Avidin fusion protein-expressing lentiviral vector for targeted drug delivery.
One of the main objectives of cancer therapy is to enhance the effectiveness of the drug by concentrating it at the target site and to minimize the undesired side effects to nontarget cells. We have previously constructed a fusion protein, Lodavin, consisting of avidin and the endocytotic part of the low-density lipoprotein receptor, and demonstrated its applicability to transient drug targeting in vivo. In this study we produced a lentiviral vector expressing this fusion protein and evaluated its safety and efficacy. The results showed that lentivirus-mediated gene transfer led to long-term avidin fusion protein expression on glioma cells and that the receptor was able to bind biotinylated compounds. Repeated administration was proven feasible and the optimal time frame(s) for administration of biotinylated therapeutic and/or imaging compounds was elucidated. Intravenous or intracranial injection of the virus into BDIX rats led to the production of antibodies against transgene (avidin), but repeated administration of the vector was unable to boost this effect. Neutralizing antibodies against the lentivirus were also detected. Furthermore, we showed that the anti-avidin antibodies did not significantly affect the ligand-binding capacity of the avidin fusion protein. The therapeutic efficacy of avidin fusion protein in tumor treatment was tested in vitro with biotinylated and nonbiotinylated nanoparticles loaded with paclitaxel. In vivo applicability of lentivirus was studied in the BDIX rat glioma model, in which high receptor expression was detected in the tumor area. The lentivirus-mediated delivery of the avidin fusion protein thus represents a potential approach for the repeated targeting of cytotoxic compounds to cancer cells.
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, FIN-70210 Kuopio, Finland.
Hanna P
HP
Lesch
Jere T
JT
Pikkarainen
Minna U
MU
Kaikkonen
Miia
M
Taavitsainen
Haritha
H
Samaranayake
Pauliina
P
Lehtolainen-Dalkilic
Taina
T
Vuorio
Ann-Marie
AM
Määttä
Thomas
T
Wirth
Kari J
KJ
Airenne
Seppo
S
Ylä-Herttuala
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D001360:Avidin / Q000235:genetics* / Q000378:metabolism*; D001710:Biotin / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D016086:Lentivirus / Q000187:drug effects / Q000235:genetics*; D009500:Neutralization Tests; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D044967:Serum; D014161:Transduction, Genetic; D014771:Virion / Q000187:drug effects / Q000235:genetics
D000906:Antibodies; D011993:Recombinant Fusion Proteins; D001360:Avidin; D001710:Biotin