The purpose of this study is to perform several major preclinical experiments toward use of MEMS devices for cancer therapy. We successfully fabricated during the previous grant period two types of MEMS devices, a solid-state silicon microchip (active device) and a resorbable polymeric microchip (passive device) in which a number of drugs or other chemicals can be stored. We have further shown that both the materials of construction and operation of the device meet the major criteria of being biocompatible. We have also shown that both devices can release single or multiple doses of a chemical substance in vitro and in vivo. Finally, we have demonstrated that a chemotherapeutic agent delivered from each type of device affects growth of a 9L glioma in an experimental rat flank model. Our specific goals are paraphrased as follows: Design for failsafe operation and accuracy of devices. This will ensure complete release of the drug payload within the necessary time frame and provide means to validate that the payload has indeed been released. Demonstrate appropriate pharmacokinetics from implanted microchip devices. We will characterize the drug transport issues both inside and outside the device, including drug transport through the thin fibrous capsule that forms on these devices upon long term implantation. A recent published report shows that the effect of drug transport through the fibrous capsule is not significant. Our proposed research will build a sound scientific basis for the limits of transport through fibrotic tissue surrounding drug delivery devices and we will study the effects of potential additives for their ability to modulate the transport through the capsule. Develop a minimally invasive drug delivery device. We will develop a passive polymeric device capable of implantation through syringe injection. This is expected to provide the largest impact for treatment of brain tumors that are unresectable or otherwise inaccessible conventional therapy. Optimize combination BCNU/IL-2 chemotherapy regimen for 9L glioma model. Demonstrate the ability of both the active and passive MEMS devices to deliver multiple compounds in a specific timed manner. This specifically requires that we: 1) Design and fabricate active and passive MEMS devices to locally release BCNU and IL-2 at specified times. 2) Evaluate these combination devices in an in vivo model to determine bioavailability, interactivity and efficacy of multiple compounds released from these devices. ? ? ?
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