Gene transfer using liposome-complexed adenovirus seems to overcome limitations due to coxsackievirus and adenovirus receptor-deficiency of cancer cells, both in vitro and in vivo.
Use of adenoviruses as vehicle for gene therapy requires that target cells express appropriate receptors such as coxsakievirus and adenovirus receptor (CAR). We show here that CAR-deficiency in cancer cells, that limits adenoviral gene delivery, can be overcome by using adenovirus complexed with the liposome, Ad-PEGPE [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly-ethylene glycol)-2000]. We first confirmed that CT-26 mouse colon cancer cells are deficient in CAR by RT-PCR, and then showed that CT-26 cells infected with Ad-GFP/PEGPE exhibited highly enhanced expression of green fluorescent protein (GFP), compared with those infected with Ad-GFP. GFP expression depends on the dose of liposome and adenovirus. Luciferase expression in livers treated with Ad-luc/PEGPE was about 1,000-fold less than those infected with Ad-luc. In a liver metastasis mouse tumor model developed by intrasplenic injection of CT-26 cells, luciferase expression following i.v. injection of Ad-luc/PEGPE was significantly higher in tumors than in adjacent non-neoplastic liver. Following systemic administration of Ad-GFP/PEGPE, GFP expression increased in tumors more than in adjacent liver while the reverse was true following administration of Ad-GFP. In the latter case, GFP expression was higher in liver than in tumors. This study demonstrates that systemic delivery of PEGPE-adenovirus complex is an effective tool of adenoviral delivery as it overcomes limitation due to CAR deficiency of target cells while reducing hepatic uptake and enhancing adenoviral gene expression in tumors.
Han
Sang-Young
SY
Department of Internal Medicine, Dong-A University College of Medicine Busan 602-714, Korea.
Lee
Yoon-Jong
YJ
Jung
Haeng-Im
HI
Lee
Sung-Wook
SW
Lim
Sue-Jeong
SJ
Hong
Seung-Hee
SH
Jeong
Jin-Sook
JS
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000090702:Constitutive Androstane Receptor; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics; D011991:Receptors, Virus / Q000172:deficiency / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D014407:Tumor Cells, Cultured
C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000090702:Constitutive Androstane Receptor; D008081:Liposomes; D010714:Phosphatidylethanolamines; D018160:Receptors, Cytoplasmic and Nuclear; D011991:Receptors, Virus; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols
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