title: Intracranial microcapsule drug delivery device for the treatment of an experimental gliosarcoma model.
abstract: Controlled-release drug delivery systems are capable of treating debilitating diseases, including cancer. Brain cancer, in particular glioblastoma multiforme (GBM), is an extremely invasive cancer with a dismal prognosis. The use of drugs capable of crossing the blood-brain barrier has shown modest prolongation in patient survival, but not without unsatisfactory systemic, dose-limiting toxicity. Among the reasons for this improvement include a better understanding of the challenges of delivery of effective agents directly to the brain tumor site. The combination of carmustine delivered by biodegradable polyanhydride wafers (Gliadel(®)), with the systemic alkylating agent, temozolomide, allows much higher effective doses of the drug while minimizing the systemic toxicity. We have previously shown that locally delivering these two drugs leads to further improvement in survival in experimental models. We postulated that microcapsule devices capable of releasing temozolomide would increase the therapeutic capability of this approach. A biocompatible drug delivery microcapsule device for the intracranial delivery of temozolomide is described. Drug release profiles from these microcapsules can be modulated based on the physical chemistry of the drug and the dimensions of the release orifices in these devices. The drug released from the microcapsules in these experiments was the clinically utilized chemotherapeutic agent, temozolomide. In vitro studies were performed in order to test the function, reliability, and drug release kinetics of the devices. The efficacy of the temozolomide-filled microcapsules was tested in an intracranial experimental rodent gliosarcoma model. Immunohistochemical analysis of tissue for evidence of DNA strand breaks via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed. The experimental release curves showed mass flow rates of 36 μg/h for single-orifice devices and an 88 μg/h mass flow rate for multiple-orifice devices loaded with temozolomide. In vivo efficacy results showed that localized intracranial delivery of temozolomide from microcapsule devices was capable of prolonging animal survival and may offer a novel form of treatment for brain tumors.
authors.affiliation: Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Scott
authors.forename: Betty M
authors.initials: BM
authors.lastname: Tyler
authors.forename: Byron C
authors.initials: BC
authors.lastname: Masi
authors.forename: Urvashi M
authors.initials: UM
authors.lastname: Upadhyay
authors.forename: Yoda R
authors.initials: YR
authors.lastname: Patta
authors.forename: Rachel
authors.initials: R
authors.lastname: Grossman
authors.forename: Luca
authors.initials: L
authors.lastname: Basaldella
authors.forename: Robert S
authors.initials: RS
authors.lastname: Langer
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cima
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D002214:Capsules / Q000008:administration & dosage*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D018316:Gliosarcoma / Q000473:pathology / Q000628:therapy*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D051381:Rats; D011916:Rats, Inbred F344; D000077204:Temozolomide
chemical_list: D002214:Capsules; D003606:Dacarbazine; D000077204:Temozolomide