Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model

Abstract

Primary malignant brain tumors (BT) are the most common and aggressive malignant brain tumor. Treatment of BTs is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved success in treating BT by circumventing the blood brain barrier and achieving high concentrations of therapeutic within the tumor. The capabilities of localized delivery can be enhanced by utilizing mircoelectromechanical systems (MEMS) technology to deliver drugs with precise temporal control over release kinetics. An intracranial MEMS based device was developed to deliver the clinically utilized chemotherapeutic temozolomide (TMZ) in a rodent glioma model. The device is a liquid crystalline polymer reservoir, capped by a MEMS microchip. The microchip contains three nitride membranes that can be independently ruptured at any point during or after implantation. The kinetics of TMZ release were validated and quantified in vitro. The safety of implanting the device intracranially was confirmed with preliminary in vivo studies. The impact of TMZ release kinetics was investigated by conducting in vivo studies that compared the effects of drug release rates and timing on animal survival. TMZ delivered from the device was effective at prolonging animal survival in a 9L rodent glioma model. Immunohistological analysis confirmed that TMZ was released in a viable, cytotoxic form. The results from the in vivo efficacy studies indicate that early, rapid delivery of TMZ from the device results in the most prolonged animal survival. The ability to actively control the rate and timing of drug(s) release holds tremendous potential for the treatment of BTs and related diseases.

Controlled Drug Delivery Using Microdevices

“…They demonstrated pulsatile (or on-demand) drug release by using fluorescently labeled protein as a model drug. In addition, Masi et al developed MEMS-based microreservoir for temozolomide (TMZ) delivery in a 9L rat gliosarcoma model [52]. They confirmed the safety of implanting the device intracranially with preliminary in vivo studies.…”

Subarachnoid pharmacodialysis for central nervous system disorders

“…[19][20][21] and intracerebral infusion of neurotrophic factors promotes neurogenesis after stroke [22], whereas clinically, localized postoperative chemotherapy is beneficial for glioma [23]. These and other studies of intracranial drug delivery have used pumps for convection-enhanced delivery (CED) via narrow-lumen intraparenchymal cannulae [21,[23][24][25], as well as drug-releasing polymers or micro-electro-mechanical-system (MEMS) microchips [26][27][28]. Owing to the reluctance to chronically cannulate the cranium, it wasn't until the development of improved antibiosis and sterility, new biologically inert materials and micro-engineering that intracranial drug therapy has been considered.…”

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies

“…Two types of microchips, microelectromechanical systems and the passive chip, have shown encouraging preclinical results in rodent flank models of glioma in the delivery of temozolomide and carmustine, two standard alkylating compounds used to treat patients with brain tumors. Both types of microchips have been miniaturized for proof of principle experiments in the rodent brain and have shown statistical increases in survival in orthotopic models of brain cancer [52]. A future application of microchip devices for intracranial chemotherapy holds tremendous potential for the treatment of malignant gliomas.…”