Animals; D016367:Baculoviridae / Q000235:genetics*; D001665:Binding Sites; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D042601:Lymphatic Vessels / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D010456:Peptides, Cyclic / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D014759:Viral Envelope Proteins / Q000235:genetics
C028391:G protein, vesicular stomatitis virus; C533969:LyP-1 peptide; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D014759:Viral Envelope Proteins