Identification and characterization of a novel peptide ligand of Tie2 for targeting gene therapy.
Tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie2) has been considered as a rational target for gene therapy in solid tumors. In order to identify a novel peptide ligand of Tie2 for targeted gene therapy, we screened a phage display peptide library and identified a candidate peptide ligand NSLSNASEFRAPY (designated GA5). Binding assays and Scatchard analysis revealed that GA5 could specifically bind to Tie2 with a dissociation constant of 2.1x10(-8)M. In addition, we showed that GA5 was internalized into tumor cells highly expressing Tie2. In the biodistribution assay, (125)I-GA5 was mainly accumulated in SPC-A1 xenograft tumors that express Tie2. In gene delivery studies, GA5-conjugated polyethylenimine vector could achieve greater transgene transduction than non-targeted vectors both in vitro and in vivo. Tumor growth inhibition was observed in SPC-A1 xenograft-bearing mice that received eight intratumoral injections of GA5-polyethylenimine/p53 complexes in 3 weeks. The difference in tumor volume between the experiment and control groups was significant (P<0.05). Our results showed that GA5 is a potentially efficient targeting element for cancer gene or molecular therapy.
Wu
Xianghua
X
Department of Medical Oncology, Cancer Hospital of Fudan University, Shanghai 200032, China.
Li
Zonghai
Z
Yao
Ming
M
Wang
Huamao
H
Qu
Sumin
S
Chen
Xianlian
X
Li
Jinjun
J
Sun
Ye
Y
Xu
Yuhong
Y
Gu
Jianren
J
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000235:genetics* / Q000627:therapeutic use*; D042787:Receptor, TIE-2 / Q000235:genetics* / Q000378:metabolism*; D014018:Tissue Distribution; D014213:Tretoquinol; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000627:therapeutic use
D010455:Peptides; D016159:Tumor Suppressor Protein p53; D042787:Receptor, TIE-2; D014213:Tretoquinol