title: Convection-enhanced delivery of a synthetic retinoid Am80, loaded into polymeric micelles, prolongs the survival of rats bearing intracranial glioblastoma xenografts.
abstract: Prognosis for the patients with glioblastoma, the most common malignant brain tumor, remains dismal. A major barrier to progress in treatment of glioblastoma is the relative inaccessibility of tumors to chemotherapeutic agents. Convection-enhanced delivery (CED) is a direct intracranial drug infusion technique to deliver chemotherapeutic agents to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. CED can provide wider distribution of infused agents compared to simple diffusion. We have reported that CED of a polymeric micelle carrier system could yield a clinically relevant distribution of encapsulated agents in the rat brain. Our aim was to evaluate the efficacy of CED of polymeric micellar Am80, a synthetic agonist with high affinity to nuclear retinoic acid receptor, in a rat model of glioblastoma xenografts. We also used systemic administration of temozolomide, a DNA-alkylating agent, which has been established as the standard of care for newly diagnosed malignant glioma. U87MG human glioma cells were injected into the cerebral hemisphere of nude rats. Rats bearing U87MG xenografts were treated with CED of micellar Am80 (2.4 mg/m(2)) on day 7 after tumor implantation. Temozolomide (200 mg/m(2)/day) was intraperitoneally administered daily for 5 days, starting on day 7 after tumor implantation. CED of micellar Am80 provided significantly longer survival than the control. The combination of CED of micellar Am80 and systemic administration of temozolomide provided significantly longer survival than single treatment. In conclusion, temozolomide combined with CED of micellar Am80 may be a promising method for the treatment of malignant gliomas.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Yokosawa
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sonoda
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Sugiyama
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Masamichi
authors.initials: M
authors.lastname: Nishihara
authors.forename: Taku
authors.initials: T
authors.lastname: Satoh
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000008:administration & dosage* / Q000737:chemistry; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D018481:Convection; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008136:Longevity / Q000187:drug effects; D008297:Male; D008823:Micelles; D011108:Polymers / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000008:administration & dosage* / Q000737:chemistry; D000077204:Temozolomide; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001565:Benzoates; D008823:Micelles; D011108:Polymers; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D003606:Dacarbazine; D000077204:Temozolomide