Long-circulating liposome-encapsulated ganciclovir enhances the efficacy of HSV-TK suicide gene therapy.
To enhance the efficacy of ganciclovir/herpes simplex virus thymidine kinase (GCV/HSV-TK) suicide gene therapy for nasopharyngeal cancer KB, we developed long-circulating liposome-encapsulated GCV, and evaluated cytotoxicity in vitro and in vivo. PEGylated liposome-encapsulated GCV (PEG-GCV-lipo) was prepared by the freeze-thawing method. In vitro experiments demonstrated that GCV from liposomes was gradually released over a period of 3 days. The in vitro cytotoxicity of PEG-GCV-lipo was similar to that of GCV solution in human cervical carcinoma HeLa cells expressing HSV-TK. Pharmacokinetics studies in mice showed that, compared with GCV solution, intravenous and intraperitoneal injection of PEG-GCV-lipo (10 mg/kg) led to long circulation in plasma; the area under the curve was 36-fold or 32-fold higher than that of GCV solution, respectively. In GCV/HSV-TK suicide gene therapy, the HSV-TK gene complexed with nanoparticle vector was directly injected into KB xenografts, and PEG-GCV-lipo or GCV solution was injected intravenously in mice once a day (25 mg/kg/day every 2nd day, 4 times). PEG-GCV-lipo was significantly 3-fold more effective than GCV solution in inhibiting tumor growth and produced durable complete tumor remissions on day 11 after injection. These findings demonstrate that long-circulating liposome-encapsulated GCV is a new approach to drug carriers to enhance the efficacy of suicide gene therapy.
Kajiwara
Eiichi
E
Institute of Medicinal Chemistry, Hoshi University, Ebara, Shinagawa-ku, Tokyo, Japan.
Kawano
Kumi
K
Hattori
Yoshiyuki
Y
Fukushima
Masayoshi
M
Hayashi
Kyoko
K
Maitani
Yoshie
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D015774:Ganciclovir / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D008081:Liposomes; D011092:Polyethylene Glycols; D013937:Thymidine Kinase; D015774:Ganciclovir