In Vivo Efficacy of MEMs Systems-Driven Intracranial Delivery of Temozolomide in the Treatment of High Grade Glioma

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Glioblastoma multiforme (GBM) remains the most common and aggressive form of primary brain tumors. Despite improvements in neurosurgical technique, neuroimaging, and radiation, the prognosis associated with these tumors remains grim. There is an important role for improvements in chemotherapy, particularly to prevent recurrence. Given that a majority of malignant gliomas recur within two centimeters of the original lesion, local delivery of chemotherapies may prove effective in reducing the risk of tumor recurrence. Delivery of chemotherapy to the GBM tumor bed has the demonstrable ability to diffuse throughout surrounding tissue. This ability is particularly attractive for infiltrative tumors, such as GBM, where tumor cells penetrate normal neural tissue.

Data from animal experiments demonstrate that a higher concentration of chemotherapy can be achieved in the brain with local delivery compared to IV injection. Until recently, efforts in local drug delivery focused on a constant rate of drug release though this may not be the ideal method of drug delivery for all tumors. The use of microchip-driven drug delivery provides the potential for on-demand and variable chemotherapy delivery to the tumor bed, that is, the most likely site of tumor recurrence. Such a system, adapted to contain several drug reservoirs, could facilitate the release of different chemotherapeutic agents over time; in turn, multi-drug treatment may mitigate chemotherapeutic-resistance seen in vivo work from several groups has supported the notion that variable drug release has improved effectiveness against glioma cell lines.

A microelectromechanical systems (MEMS) reservoir-based device has been designed by an injection-molding technique that allows for the delivery of chemotherapy on-demand. One can envision MEMS as a uniquely powerful platform in the future for delivering potent therapeutic agents whose temporal administration is vital to their efficacy, and whose effects are naturally amplified by the human body. Demonstrating that such devices have improved efficacy against a rodent glioma model would represent a departure from prior work on drug-delivery, as those efforts focused largely on achieving constant release profiles. Tunable, on-demand, pulsatile drug release from locally-implantable devices will hopefully show promise in the treatment of high-grade gliomas and may lead to the first advance in chemotherapeutic delivery for brain tumors in over one decade.