Convection-Enhanced Delivery of a Synthetic Retinoid Am80, Loaded into Polymeric Micelles, Prolongs the Survival of Rats Bearing Intracranial Glioblastoma Xenografts

• DOI: 10.1620/tjem.221.257
• Publication Date: 2010-07-07T06:05:16Z
• Authors: Michiko Yokosawa; Yukihiko Sonoda; Shin-Ichiro Sugiyama; Ryuta Saito; Yoji Yamashita; Masamichi Nishihara; Taku Satoh; Toshihiro Kumabe; Masayuki Yokoyama; Teiji Tominaga
• Keywords: Male; Brain Neoplasms; Cell Survival; Polymers; Longevity; Antineoplastic Agents; Apoptosis; Convection; Benzoates; Rats, Inbred F344; Rats; 3. Good health; Dacarbazine; Rats, Sprague-Dawley; Rats, Nude; 03 medical and health sciences; Drug Delivery Systems; 0302 clinical medicine; Animals; Humans; Glioblastoma; Antineoplastic Agents, Alkylating; Micelles

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.