Enhanced baculovirus-mediated transduction of human cancer cells by tumor-homing peptides.
Tumor cells and vasculature offer specific targets for the selective delivery of therapeutic genes. To achieve tumor-specific gene transfer, baculovirus tropism was manipulated by viral envelope modification using baculovirus display technology. LyP-1, F3, and CGKRK tumor-homing peptides, originally identified by in vivo screening of phage display libraries, were fused to the transmembrane anchor of vesicular stomatitis virus G protein and displayed on the baculoviral surface. The fusion proteins were successfully incorporated into budded virions, which showed two- to fivefold-improved binding to human breast carcinoma (MDA-MB-435) and hepatocarcinoma (HepG2) cells. The LyP-1 peptide inhibited viral binding to MDA-MB-435 cells with a greater magnitude and specificity than the CGKRK and F3 peptides. Maximal 7- and 24-fold increases in transduction, determined by transgene expression level, were achieved for the MDA-MB-435 and HepG2 cells, respectively. The internalization of each virus was inhibited by ammonium chloride treatment, suggesting the use of a similar endocytic entry route. The LyP-1 and F3 peptides showed an apparent inhibitory effect in transduction of HepG2 cells with the corresponding display viruses. Together, these results imply that the efficiency of baculovirus-mediated gene delivery can be significantly enhanced in vitro when tumor-targeting ligands are used and therefore highlight the potential of baculovirus vectors in cancer gene therapy.
Mäkelä
Anna R
AR
NanoScience Center, Department of Biological and Environmental Science, P.O. Box 35, FIN-40014 University of Jyväskylä, Finland.
Matilainen
Heli
H
White
Daniel J
DJ
Ruoslahti
Erkki
E
Oker-Blom
Christian
C
D016367:Baculoviridae / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy; D036022:Capsid Proteins / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000494:pharmacology; D019151:Peptide Library; D010455:Peptides / Q000235:genetics / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D014161:Transduction, Genetic; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics
D036022:Capsid Proteins; D006023:Glycoproteins; D009363:Neoplasm Proteins; D019151:Peptide Library; D010455:Peptides