Local exposure and efficacy of a reservoir-based drug delivery device

Abstract

Prognoses for primary or metastatic brain tumor patients have been poor, despite developments in treatment over the last twenty years. 14,000 people die each year from glioblastoma multiforme (GBM). 200,000 new cases of breast cancer are diagnosed each year, with 15% of those patients experiencing multiple metastases into the brain. The primary cause of mortality is tumor recurrence, often centimeters away from the original lesion site. Current treatments involve systemic radiotherapy or chemotherapy, and improve median survival time by only a few months. Efforts to develop local treatment modules are motivated by the fact that patients experience systemic toxicities during conventional treatment. Implantable Gliadel® BCNU wafers were approved by the FDA, but patients still experienced side effects such as edema, and median survival time was improved only by 2 months. Convection-enhanced delivery (the infusion of chemotherapeutics via catheters) may achieve further distribution on the scale of centimeters, but there is a tendency for preferential flow along paths of least resistance. An implantable, biocompatible microcapsule for localized delivery of chemotherapeutics in the brain was developed in the Cima Lab. In vitro experiments confirmed linear initial rates of release of temozolomide, an alkylating agent, and doxorubicin, a topoisomerase inhibitor, from the microcapsules. In vivo survival studies were conducted to compare the efficacies of these microcapsules against 9L rat gliosarcoma and CRL1666 rat mammary adenocarcinoma tumors. Local delivery of temozolomide via implanted microcapsules was efficacious against both tumor types and comparable to or better than systemic delivery of temozolomide via oral gavage. Local delivery of doxorubicin was not efficacious against either tumor type, and not significantly distinguishable from control groups. Exposure data revealed much higher levels of retained temozolomide across a larger area of brain tissue than doxorubicin after microcapsule delivery. Thus, successful local delivery of chemotherapeutics in the brain depends on the achievement of sufficient exposures over sufficient (cm-length) distances away from the implant. Microcapsules developed for this work could potentially be implanted at different locations in the brain, with each achieving mm-distance exposure. The overlapping exposures would add together to help treat excess tumor cells post-resection and prevent tumor recurrence.