New drug delivery system for water-soluble drugs using silicone and its usefulness for local treatment: application of GCV-silicone to GCV/HSV-tk gene therapy for brain tumor.
Controlled release of a water-soluble low-molecular-weight drug from silicone and its usefulness as a local therapeutic drug were studied. For application to ganciclovir/helpes simplex virus thymidine kinase (GCV/HSV-tk) suicide gene therapy for brain tumor, two kinds of GCV-containing silicone formulations were prepared for evaluation. In vitro, GCV release from matrix-type formulation consisting of a single matrix was characterized by Fickian diffusion, while covered-rod-type formulation, in which the side surface of the outer layer was covered with 100% silicone, exhibited a near-zero-order release pattern. In an in vivo study using a rat 9L glioblastoma model, administration of GCV-silicone formulation into brain tumor yielded sustained intracerebral GCV concentration for 4 days after administration, with excellent antitumor effect equal to or better than that of daily intraperitoneal administration of aqueous solution of GCV, at a dose less than 1/100 of the total dose of solution for intraperitoneal administration. Furthermore, GCV was undetectable in blood, suggesting that decrease in systemic adverse reactions can be expected with intracerebral administration of GCV-silicone formulation.
Maeda
Miho
M
Sumitomo Pharmaceuticals Research Division, 3-45, Kurakakiuchi 1-chome, Osaka 567-0878, Ibaraki, Japan.
Moriuchi
Shusuke
S
Sano
Akihiko
A
Yoshimine
Toshiki
T
D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D001672:Biocompatible Materials; D001932:Brain Neoplasms / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D015774:Ganciclovir / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D018316:Gliosarcoma / Q000188:drug therapy*; D006561:Herpes Simplex / Q000201:enzymology*; D006863:Hydrogen-Ion Concentration; D015918:Infusion Pumps, Implantable; D009368:Neoplasm Transplantation; D051381:Rats; D012828:Silicones / Q000737:chemistry*; D012995:Solubility; D013937:Thymidine Kinase / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D012828:Silicones; D013937:Thymidine Kinase; D015774:Ganciclovir