VP22-mediated and light-activated delivery of an anti-c-raf1 antisense oligonucleotide improves its activity after intratumoral injection in nude mice.
VP22, a protein of the herpes simplex virus tegument, can form complexes with fluorescein-labeled oligonucleotides. These particles, termed "Vectosomes," are efficiently taken up by cells and remain stable in the cell cytoplasm without any particular activity. Interestingly, these Vectosomes can be disrupted by light, which releases the antisense activity. Here we show that anti-c-raf1 Vectosomes are efficiently activated by light in vivo after injection into subcutaneous A549 (non-small-cell lung cancer) tumors implanted in nude mice. Moreover, two injections per week of anti-c-raf1 Vectosomes followed by illumination result in a stronger inhibition of tumor growth than injections of the antisense alone or of the different control Vectosomes. This effect correlates with a strong inhibition of the c-Raf1 protein expression. As a consequence of c-Raf1 loss, apoptosis was also detected in these tumors. Vectosomes thus represent a new powerful tool to improve the delivery of oligonucleotides in vitro and in vivo.
INSERM U578, Lung Cancer Research Group, Albert Bonniot Institute, 38706, Grenoble, France.
David
D
Zavaglia
Nadia
N
Normand
Neil
N
Brewis
Peter
P
O'Hare
Marie Christine
MC
Favrot
Jean-luc
JL
Coll
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D008027:Light; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D010778:Photochemotherapy; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D015678:Viral Structural Proteins / Q000235:genetics*
D016376:Oligonucleotides, Antisense; D015678:Viral Structural Proteins; C073413:herpes simplex virus type 1 protein VP22; D019908:Proto-Oncogene Proteins c-raf